Journal of Neuroscience recent issues

This Week in The Journal

Wed, 18 Nov 2009 10:02:12 PST

Correction for Mathieu Boudes et al., Best1 Is a Gene Regulated by Nerve Injury and Required for Ca2+-Activated Cl- Current Expression in Axotomized Sensory Neurons

Wed, 18 Nov 2009 10:02:12 PST

Can Major Depression Improve the Perception of Visual Motion?

Wallisch, P., Kumbhani, R. D. — Wed, 18 Nov 2009 10:02:12 PST

Timing in the Absence of Supraspinal Input II: Regularly Spaced Stimulation Induces a Lasting Alteration in Spinal Function That Depends on the NMDA Receptor, BDNF Release, and Protein Synthesis

Baumbauer, K. M., Huie, J. R., Hughes, A. J., Grau, J. W. — Wed, 18 Nov 2009 10:02:12 PST

The detection of temporal regularity allows organisms to predict the occurrence of future events. When events occur in an irregular manner, uncertainty is increased, and negative outcomes can ensue (e.g., stress). The present study shows that spinal neurons can discriminate between variable- and fixed-spaced stimulation and that the detection of regularity requires training and engages a form of NMDA receptor-mediated plasticity. The impact of stimulus exposure was assessed using a spinally mediated instrumental response, wherein spinally transected rats are given legshock whenever one hindlimb is extended. Over time, they learn to maintain the leg in a flexed position that minimizes net shock exposure. Prior exposure to 180–900 tailshocks given in a variable (unpredictable) manner inhibited this learning. A learning deficit was not observed when 900 tailshocks were applied using a fixed (predictable) spacing. Fixed-spaced stimulation did not have a divergent effect when fewer (180) shocks were presented, implying that the abstraction of temporal regularity required repeated exposure (training). Moreover, fixed-spaced stimulation both prevented and reversed the learning deficit. The protective effect of fixed-spaced shock lasted 48 h, and was prevented by pretreatment with the NMDA receptor antagonist MK-801. Administration of the protein synthesis inhibitor cycloheximide after training blocked the long-term effect. Inhibiting BDNF function, using TrkB-IgG, also eliminated the beneficial effect of fixed-spaced stimulation. The results suggest that spinal systems can detect regularity and that this type of stimulation promotes adaptive plasticity, which may foster recovery after spinal injury.

Telomere Shortening in Neural Stem Cells Disrupts Neuronal Differentiation and Neuritogenesis

Wed, 18 Nov 2009 10:02:12 PST

Proliferation in the subependymal zone (SEZ) and neurogenesis in the olfactory bulb decline in the forebrain of telomerase-deficient mice. The present work reveals additional effects of telomere shortening on neuronal differentiation, as adult multipotent progenitors with critically short telomeres yield reduced numbers of neurons that, furthermore, exhibit underdeveloped neuritic arbors. Genetic data indicate that the tumor suppressor protein p53 not only mediates the adverse effects of telomere attrition on proliferation and self-renewal but it is also involved in preventing normal neuronal differentiation of adult progenitors with dysfunctional telomeres. Interestingly, progenitor cells with short telomeres obtained from fetal brains do not exhibit any replicative defects but also fail to acquire a fully mature neuritic arbor, demonstrating cell cycle-independent effects of telomeres on neuronal differentiation. The negative effect of p53 on neuritogenesis is mechanistically linked to its cooperation with the Notch pathway in the upregulation of small GTPase RhoA kinases, Rock1 and Rock2, suggesting a potential link between DNA damage and the Notch signaling pathway in the control of neuritogenesis. We also show that telomerase expression is downregulated in the SEZ of aging mice leading to telomere length reductions in neurosphere-forming cells and deficient neurogenesis and neuritogenesis. Our results suggest that age-related deficits could be caused partly by dysfunctional telomeres and demonstrate that p53 is a central modulator of adult neurogenesis, regulating both the production and differentiation of postnatally generated olfactory neurons.

Schwann Cells Inhibit Ectopic Clustering of Axonal Sodium Channels

Voas, M. G., Glenn, T. D., Raphael, A. R., Talbot, W. S. — Wed, 18 Nov 2009 10:02:12 PST

The clustering of voltage-gated sodium channels at the axon initial segment (AIS) and nodes of Ranvier is essential for the initiation and propagation of action potentials in myelinated axons. Sodium channels localize to the AIS through an axon-intrinsic mechanism driven by ankyrin G, while clustering at the nodes requires cues from myelinating glia that interact with axonal neurofascin186 (Sherman et al., 2005; Dzhashiashvili et al., 2007; Yang et al., 2007). Here, we report that in zebrafish mutants lacking Schwann cells in peripheral nerves (erbb2, erbb3, and sox10/colorless), axons form numerous aberrant sodium channel clusters throughout their length. Morpholino knockdown of ankyrin G, but not neurofascin, reduces the number of sodium channel clusters in Schwann cell-deficient mutants, suggesting that these aberrant clusters form by an axon-intrinsic mechanism. We also find that gpr126 mutants, in which Schwann cells are arrested at the promyelinating stage (Monk et al., 2009), are deficient in the clustering of neurofascin at the nodes of Ranvier. When Schwann cell migration in gpr126 mutants is blocked, there is an increase in the number of neurofascin clusters in peripheral axons. Our results suggest that Schwann cells inhibit the ability of ankyrin G to cluster sodium channels at ectopic locations, restricting its activity to the AIS and nodes of Ranvier.

T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity

Wed, 18 Nov 2009 10:02:12 PST

Partial peripheral nerve injury in adult rats results in neuropathic pain-like hypersensitivity, while that in neonatal rats does not, a phenomenon also observed in humans. We therefore compared gene expression profiles in the dorsal horn of adult and neonatal rats in response to the spared nerve injury (SNI) model of peripheral neuropathic pain. The 148 differentially regulated genes in adult, but not young, rat spinal cords indicate a greater microglial and T-cell response in adult than in young animals. T-cells show a large infiltration in the adult dorsal horn but not in the neonate after SNI. T-cell-deficient Rag1-null adult mice develop less neuropathic mechanical allodynia than controls, and central expression of cytokines involved in T-cell signaling exhibits large relative differences between young and adult animals after SNI. One such cytokine, interferon- (IFN), is upregulated in the dorsal horn after nerve injury in the adult but not neonate, and we show that IFN signaling is required for full expression of adult neuropathic hypersensitivity. These data reveal that T-cell infiltration and activation in the dorsal horn of the spinal cord following peripheral nerve injury contribute to the evolution of neuropathic pain-like hypersensitivity. The neuroimmune interaction following peripheral nerve injury has therefore a substantial adaptive immune component, which is absent or suppressed in the young CNS.

Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models

Wed, 18 Nov 2009 10:02:12 PST

To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep–wake phenotypes of orexin (Ox) knock-out (–/–) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizing enzyme)–/– mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC^–/– mice was seen during lightness, whereas that in Ox^–/– mice occurred during darkness; (2) contrary to HDC^–/–, Ox^–/– mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox^–/–, but not HDC^–/– mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox^–/– mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox^–/– mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired W and locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.

Divergent Pathways Mediate Spine Alterations and Cell Death Induced by Amyloid-{beta}, Wild-Type Tau, and R406W Tau

Tackenberg, C., Brandt, R. — Wed, 18 Nov 2009 10:02:12 PST

Alzheimer's disease is characterized by synaptic alterations and neurodegeneration. Histopathological hallmarks represent amyloid plaques composed of amyloid-β (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. To determine whether synaptic changes and neurodegeneration share common pathways, we established an ex vivo model using organotypic hippocampal slice cultures from amyloid precursor protein transgenic mice combined with virus-mediated expression of EGFP-tagged tau constructs. Confocal high-resolution imaging, algorithm-based evaluation of spines, and live imaging were used to determine spine changes and neurodegeneration. We report that Aβ but not tau induces spine loss and shifts spine shape from mushroom to stubby through a mechanism involving NMDA receptor (NMDAR), calcineurin, and GSK-3β activation. In contrast, Aβ alone does not cause neurodegeneration but induces toxicity through phosphorylation of wild-type (wt) tau in an NMDAR-dependent pathway. We show that GSK-3β levels are elevated in APP transgenic cultures and that inhibiting GSK-3β activity or use of phosphorylation-blocking tau mutations prevented Aβ-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by Aβ. While R406W tau shows increased toxicity in the presence of Aβ, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3β only protects against toxicity of wt tau but not of R406W tau induced by Aβ. Tau aggregation does not correlate with toxicity. We propose that Aβ-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDAR activation and suggest that Aβ affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity.

Amyloid Precursor Protein Mediates a Tyrosine Kinase-Dependent Activation Response in Endothelial Cells

Austin, S. A., Sens, M. A., Combs, C. K. — Wed, 18 Nov 2009 10:02:12 PST

Amyloid precursor protein (APP) is a ubiquitously expressed type 1 integral membrane protein. It has the ability to bind numerous extracellular matrix components and propagate signaling responses via its cytoplasmic phospho-tyrosine, ₆₈₂YENPTY₆₈₇, binding motif. We recently demonstrated increased protein levels of APP, phosphorylated APP (Tyr682), and β-amyloid (Aβ) in brain vasculature of atherosclerotic and Alzheimer's disease (AD) tissue colocalizing primarily within the endothelial layer. This study demonstrates similar APP changes in peripheral vasculature from human and mouse apoE^–/– aorta, suggesting that APP-related changes are not restricted to brain vasculature. Therefore, primary mouse aortic endothelial cells and human umbilical vein endothelial cells were used as a model system to examine the function of APP in endothelial cells. APP multimerization with an anti-N-terminal APP antibody, 22C11, to simulate ligand binding stimulated an Src kinase family-dependent increase in protein phospho-tyrosine levels, APP phosphorylation, and Aβ secretion. Furthermore, APP multimerization stimulated increased protein levels of the proinflammatory proteins, cyclooxygenase-2 and vascular cell adhesion molecule-1 also in an Src kinase family-dependent manner. Endothelial APP was also involved in mediating monocytic cell adhesion. Collectively, these data demonstrate that endothelial APP regulates immune cell adhesion and stimulates a tyrosine kinase-dependent response driving acquisition of a reactive endothelial phenotype. These APP-mediated events may serve as therapeutic targets for intervention in progressive vascular changes common to cerebrovascular disease and AD.

Default Mode of Brain Activity Demonstrated by Positron Emission Tomography Imaging in Awake Monkeys: Higher Rest-Related than Working Memory-Related Activity in Medial Cortical Areas

Kojima, T., Onoe, H., Hikosaka, K., Tsutsui, K.-i., Tsukada, H., Watanabe, M. — Wed, 18 Nov 2009 10:02:12 PST

Human neuroimaging studies have demonstrated the presence of a "default system" in the brain, which shows a "default mode of brain activity," i.e., greater activity during the resting state than during an attention-demanding cognitive task. The default system mainly involves the medial prefrontal and medial parietal areas, including the anterior and posterior cingulate cortex. It has been proposed that this default activity is concerned with internal thought processes. Recently, it has been indicated that chimpanzees show high metabolic levels in these medial brain areas during rest. Correlated low-frequency spontaneous activity as measured by functional magnetic resonance imaging was observed between the medial parietal and medial prefrontal areas in the anesthetized monkey. However, there have been few attempts to demonstrate a default system that shows task-induced deactivation in nonhuman primates. We conducted a positron emission tomography study with [¹⁵O]H₂O to demonstrate a default mode of brain activity in the awake monkey sitting on a primate chair. Macaque monkeys showed higher level of regional blood flow in these medial brain areas as well as lateral and orbital prefrontal areas during rest compared with that under a working memory task, suggesting the existence of internal thought processes in the monkey. However, during rest in the monkey, the highest level of blood flow relative to that in other brain regions was observed not in the default system but in the dorsal striatum, suggesting that regions with the highest cerebral blood flow during rest may differ depending on the resting condition and/or species.

Complementary Theta Resonance Filtering by Two Spatially Segregated Mechanisms in CA1 Hippocampal Pyramidal Neurons

Hu, H., Vervaeke, K., Graham, L. J., Storm, J. F. — Wed, 18 Nov 2009 10:02:12 PST

Synaptic input to a neuron may undergo various filtering steps, both locally and during transmission to the soma. Using simultaneous whole-cell recordings from soma and apical dendrites from rat CA1 hippocampal pyramidal cells, and biophysically detailed modeling, we found two complementary resonance (bandpass) filters of subthreshold voltage signals. Both filters favor signals in the theta (3–12 Hz) frequency range, but have opposite location, direction, and voltage dependencies: (1) dendritic H-resonance, caused by h/HCN-channels, filters signals propagating from soma to dendrite when the membrane potential is close to rest; and (2) somatic M-resonance, caused by M/Kv7/KCNQ and persistent Na⁺ (NaP) channels, filters signals propagating from dendrite to soma when the membrane potential approaches spike threshold. Hippocampal pyramidal cells participate in theta network oscillations during behavior, and we suggest that that these dual, polarized theta resonance mechanisms may convey voltage-dependent tuning of theta-mediated neural coding in the entorhinal/hippocampal system during locomotion, spatial navigation, memory, and sleep.

Adult-Born Hippocampal Neurons Are More Numerous, Faster Maturing, and More Involved in Behavior in Rats than in Mice

Wed, 18 Nov 2009 10:02:12 PST

Neurons are born throughout adulthood in the hippocampus and show enhanced plasticity compared with mature neurons. However, there are conflicting reports on whether or not young neurons contribute to performance in behavioral tasks, and there is no clear relationship between the timing of maturation of young neurons and the duration of neurogenesis reduction in studies showing behavioral deficits. We asked whether these discrepancies could reflect differences in the properties of young neurons in mice and rats. We report that young neurons in adult rats show a mature neuronal marker profile and activity-induced immediate early gene expression 1–2 weeks earlier than those in mice. They are also twice as likely to escape cell death, and are 10 times more likely to be recruited into learning circuits. This comparison holds true in two different strains of mice, both of which show high rates of neurogenesis relative to other background strains. Differences in adult neurogenesis are not limited to the hippocampus, as the density of new neocortical neurons was 5 times greater in rats than in mice. Finally, in a test of function, we find that the contribution of young neurons to fear memory is much greater in rats than in mice. These results reveal substantial differences in new neuron plasticity and function between these two commonly studied rodent species.

Investigating the Functional Heterogeneity of the Default Mode Network Using Coordinate-Based Meta-Analytic Modeling

Laird, A. R., Eickhoff, S. B., Li, K., Robin, D. A., Glahn, D. C., Fox, P. T. — Wed, 18 Nov 2009 10:02:12 PST

The default mode network (DMN) comprises a set of regions that exhibit ongoing, intrinsic activity in the resting state and task-related decreases in activity across a range of paradigms. However, DMN regions have also been reported as task-related increases, either independently or coactivated with other regions in the network. Cognitive subtractions and the use of low-level baseline conditions have generally masked the functional nature of these regions. Using a combination of activation likelihood estimation, which assesses statistically significant convergence of neuroimaging results, and tools distributed with the BrainMap database, we identified core regions in the DMN and examined their functional heterogeneity. Meta-analytic coactivation maps of task-related increases were independently generated for each region, which included both within-DMN and non-DMN connections. Their functional properties were assessed using behavioral domain metadata in BrainMap. These results were integrated to determine a DMN connectivity model that represents the patterns of interactions observed in task-related increases in activity across diverse tasks. Subnetwork components of this model were identified, and behavioral domain analysis of these cliques yielded discrete functional properties, demonstrating that components of the DMN are differentially specialized. Affective and perceptual cliques of the DMN were identified, as well as the cliques associated with a reduced preference for motor processing. In summary, we used advanced coordinate-based meta-analysis techniques to explicate behavior and connectivity in the default mode network; future work will involve applying this analysis strategy to other modes of brain function, such as executive function or sensorimotor systems.

Dissociating Response Conflict and Error Likelihood in Anterior Cingulate Cortex

Yeung, N., Nieuwenhuis, S. — Wed, 18 Nov 2009 10:02:12 PST

Neuroimaging studies consistently report activity in anterior cingulate cortex (ACC) in conditions of high cognitive demand, leading to the view that ACC plays a crucial role in the control of cognitive processes. According to one prominent theory, the sensitivity of ACC to task difficulty reflects its role in monitoring for the occurrence of competition, or "conflict," between responses to signal the need for increased cognitive control. However, a contrasting theory proposes that ACC is the recipient rather than source of monitoring signals, and that ACC activity observed in relation to task demand reflects the role of this region in learning about the likelihood of errors. Response conflict and error likelihood are typically confounded, making the theories difficult to distinguish empirically. The present research therefore used detailed computational simulations to derive contrasting predictions regarding ACC activity and error rate as a function of response speed. The simulations demonstrated a clear dissociation between conflict and error likelihood: fast response trials are associated with low conflict but high error likelihood, whereas slow response trials show the opposite pattern. Using the N2 component as an index of ACC activity, an EEG study demonstrated that when conflict and error likelihood are dissociated in this way, ACC activity tracks conflict and is negatively correlated with error likelihood. These findings support the conflict-monitoring theory and suggest that, in speeded decision tasks, ACC activity reflects current task demands rather than the retrospective coding of past performance.

Caudate Nucleus Is Critically Involved in Trace Eyeblink Conditioning

Flores, L. C., Disterhoft, J. F. — Wed, 18 Nov 2009 10:02:12 PST

The basal ganglia are a collection of brain regions involved with motor planning and initiation. The major site of cortical and thalamic input into the basal ganglia network is the striatum, which includes a differentiated caudate nucleus (CN) and the putamen in rabbits. Trace eyeblink conditioning (EBC) is a forebrain-dependent associative learning task in which a stimulus-free time interval separates the presentation of a behaviorally neutral conditioned stimulus (CS) and a behaviorally salient unconditioned stimulus. We investigated whether the CN is essential for acquisition of trace EBC and whether learning-related changes in neuronal activity occur in the caudate nucleus during trace EBC. Bilateral lesions of the CN in rabbits prevent acquisition of trace EBC. In separate cohorts of rabbits, single-unit recordings showed that medium spiny neurons from regions shown to be critical by lesions display strong responses to the CS, especially in the initial days of training before acquisition. Cholinergic interneurons, or tonically active neurons, become responsive to the CS and show dramatic firing rate changes during the trace interval after learning criterion has been met. These data demonstrate that the CN is required for and involved in trace EBC.

Disruption of the Head Direction Cell Signal after Occlusion of the Semicircular Canals in the Freely Moving Chinchilla

Wed, 18 Nov 2009 10:02:12 PST

Head direction (HD) cells in the rat anterodorsal thalamic nucleus (ADN) fire relative to the animal's directional heading. Lesions of the entire vestibular labyrinth have been shown to severely alter VIIIth nerve input and disrupt these HD signals. To assess the specific contributions of the semicircular canals without altering tonic VIIIth nerve input, ADN cells were recorded from chinchillas after bilateral semicircular canal occlusion. Although ADN HD cells (and also hippocampal place cells and theta cells) were identified in intact chinchillas, no direction-specific activity was seen after canal occlusions. Instead, "bursty" cells were observed that exhibited burst-firing patterns similar to normal HD cells but with firing unrelated to the animal's actual head direction. Importantly, when pairs of bursty cells were recorded, the temporal order of their firing was dependent on the animal's turning direction, as is the case for pairs of normal HD cells. These results suggest that bursty cells are actually disrupted HD cells. The present findings further suggest that the HD cell network is still able to generate spiking activity after canal occlusions, but the semicircular canal input is critical for updating the network activity in register with changes in the animal's HD.

APP Anterograde Transport Requires Rab3A GTPase Activity for Assembly of the Transport Vesicle

Wed, 18 Nov 2009 10:02:12 PST

The amyloid precursor protein (APP) is anterogradely transported by conventional kinesin in a distinct transport vesicle, but both the biochemical composition of such a vesicle and the specific kinesin-1 motor responsible for transport are poorly defined. APP may be sequentially cleaved by β- and -secretases leading to accumulation of β-amyloid (Aβ) peptides in brains of Alzheimer's disease patients, whereas cleavage of APP by -secretases prevents Aβ generation. Here, we demonstrate by time-lapse analysis and immunoisolations that APP is a cargo of a vesicle containing the kinesin heavy chain isoform kinesin-1C, the small GTPase Rab3A, and a specific subset of presynaptic protein components. Moreover, we report that assembly of kinesin-1C and APP in this vesicle type requires Rab3A GTPase activity. Finally, we show cleavage of APP in transport vesicles by -secretase activity, likely mediated by ADAM10. Together, these data indicate that maturation of APP transport vesicles, including recruitment of conventional kinesin, requires Rab3 GTPase activity.

SR1, a Mouse Odorant Receptor with an Unusually Broad Response Profile

Wed, 18 Nov 2009 10:02:12 PST

The current consensus model in mammalian olfaction is that the detection of millions of odorants requires a large number of odorant receptors (ORs) and that each OR interacts selectively with a small subset of odorants, which are typically related in structure. Here, we report the odorant response properties of an OR that deviates from this model: SR1, a mouse OR that is abundantly expressed in sensory neurons of the septal organ and also of the main olfactory epithelium. Patch-clamp recordings reveal that olfactory sensory neurons (OSNs) that express SR1 respond to many, structurally unrelated odorants, and over a wide concentration range. Most OSNs expressing a gene-targeted SR1 locus that lacks the SR1 coding sequence do not show this broad responsiveness. Gene transfer in the heterologous expression system Hana3A confirms the broad response profile of SR1. There may be other mouse ORs with such broad response profiles.

Correlations of Neuronal and Microvascular Densities in Murine Cortex Revealed by Direct Counting and Colocalization of Nuclei and Vessels

Wed, 18 Nov 2009 10:02:12 PST

It is well known that the density of neurons varies within the adult brain. In neocortex, this includes variations in neuronal density between different lamina as well as between different regions. Yet the concomitant variation of the microvessels is largely uncharted. Here, we present automated histological, imaging, and analysis tools to simultaneously map the locations of all neuronal and non-neuronal nuclei and the centerlines and diameters of all blood vessels within thick slabs of neocortex from mice. Based on total inventory measurements of different cortical regions (~10⁷ cells vectorized across brains), these methods revealed: (1) In three dimensions, the mean distance of the center of neuronal somata to the closest microvessel was 15 µm. (2) Volume samples within lamina of a given region show that the density of microvessels does not match the strong laminar variation in neuronal density. This holds for both agranular and granular cortex. (3) Volume samples in successive radii from the midline to the ventral-lateral edge, where each volume summed the number of cells and microvessels from the pia to the white matter, show a significant correlation between neuronal and microvessel densities. These data show that while neuronal and vascular densities do not track each other on the 100 µm scale of cortical lamina, they do track each other on the 1–10 mm scale of the cortical mantle. The absence of a disproportionate density of blood vessels in granular lamina is argued to be consistent with the initial locus of functional brain imaging signals.

The Transition from Radial Glial to Intermediate Progenitor Cell Is Inhibited by FGF Signaling during Corticogenesis

Kang, W., Wong, L. C., Shi, S.-H., Hebert, J. M. — Wed, 18 Nov 2009 10:02:12 PST

During corticogenesis, the balance between the self-renewal of radial glial stem cells and the production of their descendent progenitor cells is essential in generating the correct size and cell composition of the neocortex. How the stem-to-progenitor cell transition is regulated is poorly understood. FGFs are commonly implicated in promoting proliferation of neural precursor cells, but it is unclear how they exert their effects on stem cells, progenitor cells, or both in vivo. Here, three FGF receptor genes are simultaneously deleted during cortical neurogenesis. In these mutants, radial glia are depleted due to an increased transition from an uncommitted state to a more differentiated one, initially causing an increase in progenitors, but ultimately resulting in a smaller cortex. The proliferation rate of progenitors themselves, however, is unchanged. These results indicate that FGFs normally repress the radial glia to progenitor cell transition during corticogenesis.

Neuronal Transporters Regulate Glutamate Clearance, NMDA Receptor Activation, and Synaptic Plasticity in the Hippocampus

Scimemi, A., Tian, H., Diamond, J. S. — Wed, 18 Nov 2009 10:02:12 PST

In the mammalian brain, the specificity of excitatory synaptic transmission depends on rapid diffusion of glutamate away from active synapses and the powerful uptake capacity of glutamate transporters in astrocytes. The extent to which neuronal glutamate transporters influence the lifetime of glutamate in the extracellular space remains unclear. Here we show that EAAC1, the predominant neuronal glutamate transporter at excitatory synapses in hippocampal area CA1, buffers glutamate released during synaptic events and prolongs the time course of its clearance by astrocytes. EAAC1 does not significantly alter activation of receptors in the synaptic cleft. Instead, it reduces recruitment of perisynaptic/extrasynaptic NR2B-containing NMDARs, thereby facilitating induction of long-term potentiation by short bursts of high-frequency stimulation. We describe novel roles of EAAC1 in regulating glutamate diffusion and propose that NMDARs at different subsynaptic locations can make distinct contributions to the regulation of synaptic strength.

Reliable Recall of Spontaneous Activity Patterns in Cortical Networks

Marre, O., Yger, P., Davison, A. P., Fregnac, Y. — Wed, 18 Nov 2009 10:02:12 PST

Irregular ongoing activity in cortical networks is often modeled as arising from recurrent connectivity. Yet it remains unclear to what extent its presence corrupts sensory signal transmission and network computational capabilities. In a recurrent cortical-like network, we have determined the activity patterns that are better transmitted and self-sustained by the network. We show that reproducible spiking and subthreshold dynamics can be triggered if the statistics of the imposed external drive are consistent with patterns previously seen in the ongoing activity. A subset of neurons in the network, constrained to replay temporal pattern segments extracted from the recorded ongoing activity of the same network, reliably drives the remaining, free-running neurons to call the rest of the pattern. Comparison with surrogate Poisson patterns indicates that the efficiency of the recall and completion process depends on the similarity between the statistical properties of the input with previous ongoing activity The reliability of evoked dynamics in recurrent networks is thus dependent on the stimulus used, and we propose that the similarity between spontaneous and evoked activity in sensory cortical areas could be a signature of efficient transmission and propagation across cortical networks.

A Comparative Magnetic Resonance Imaging Study of the Anatomy, Variability, and Asymmetry of Broca's Area in the Human and Chimpanzee Brain

Keller, S. S., Roberts, N., Hopkins, W. — Wed, 18 Nov 2009 10:02:12 PST

The frontal operculum—classically considered to be Broca's area—has special significance and interest in clinical, cognitive, and comparative neuroscience given its role in spoken language and the long-held assumption that structural asymmetry of this region of cortex may be related to functional lateralization of human language. We performed a detailed morphological and morphometric analysis of this area of the brain in humans and chimpanzees using identical image acquisition parameters, image analysis techniques, and consistent anatomical boundaries in both species. We report great inter-individual variability of the sulcal contours defining the operculum in both species, particularly discontinuity of the inferior frontal sulcus in humans and bifurcation of the inferior precentral sulcus in chimpanzees. There was no evidence of population-based asymmetry of the frontal opercular gray matter in humans or chimpanzees. The diagonal sulcus was only identified in humans, and its presence was significantly (F = 12.782, p < 0.001) associated with total volume of the ipsilateral operculum. The findings presented here suggest that there is no population-based interhemispheric macroscopic asymmetry of Broca's area in humans or Broca's area homolog in chimpanzees. However, given that previous studies have reported asymmetry in the cytoarchitectonic fields considered to represent Broca's area—which is important given that cytoarchitectonic boundaries are more closely related to the regional functional properties of cortex relative to sulcal landmarks—it may be that the gross morphology of the frontal operculum is not a reliable indicator of Broca's area per se.

How Humans Integrate the Prospects of Pain and Reward during Choice

Talmi, D., Dayan, P., Kiebel, S. J., Frith, C. D., Dolan, R. J. — Wed, 18 Nov 2009 10:02:12 PST

The maxim "no pain, no gain" summarizes scenarios in which an action leading to reward also entails a cost. Although we know a substantial amount about how the brain represents pain and reward separately, we know little about how they are integrated during goal-directed behavior. Two theoretical models might account for the integration of reward and pain. An additive model specifies that the disutility of costs is summed linearly with the utility of benefits, whereas an interactive model suggests that cost and benefit utilities interact so that the sensitivity to benefits is attenuated as costs become increasingly aversive. Using a novel task that required integration of physical pain and monetary reward, we examined the mechanism underlying cost–benefit integration in humans. We provide evidence in support of an interactive model in behavioral choice. Using functional neuroimaging, we identify a neural signature for this interaction such that, when the consequences of actions embody a mixture of reward and pain, there is an attenuation of a predictive reward signal in both ventral anterior cingulate cortex and ventral striatum. We conclude that these regions subserve integration of action costs and benefits in humans, a finding that suggests a cross-species similarity in neural substrates that implement this function and illuminates mechanisms that underlie altered decision making under aversive conditions.

Regaining Motor Control in Musician's Dystonia by Restoring Sensorimotor Organization

Rosenkranz, K., Butler, K., Williamon, A., Rothwell, J. C. — Wed, 18 Nov 2009 10:02:12 PST

Professional musicians are an excellent model of long-term motor learning effects on structure and function of the sensorimotor system. However, intensive motor skill training has been associated with task-specific deficiency in hand motor control, which has a higher prevalence among musicians (musician's dystonia) than in the general population. Using a transcranial magnetic stimulation paradigm, we previously found an expanded spatial integration of proprioceptive input into the hand motor cortex [sensorimotor organization (SMO)] in healthy musicians. In musician's dystonia, however, this expansion was even larger. Whereas motor skills of musicians are likely to be supported by a spatially expanded SMO, we hypothesized that in musician's dystonia this might have developed too far and now disrupts rather than assists task-specific motor control. If so, motor control should be regained by reversing the excessive reorganization in musician's dystonia. Here, we test this hypothesis and show that a 15 min intervention with proprioceptive input (proprioceptive training) restored SMO in pianists with musician's dystonia to the pattern seen in healthy pianists. Crucially, task-specific motor control improved significantly and objectively as measured with a MIDI (musical instrument digital interface) piano, and the amount of behavioral improvement was significantly correlated to the degree of sensorimotor reorganization. In healthy pianists and nonmusicians, the SMO and motor performance remained essentially unchanged. These findings suggest that the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks are significantly linked and finely balanced. Proprioceptive training restored this balance in musician's dystonia to the behaviorally beneficial level of healthy musicians.

Disruption of the Ether-a-go-go K+ Channel Gene BEC1/KCNH3 Enhances Cognitive Function

Wed, 18 Nov 2009 10:02:13 PST

The K⁺ channel, one of the determinants for neuronal excitability, is genetically heterogeneous, and various K⁺ channel genes are expressed in the CNS. The therapeutic potential of K⁺ channel blockers for cognitive enhancement has been discussed, but the contribution each K⁺ channel gene makes to cognitive function remains obscure. BEC1 (KCNH3) is a member of the K⁺ channel superfamily that shows forebrain-preferential distribution. Here, we show the critical involvement of BEC1 in cognitive function. BEC1 knock-out mice performed behavioral tasks related to working memory, reference memory, and attention better than their wild-type littermates. Enhanced performance was also observed in heterozygous mutants. The knock-out mice had neither the seizures nor the motor dysfunction that are often observed in K⁺ channel-deficient mice. In contrast to when it is disrupted, overexpression of BEC1 in the forebrain caused the impaired performance of those tasks. It was also found that altering BEC1 expression could change hippocampal neuronal excitability and synaptic plasticity. The results indicate that BEC1 may represent the first K⁺ channel that contributes preferentially and bidirectionally to cognitive function.

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Wed, 18 Nov 2009 10:02:13 PST

Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1^C133W) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1^C133W, but not in the wild-type, double-transgenic tgSPTLC1^{WT + C133W} or SPTLC1^+/– mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.

Novel Repression of Kcc2 Transcription by REST-RE-1 Controls Developmental Switch in Neuronal Chloride

Yeo, M., Berglund, K., Augustine, G., Liedtke, W. — Wed, 18 Nov 2009 10:02:13 PST

Transcriptional upregulation of Kcc2b, the gene variant encoding the major isoform of the KCC2 chloride transporter, underlies a rapid perinatal decrease in intraneuronal chloride concentration (chloride shift), which is necessary for GABA to act inhibitory. Here we identify a novel repressor element-1 (RE-1) site in the 5' regulatory region of Kcc2b. In primary cortical neurons, which recapitulate the chloride shift in culture, the novel upstream RE-1 together with a known intronic RE-1 site function in concerted interaction to suppress Kcc2b transcription. With critical relevance for the chloride shift, only in the presence of the dual RE-1 site could inhibition of REST upregulate Kcc2b transcription. For this, we confirmed increased KCC2 protein expression and decreased intraneuronal chloride. Kcc2b developmental upregulation was potentiated by BDNF application, which was fully dependent on the presence of dual RE-1. In addition, the developmental chloride shift and GABA switch, from excitatory to inhibitory action, was accelerated by REST inhibition and slowed by REST overexpression. These results identify the REST–dual RE-1 interaction as a novel mechanism of transcriptional Kcc2b upregulation that significantly contributes to the ontogenetic shift in chloride concentration and GABA action in cortical neurons, which is fundamental for brain function in health and disease. Thus, we present here a new logic for the perinatal chloride shift, which is critical for establishment of GABAergic cortical inhibitory neurotransmission.

In Vivo Quantification of Myelin Changes in the Vertebrate Nervous System

Wed, 18 Nov 2009 10:02:13 PST

Destruction or changes associated with myelin membranes in the CNS play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. A long-standing goal has been to detect and quantify myelin content in vivo. For this reason, we have developed a myelin-imaging technique based on positron emission tomography (PET). PET is a quantitative imaging modality that has been widely used in clinical settings for direct assessment of biological processes at the molecular level. However, lack of myelin-imaging probes has hampered the use of PET for imaging of myelination in the CNS. Here, we report a myelin-imaging agent, termed Case Imaging Compound (CIC) that readily penetrates the blood–brain barrier and preferentially localizes to myelinated regions of the brain. After radiolabeling with positron-emitting carbon-11, [¹¹C]CIC–PET was conducted in longitudinal studies using a lysolethicin-induced rat model of focal demyelination and subsequent remyelination. Quantitative analysis showed that the retention of [¹¹C]CIC correlates with the level of demyelination/remyelination. These studies indicate that, for the first time, [¹¹C]CIC–PET can be used as an imaging marker of myelination, which has the potential to be translated into clinical studies in multiple sclerosis and other myelin-related diseases for early diagnosis, subtyping, and efficacy evaluation of therapeutic treatments aimed at myelin repair.

Functional Heterogeneity at Dopamine Release Sites

Daniel, J. A., Galbraith, S., Iacovitti, L., Abdipranoto, A., Vissel, B. — Wed, 18 Nov 2009 10:02:13 PST

Although drugs used to treat several neurological diseases are presumed to target synapses that secrete dopamine (DA), relatively little is known about synaptic vesicle (SV) release mechanisms at single DA synapses. We found that the relative probability of release (Pr) varied between individual DA synapses. Furthermore, DA terminals generally exhibited lower Pr than glutamatergic hippocampal (Hpc) terminals, suggesting that DA release is less reliable than the release of glutamate. Our mathematical model of fluorescence loss shows that Pr is regulated by two independent and heterogeneous elements. First, the size of the recycling SV pool regulates Pr. Second, Pr is also independently regulated by additional factors, which are reflected in the time constant of FM 1-43 destaining, . We found that the observed difference in Pr between Hpc and DA neurons results because the recycling SV pool is smaller in DA neurons than in Hpc neurons. However, does not vary between these two neuron populations. We also identified a population of functional nonsynaptic boutons in DA axons, which are not associated with a postsynaptic element and which are not functionally different from boutons that formed conventional synapses. Our work provides a new approach to the study of SV exocytosis in DA neurons and shows that synaptic terminals of DA neurons are functionally heterogeneous and differ from excitatory terminals in terms of Pr.

Endogenous Rhythms in Period1 Mutant Suprachiasmatic Nuclei In Vitro Do Not Represent Circadian Behavior

Pendergast, J. S., Friday, R. C., Yamazaki, S. — Wed, 18 Nov 2009 10:02:13 PST

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1^–/–) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1^–/– mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1^+/+) mice. While some neurons in Per1^–/– SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1^–/– SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1^–/– SCN.

This Week in The Journal

Wed, 11 Nov 2009 10:02:14 PST

Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism

Wed, 11 Nov 2009 10:02:14 PST

Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.

Regulation of Radial Glial Motility by Visual Experience

Wed, 11 Nov 2009 10:02:14 PST

Radial glia in the developing optic tectum express the key guidance molecules responsible for topographic targeting of retinal axons. However, the extent to which the radial glia are themselves influenced by retinal inputs and visual experience remains unknown. Using multiphoton live imaging of radial glia in the optic tectum of intact Xenopus laevis tadpoles in conjunction with manipulations of neural activity and sensory stimuli, radial glia were observed to exhibit spontaneous calcium transients that were modulated by visual stimulation. Structurally, radial glia extended and retracted many filopodial processes within the tectal neuropil over minutes. These processes interacted with retinotectal synapses and their motility was modulated by nitric oxide (NO) signaling downstream of neuronal NMDA receptor (NMDAR) activation and visual stimulation. These findings provide the first in vivo demonstration that radial glia actively respond both structurally and functionally to neural activity, via NMDAR-dependent NO release during the period of retinal axon ingrowth.

Adding Insult to Injury: Cochlear Nerve Degeneration after "Temporary" Noise-Induced Hearing Loss

Kujawa, S. G., Liberman, M. C. — Wed, 11 Nov 2009 10:02:14 PST

Overexposure to intense sound can cause temporary or permanent hearing loss. Postexposure recovery of threshold sensitivity has been assumed to indicate reversal of damage to delicate mechano-sensory and neural structures of the inner ear and no persistent or delayed consequences for auditory function. Here, we show, using cochlear functional assays and confocal imaging of the inner ear in mouse, that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of afferent nerve terminals and delayed degeneration of the cochlear nerve. Results suggest that noise-induced damage to the ear has progressive consequences that are considerably more widespread than are revealed by conventional threshold testing. This primary neurodegeneration should add to difficulties hearing in noisy environments, and could contribute to tinnitus, hyperacusis, and other perceptual anomalies commonly associated with inner ear damage.

Hyperdopaminergic Tone Erodes Prefrontal Long-Term Potential via a D2 Receptor-Operated Protein Phosphatase Gate

Wed, 11 Nov 2009 10:02:14 PST

Dopamine (DA) plays crucial roles in the cognitive functioning of the prefrontal cortex (PFC), which, to a large degree, depends on lasting neural traces formed in prefrontal networks. The establishment of these permanent traces requires changes in cortical synaptic efficacy. DA, via the D₁-class receptors, is thought to gate or facilitate synaptic plasticity in the PFC, with little role recognized for the D₂-class receptors. Here we show that, when significantly elevated, DA erodes, rather than facilitates, the induction of long-term potentiation (LTP) in the PFC by acting at the far less abundant cortical D₂-class receptors through a dominant coupling to the protein phosphatase 1 (PP1) activity in postsynaptic neurons. In mice with persistently elevated extracellular DA, resulting from inactivation of the DA transporter (DAT) gene, LTP in layer V PFC pyramidal neurons cannot be established, regardless of induction protocols. Acute increase of dopaminergic transmission by DAT blockers or overstimulation of D₂ receptors in normal mice have similar LTP shutoff effects. LTP in mutant mice can be rescued by a single in vivo administration of D₂-class antagonists. Suppression of postsynaptic PP1 mimics and occludes the D₂-mediated rescue of LTP in mutant mice and prevents the acute erosion of LTP by D₂ agonists in normal mice. Our studies reveal a mechanistically unique heterosynaptic PP1 gate that is constitutively driven by background DA to influence LTP induction. By blocking prefrontal synaptic plasticity, excessive DA may prevent storage of lasting memory traces in PFC networks and impair executive functions.

Musical Experience Limits the Degradative Effects of Background Noise on the Neural Processing of Sound

Parbery-Clark, A., Skoe, E., Kraus, N. — Wed, 11 Nov 2009 10:02:14 PST

Musicians have lifelong experience parsing melodies from background harmonies, which can be considered a process analogous to speech perception in noise. To investigate the effect of musical experience on the neural representation of speech-in-noise, we compared subcortical neurophysiological responses to speech in quiet and noise in a group of highly trained musicians and nonmusician controls. Musicians were found to have a more robust subcortical representation of the acoustic stimulus in the presence of noise. Specifically, musicians demonstrated faster neural timing, enhanced representation of speech harmonics, and less degraded response morphology in noise. Neural measures were associated with better behavioral performance on the Hearing in Noise Test (HINT) for which musicians outperformed the nonmusician controls. These findings suggest that musical experience limits the negative effects of competing background noise, thereby providing the first biological evidence for musicians' perceptual advantage for speech-in-noise.

A{beta} Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

Biscaro, B., Lindvall, O., Hock, C., Ekdahl, C. T., Nitsch, R. M. — Wed, 11 Nov 2009 10:02:14 PST

The hippocampus is heavily affected by progressive neurodegeneration and β-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of β-amyloid peptide (Aβ)-related toxicity induced by passive Aβ immunotherapy. Aβ immunotherapy of 8–9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against Aβ decreased compact β-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. Aβ immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that Aβ immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrP^c) on the dendrites of the GFP⁺ newly born neurons is compatible with a putative role of PrP^c in mediating Aβ-related toxicity in these cells. In addition, passive Aβ immunotherapy was accompanied by increased angiogenesis. Our data establish that passive Aβ immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of Aβ immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that Aβ immunotherapy can recover neuronal and vascular functions in brains with β-amyloidosis.

Individual Calcium Syntillas Do Not Trigger Spontaneous Exocytosis from Nerve Terminals of the Neurohypophysis

McNally, J. M., De Crescenzo, V., Fogarty, K. E., Walsh, J. V., Lemos, J. R. — Wed, 11 Nov 2009 10:02:14 PST

Recently, highly localized Ca²⁺ release events, similar to Ca²⁺ sparks in muscle, have been observed in neuronal preparations. Specifically, in murine neurohypophysial terminals (NHT), these events, termed Ca²⁺ syntillas, emanate from a ryanodine-sensitive intracellular Ca²⁺ pool and increase in frequency with depolarization in the absence of Ca²⁺ influx. Despite such knowledge of the nature of these Ca²⁺ release events, their physiological role in this system has yet to be defined. Such localized Ca²⁺ release events, if they occur in the precise location of the final exocytotic event(s), may directly trigger exocytosis. However, directly addressing this hypothesis has not been possible, since no method capable of visualizing individual release events in these CNS terminals has been available. Here, we have adapted an amperometric method for studying vesicle fusion to this system which relies on loading the secretory granules with the false transmitter dopamine, thus allowing, for the first time, the recording of individual exocytotic events from peptidergic NHT. Simultaneous use of this technique along with high-speed Ca²⁺ imaging has enabled us to establish that spontaneous neuropeptide release and Ca²⁺ syntillas do not display any observable temporal or spatial correlation, confirming similar findings in chromaffin cells. Although these results indicate that syntillas do not play a direct role in eliciting spontaneous release, they do not rule out indirect modulatory effects of syntillas on secretion.

The Synaptic Representation of Sound Source Location in Auditory Cortex

Chadderton, P., Agapiou, J. P., McAlpine, D., Margrie, T. W. — Wed, 11 Nov 2009 10:02:14 PST

A key function of the auditory system is to provide reliable information about the location of sound sources. Here, we describe how sound location is represented by synaptic input arriving onto pyramidal cells within auditory cortex by combining free-field acoustic stimulation in the frontal azimuthal plane with in vivo whole-cell recordings. We found that subthreshold activity was panoramic in that EPSPs could be evoked from all locations in all cells. Regardless of the sound location that evoked the largest EPSP, we observed a slowing in the EPSP slope along the contralateral–ipsilateral plane that was reflected in a temporal sequence of peak EPSP times. Contralateral sounds evoked EPSPs with earlier peak times and consequently generated action potential firing with shorter latencies than ipsilateral sounds. Thus, whereas spiking probability reflected the region of space evoking the largest EPSP, across the population, synaptic inputs enforced a gradient of spike latency and precision along the horizontal axis. Therefore, within auditory cortex and regardless of preferred location, the time window of synaptic integration reflects sound source location and ensures that spatial acoustic information is represented by relative timings of pyramidal cell output.

A Novel, Nongenomic Mechanism Underlies Retinoic Acid-Induced Growth Cone Turning

Farrar, N. R., Dmetrichuk, J. M., Carlone, R. L., Spencer, G. E. — Wed, 11 Nov 2009 10:02:14 PST

The vitamin A metabolite, retinoic acid (RA), is well known for its roles in neural development and regeneration. We have previously shown that RA can induce positive growth cone turning in regenerating neurons in vitro. In this study, we address the subcellular mechanisms underlying this chemo-attractive response, using identified central neurons from the adult mollusc, Lymnaea stagnalis. We show that the RA-induced positive growth cone turning was maintained in the presence of the transcriptional inhibitor, actinomycin D. We also physically transected the neurites from the cell body and showed that isolated growth cones retain the capacity to turn toward a gradient of RA. Moreover, this attractive turning is dependent on de novo local protein synthesis and Ca²⁺ influx. Most of RA's actions during neurite outgrowth and regeneration require gene transcription, although these data show for the first time in any species, that the chemotropic action of RA in guiding neurite outgrowth, involves a novel, nongenomic mechanism.

Local and Large-Range Inhibition in Feature Detection

Bolzon, D. M., Nordstrom, K., O'Carroll, D. C. — Wed, 11 Nov 2009 10:02:14 PST

Lateral inhibition is perhaps the most ubiquitous of neuronal mechanisms, having been demonstrated in early stages of processing in many different sensory pathways of both mammals and invertebrates. Recent work challenges the long-standing view that assumes that similar mechanisms operate to tune neuronal responses to higher order properties. Scant evidence for lateral inhibition exists beyond the level of the most peripheral stages of visual processing, leading to suggestions that many features of the tuning of higher order visual neurons can be accounted for by the receptive field and other intrinsic coding properties of visual neurons. Using insect target neurons as a model, we present unequivocal evidence that feature tuning is shaped not by intrinsic properties but by potent spatial lateral inhibition operating well beyond the first stages of visual processing. In addition, we present evidence for a second form of higher-order spatial inhibition—a long-range interocular transfer of information that we argue serves a role in establishing interocular rivalry and thus potentially a neural substrate for directing attention to single targets in the presence of distracters. In so doing, we demonstrate not just one, but two levels of spatial inhibition acting beyond the level of peripheral processing.

The Conserved Ig Superfamily Member Turtle Mediates Axonal Tiling in Drosophila

Ferguson, K., Long, H., Cameron, S., Chang, W.-T., Rao, Y. — Wed, 11 Nov 2009 10:02:14 PST

Restriction of adjacent same-type axons/dendrites to separate single columns for specific neuronal connections is commonly observed in vertebrates and invertebrates, and is necessary for proper processing of sensory information. Columnar restriction is conceptually similar to tiling, a phenomenon referring to the avoidance of neurites from adjacent same-type neurons. The molecular mechanism underlying the establishment of columnar restriction or axonal/dendritic tiling remains largely undefined. Here, we identify Turtle (Tutl), a member of the conserved Tutl/Dasm1/IgSF9 subfamily of the Ig superfamily, as a key player in regulating the tiling pattern of R7 photoreceptor terminals in Drosophila. Tutl functions to prevent fusion between two adjacent R7 terminals, and acts in parallel to the Activin pathway. Tutl mediates homophilic cell–cell interactions. We propose that extrinsic terminal–terminal recognition mediated by Tutl, acts in concert with intrinsic Activin-dependent control of terminal growth, to restrict the connection made by each R7 axon to a single column.

Neural Activity in the Middle Temporal Area and Lateral Intraparietal Area during Endogenously Cued Shifts of Attention

Herrington, T. M., Assad, J. A. — Wed, 11 Nov 2009 10:02:14 PST

We measured the behavioral time course of endogenously cued attentional shifts while recording from neurons in the middle temporal area (MT) and lateral intraparietal area (LIP) of two macaque monkeys. The monkeys were required to detect a subtle speed change of one of two continuously moving stimuli. The likely location of the speed change was cued throughout each trial but could switch at an unpredictable time. Attention was evident as an improvement in detection ability and reaction time at the cued location, and the focus of attention shifted over a 400 ms period in response to a switch of the cued stimulus. Attention modulated the ongoing neural response in both MT and LIP, and the sign of this modulation also rapidly shifted after a cue switch. Our data provide a framework for understanding the link between the neural and behavioral effects of attention. The responses of single neurons to the test stimulus in MT and LIP were correlated with stimulus detection and reaction time and, at the population level, a spike-rate threshold model was able to account for the effect of attention on detection rate and reaction time. In this view, the time course of the attentional shift can be understood as an interaction between the emerging attentional modulation and the neural response to the test stimulus in LIP. We also present evidence that the threshold model is not wholly explained by sensory (feedforward) information but may also be influenced by cognitive (feedback) processes at the time of stimulus detection.

NOS2 Gene Deficiency Protects from Sepsis-Induced Long-Term Cognitive Deficits

Wed, 11 Nov 2009 10:02:14 PST

To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learning, and memory capabilities and factors involved are poorly understood. In this study, we used a murine sepsis model to demonstrate that bacterial lipopolysaccharide (LPS) causes long-term cognitive deficits in mice. Two months after LPS treatment, wild-type mice committed more working and reference memory errors than controls. The behavioral impairment was independent of the cerebral glucose uptake as evidenced by ¹⁸F-Fluordeoxyglucose small animal positron emission tomography. In contrast, mice deficient for the inducible nitric oxide synthase gene (NOS2–/–) did not show any cognitive changes when challenged with LPS. Immunohistochemical analysis demonstrated that LPS did not lead to neuronal cell death but caused sustained microglial activation in wild-type as compared to NOS2–/– mice. Expression analysis showed that LPS-treated NOS2–/– mice had lower brain mRNA levels for proinflammatory factors compared with wild-type mice. Expression analysis demonstrated distinct changes in the content of synaptic proteins in wild-type mice, which were not observed in the NOS2–/– mice. Together, this data set outlines the importance of the NOS2 activation for long-term cerebral changes after severe sepsis.

Differential Activity-Dependent Secretion of Brain-Derived Neurotrophic Factor from Axon and Dendrite

Wed, 11 Nov 2009 10:02:14 PST

Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival and differentiation during development and for synaptic function and plasticity in the mature brain. BDNF-containing vesicles are widely distributed and bidirectionally transported in neurons, and secreted BDNF can act on both presynaptic and postsynaptic cells. Activity-dependent BDNF secretion from neuronal cultures has been reported, but it remains unknown where the primary site of BDNF secretion is and whether neuronal activity can trigger BDNF secretion from axons and dendrites with equal efficacy. Using BDNF fused with pH-sensitive green fluorescent protein to visualize BDNF secretion, we found that BDNF-containing vesicles exhibited markedly different properties of activity-dependent exocytic fusion at the axon and dendrite of cultured hippocampal neurons. Brief spiking activity triggered a transient fusion pore opening, followed by immediate retrieval of vesicles without dilation of the fusion pore, resulting in very little BDNF secretion at the axon. On the contrary, the same brief spiking activity induced "full-collapse" vesicle fusion and substantial BDNF secretion at the dendrite. However, full vesicular fusion with BDNF secretion could occur at the axon when the neuron was stimulated by prolonged high-frequency activity, a condition neurons may encounter during epileptic discharge. Thus, activity-dependent axonal secretion of BDNF is highly restricted as a result of incomplete fusion of BDNF-containing vesicles, and normal neural activity induces BDNF secretion from dendrites, consistent with the BDNF function as a retrograde factor. Our study also revealed a novel mechanism by which differential exocytosis of BDNF-containing vesicles may regulate BDNF–TrkB signaling between connected neurons.

Overexpressing Temperature-Sensitive Dynamin Decelerates Phototransduction and Bundles Microtubules in Drosophila Photoreceptors

Wed, 11 Nov 2009 10:02:14 PST

shibire^ts1, a temperature-sensitive mutation of the Drosophila gene encoding a Dynamin orthologue, blocks vesicle endocytosis and thus synaptic transmission, at elevated, or restrictive temperatures. By targeted Gal4 expression, UAS-shibire^ts1 has been used to dissect neuronal circuits. We investigated the effects of UAS-shibire^ts1 overexpression in Drosophila photoreceptors at permissive (19°C) and restrictive (31°C) temperatures. At 19°C, overexpression of UAS-shi^ts1 causes decelerated phototransduction and reduced neurotransmitter release. This phenotype is exacerbated with dark adaptation, age and in white mutants. Photoreceptors overexpressing UAS-shibire^ts1 contain terminals with widespread vacuolated mitochondria, reduced numbers of vesicles and bundled microtubules. Immuno-electron microscopy reveals that the latter are dynamin coated. Further, the microtubule phenotype is not restricted to photoreceptors, as UAS-shibire^ts1 overexpression in lamina cells also bundles microtubules. We conclude that dynamin has multiple functions that are interrupted by UAS-shibire^ts1 overexpression in Drosophila photoreceptors, destabilizing their neural communication irreversibly at previously reported permissive temperatures.

Robo-2 Controls the Segregation of a Portion of Basal Vomeronasal Sensory Neuron Axons to the Posterior Region of the Accessory Olfactory Bulb

Wed, 11 Nov 2009 10:02:14 PST

The ability of sensory systems to detect and process information from the environment relies on the elaboration of precise connections between sensory neurons in the periphery and second order neurons in the CNS. In mice, the accessory olfactory system is thought to regulate a wide variety of social and sexual behaviors. The expression of the Slit receptors Robo-1 and Robo-2 in vomeronasal sensory neurons (VSNs) suggests they may direct the stereotypic targeting of their axons to the accessory olfactory bulb (AOB). Here, we have examined the roles of Robo-1 and Robo-2 in the formation of connections by VSN axons within the AOB. While Robo-1 is not necessary for the segregation of VSN axons within the anterior and posterior regions of the AOB, Robo-2 is required for the targeting of some basal VSN axons to the posterior region of the AOB but is dispensable for the fasciculation of VSN axons. Furthermore, the specific ablation of Robo-2 expression in VSNs leads to mistargeting of a portion of basal VSN axons to the anterior region of the AOB, indicating that Robo-2 expression is required on projecting VSN axons. Together, these results identify Robo-2 as a receptor that controls the targeting of basal VSN axons to the posterior AOB.

The Spinothalamic System Targets Motor and Sensory Areas in the Cerebral Cortex of Monkeys

Dum, R. P., Levinthal, D. J., Strick, P. L. — Wed, 11 Nov 2009 10:02:14 PST

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

Cerebral and Cerebrospinal Processes Underlying Counterirritation Analgesia

Piche, M., Arsenault, M., Rainville, P. — Wed, 11 Nov 2009 10:02:14 PST

Pain is a complex experience involving extensive interactions between brain and spinal cord processes. Various interventions that modulate pain, such as the application of a competing noxious stimulus (counterirritation), are thought to involve cerebrospinal regulation through diffuse noxious inhibitory controls (DNICs). However, no study has yet examined the relation between brain and spinal cord activity during counterirritation analgesia in humans. This fMRI study investigates brain responses to phasic painful electrical stimulation administered to the sural nerve to evoke a spinal nociceptive response (RIII reflex) before, during and after counterirritation induced by the immersion of the left contralateral foot in cold water. Responses are compared with a control condition without counterirritation. As expected, counterirritation produced robust pain inhibition with residual analgesia persisting during the recovery period. In contrast, RIII reflex amplitude was significantly decreased by counterirritation only in a subset of subjects. Modulatory effects of counterirritation on pain perception and spinal nociception were paralleled by decreased shock-evoked activity in pain-related areas. Individual changes in shock-evoked brain activity were specifically related to analgesia in primary somatosensory cortex (SI), anterior cingulate cortex and amygdala, and to RIII modulation in supplementary motor area and orbitofrontal cortex (OFC). Moreover, sustained activation induced by the counterirritation stimulus in the OFC predicted shock-pain decrease while sustained activity in SI and the periaqueductal gray matter predicted RIII modulation. These results provide evidence for the implication of at least two partly separable neural mechanisms underlying the effects of counterirritation on pain and spinal nociception in humans.

Surviving Hilar Somatostatin Interneurons Enlarge, Sprout Axons, and Form New Synapses with Granule Cells in a Mouse Model of Temporal Lobe Epilepsy

Wed, 11 Nov 2009 10:02:14 PST

In temporal lobe epilepsy, seizures initiate in or near the hippocampus, which frequently displays loss of neurons, including inhibitory interneurons. It is unclear whether surviving interneurons function normally, are impaired, or develop compensatory mechanisms. We evaluated GABAergic interneurons in the hilus of the dentate gyrus of epileptic pilocarpine-treated GIN mice, specifically a subpopulation of somatostatin interneurons that expresses enhanced green fluorescence protein (GFP). GFP-immunocytochemistry and stereological analyses revealed substantial loss of GFP-positive hilar neurons (GPHNs) but increased GFP-positive axon length per dentate gyrus in epileptic mice. Individual biocytin-labeled GPHNs in hippocampal slices from epileptic mice also had larger somata, more axon in the molecular layer, and longer dendrites than controls. Dual whole-cell patch recording was used to test for monosynaptic connections from hilar GPHNs to granule cells. Unitary IPSCs (uIPSCs) recorded in control and epileptic mice had similar average rise times, amplitudes, charge transfers, and decay times. However, the probability of finding monosynaptically connected pairs and evoking uIPSCs was 2.6 times higher in epileptic mice compared to controls. Together, these findings suggest that surviving hilar somatostatin interneurons enlarge, extend dendrites, sprout axon collaterals in the molecular layer, and form new synapses with granule cells. These epilepsy-related changes in cellular morphology and connectivity may be mechanisms for surviving hilar interneurons to inhibit more granule cells and compensate for the loss of vulnerable interneurons.

Polar Residues in the Second Transmembrane Domain of the Rat P2X2 Receptor That Affect Spontaneous Gating, Unitary Conductance, and Rectification

Cao, L., Broomhead, H. E., Young, M. T., North, R. A. — Wed, 11 Nov 2009 10:02:14 PST

Membrane ion channels activated by extracellular ATP (P2X receptors) are widely distributed in the nervous system. Their molecular architecture is fundamentally distinct from that of the nicotinic or glutamate receptor families. We have measured single-channel currents, spontaneous gating, and rectification of rat P2X2 receptor in which polar and charged residues of the second transmembrane domain (TM2) were systematically probed by mutagenesis. The results suggest that Asn³³³ and Asp³⁴⁹ lie respectively in external and internal vestibules. Substitutions at Asn³³³, Thr³³⁶, and Ser³⁴⁰ were particularly likely to cause spontaneously active channels. At Thr³³⁶, Thr³³⁹, and Ser³⁴⁰, the introduction of positive charge (Arg, Lys, or His, or Cys followed by treatment with 2-aminoethyl methanethiosulphonate) greatly enhanced outward currents, suggesting that side-chains of these three residues are exposed in the permeation pathway of the open channel. These functional findings are interpreted in the context of the recently reported 3.1 Å crystal structure of the zebrafish P2X4.1 receptor in the closed state. They imply that the gate is formed by residues Asn³³³ to Thr³³⁹ and that channel opening involves a counter-clockwise rotation and separation of the TM2 helices.

Why Sex Matters: Brain Size Independent Differences in Gray Matter Distributions between Men and Women

Luders, E., Gaser, C., Narr, K. L., Toga, A. W. — Wed, 11 Nov 2009 10:02:14 PST

The different brain anatomy of men and women is both a classic and continuing topic of major interest. Among the most replicated and robust sex differences are larger overall brain dimensions in men, and relative increases of global and regional gray matter (GM) in women. However, the question remains whether sex-typical differences in brain size (i.e., larger male and smaller female brains) or biological sex itself account for the observed sex effects on tissue amount and distribution. Exploring cerebral structures in men and women with similar brain size may clarify the true contribution of biological sex. We thus examined a sample of 24 male and 24 female subjects with brains identical in size, in addition to 24 male and 24 female subjects with considerable brain size differences. Using this large set of brains (n = 96), we applied a well validated and automated voxel-based approach to examine regional volumes of GM. While we revealed significant main effects of sex, there were no significant effects of brain size (and no significant interactions between sex and brain size). When conducting post hoc tests, we revealed a number of regions where women had larger GM volumes than men. Importantly, these sex effects remained evident when comparing men and women with the same brain size. Altogether, our findings suggest that the observed increased regional GM volumes in female brains constitute sex-dependent redistributions of tissue volume, rather than individual adjustments attributable to brain size.

A Selective Allosteric Potentiator of the M1 Muscarinic Acetylcholine Receptor Increases Activity of Medial Prefrontal Cortical Neurons and Restores Impairments in Reversal Learning

Wed, 11 Nov 2009 10:02:14 PST

M₁ muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M₁ receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M₁ receptor affinity for acetylcholine. We found that activation of the M₁ receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M₁ receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M₁ receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M₁ receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M₁ mAChR subtype may ameliorate impairments in cognitive function.

Trafficking of Membrane Proteins to Cone But Not Rod Outer Segments Is Dependent on Heterotrimeric Kinesin-II

Wed, 11 Nov 2009 10:02:15 PST

Heterotrimeric kinesin-II is a molecular motor localized to the inner segment, connecting cilium and axoneme of mammalian photoreceptors. Our purpose was to identify the role of kinesin-II in anterograde intraflagellar transport by photoreceptor-specific deletions of kinesin family member 3A (KIF3A), its obligatory motor subunit. In cones lacking KIF3A, membrane proteins involved in phototransduction did not traffic to the outer segments resulting in complete absence of a photopic electroretinogram and progressive cone degeneration. Rod photoreceptors lacking KIF3A degenerated rapidly between 2 and 4 weeks postnatally, but the phototransduction components including rhodopsin trafficked to the outer segments during the course of degeneration. Furthermore, KIF3A deletion did not affect synaptic anterograde trafficking. The results indicate that trafficking of membrane proteins to the outer segment is dependent on kinesin-II in cone, but not rod photoreceptors, even though rods and cones share similar structures, and closely related phototransduction polypeptides.

Glucocorticoid Effects on Memory Consolidation Depend on Functional Interactions between the Medial Prefrontal Cortex and Basolateral Amygdala

Wed, 11 Nov 2009 10:02:15 PST

Considerable evidence indicates that the basolateral complex of the amygdala (BLA) interacts with efferent brain regions in mediating glucocorticoid effects on memory consolidation. Here, we investigated whether glucocorticoid influences on the consolidation of memory for emotionally arousing training depend on functional interactions between the BLA and the medial prefrontal cortex (mPFC), a brain region involved in higher-order cognitive and affective processing. The glucocorticoid receptor (GR) agonist 11β,17β-dihydroxy-6,21-dimethyl-17-pregna-4,6-trien-20yn-3-one (RU 28362) administered unilaterally into the left mPFC of male Sprague Dawley rats immediately after inhibitory avoidance training enhanced 48 h retention performance. An ipsilateral, but not contralateral, lesion of the BLA blocked the memory enhancement. In a second experiment, RU 28362 infused into the mPFC after inhibitory avoidance training increased BLA levels of phosphorylated extracellular signal-regulated kinase 1/2 (pErk1/2). Blockade of this pErk1/2 activity in the BLA with the mitogen-activated protein kinase kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] prevented the memory enhancement, suggesting that GR agonist administration into the mPFC enhances memory consolidation via modulation of BLA activity. Conversely, GR agonist infusions administered into the BLA posttraining increased pErk1/2 levels in the mPFC in regulating memory consolidation. Moreover, as assessed with a two-phase inhibitory avoidance procedure designed to separate modulatory influences on memory of context and footshock, posttraining GR agonist infusions into either the BLA or mPFC enhanced memory of the contextual as well as aversive information acquired during inhibitory avoidance training. These findings indicate that glucocorticoid effects on memory consolidation depend on bidirectional interactions between the BLA and mPFC.

Brn3a and Nurr1 Mediate a Gene Regulatory Pathway for Habenula Development

Quina, L. A., Wang, S., Ng, L., Turner, E. E. — Wed, 11 Nov 2009 10:02:15 PST

The habenula is a dorsal diencephalic structure consisting of medial and lateral subnuclei and a principal output tract, the fasciculus retroflexus, which together form a link between the limbic forebrain and ventral midbrain. Here, we have used microarray and bioinformatic approaches in the mouse to show that the habenula is a distinctive molecular territory of the CNS, with a unique profile of neurotransmitter, ion channel, and regulatory factor expression. Neurons of the medial habenula and part of the lateral habenula express the transcription factor Brn3a/Pou4f1, and Brn3a-expressing habenular neurons project exclusively to the interpeduncular nucleus in the ventral midbrain. In Brn3a mutant embryos, the fasciculus retroflexus is directed appropriately, but habenular neurons fail to innervate their targets. Microarray analysis of Brn3a null embryos shows that this factor regulates an extensive program of habenula-enriched genes, but not generic neural properties. The orphan nuclear receptor Nurr1/Nr4a2 is coexpressed with Brn3a in the developing habenula, is downstream of Brn3a, and mediates expression of a subset of Brn3a-regulated transcripts. Together, these findings begin to define a gene regulatory pathway for habenula development in mammals.

Evidence for Hierarchical Processing in Cat Auditory Cortex: Nonreciprocal Influence of Primary Auditory Cortex on the Posterior Auditory Field

Carrasco, A., Lomber, S. G. — Wed, 11 Nov 2009 10:02:15 PST

The auditory cortex of the cat is composed of 13 distinct fields that have been defined on the basis of anatomy, physiology, and behavior. Although an anatomically based hierarchical processing scheme has been proposed in auditory cortex, few functional studies have examined how these areas influence one another. The purpose of the present study was to examine the bidirectional processing contributions between primary auditory cortex (A1) and the nonprimary posterior auditory field (PAF). Multiunit acute recording techniques in eight mature cats were used to measure neuronal responses to tonal stimuli in A1 or PAF while synaptic activity from PAF or A1 was suppressed with reversible cooling deactivation techniques. Specifically, in four animals, electrophysiological recordings in A1 were conducted before, during, and after deactivation of PAF. Similarly, in the other four animals, PAF activity was measured before, during, and after deactivation of A1. The characteristic frequency, bandwidth, and neuronal threshold were calculated at each receptive field collected and the response strength and response latency measures were calculated from cumulative peristimulus time histograms. Two major changes in PAF response properties were observed during A1 deactivation: a decrease in response strength and a reduction in receptive field bandwidths. In comparison, we did not identify any significant changes in A1 neuronal responses during deactivation of PAF neurons. These findings support proposed models of hierarchal processing in cat auditory cortex.

Neuroprotective and Axon Growth-Promoting Effects following Inflammatory Stimulation on Mature Retinal Ganglion Cells in Mice Depend on Ciliary Neurotrophic Factor and Leukemia Inhibitory Factor

Leibinger, M., Muller, A., Andreadaki, A., Hauk, T. G., Kirsch, M., Fischer, D. — Wed, 11 Nov 2009 10:02:15 PST

After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.

Representation of Cross-Frequency Spatial Phase Relationships in Human Visual Cortex

Henriksson, L., Hyvarinen, A., Vanni, S. — Wed, 11 Nov 2009 10:02:15 PST

An image patch can be locally decomposed into sinusoidal waves of different orientations, spatial frequencies, amplitudes, and phases. The local phase information is essential for perception, because important visual features like edges emerge at locations of maximal local phase coherence. Detection of phase coherence requires integration of spatial frequency information across multiple spatial scales. Models of early visual processing suggest that the visual system should implement phase-sensitive pooling of spatial frequency information in the identification of broadband edges. We used functional magnetic resonance imaging (fMRI) adaptation to look for phase-sensitive neural responses in the human visual cortex. We found sensitivity to the phase difference between spatial frequency components in all studied visual areas, including the primary visual cortex (V1). Control experiments demonstrated that these results were not explained by differences in contrast or position. Next, we compared fMRI responses for broadband compound grating stimuli with congruent and random phase structures. All studied visual areas showed stronger responses for the stimuli with congruent phase structure. In addition, selectivity to phase congruency increased from V1 to higher-level visual areas along both the ventral and dorsal streams. We conclude that human V1 already shows phase-sensitive pooling of spatial frequencies, but only higher-level visual areas might be capable of pooling spatial frequency information across spatial scales typical for broadband natural images.

Local Changes in the Excitability of the Cerebellar Cortex Produce Spatially Restricted Changes in Complex Spike Synchrony

Marshall, S. P., Lang, E. J. — Wed, 11 Nov 2009 10:02:15 PST

Complex spike (CS) synchrony patterns are modulated by the release of GABA within the inferior olive (IO). The GABAergic projection to most of the IO arises from the cerebellar nuclei, which are themselves subject to strong inhibitory control by Purkinje cells in the overlying cortex. Moreover, the connections between the IO and cerebellum are precisely aligned, raising the possibility that each cortical region controls its own CS synchrony distribution. This possibility was tested using multielectrode recordings of CSs and simple spikes (SSs) in crus 2a of anesthetized rats. Picrotoxin or muscimol was applied to the cerebellar cortex at the borders of the recording array. These drugs induced significant changes in CS synchrony and in CS and SS firing rates and changes in post-CS pauses and modulation of SS activity. The level of CS synchrony was correlated with SS firing rate in control, and application of picrotoxin increased both. In contrast, muscimol decreased CS synchrony. Furthermore, when picrotoxin was applied only at the lateral edge of the array, changes in CS synchrony occurred sequentially across the recording array, with cells located in the lateral half of the array having earlier and larger changes in CS synchrony than cells in the medial half. The results indicate that a double-inhibitory feedback circuit from Purkinje cells to the IO provides a mechanism by which SS activity may regulate CS synchrony. Thus, CS synchrony may be a physiologically controlled parameter of cerebellar activity, with the cerebellum and IO comprising a series of self-updating circuits.

Brain Control of Movement Execution Onset Using Local Field Potentials in Posterior Parietal Cortex

Hwang, E. J., Andersen, R. A. — Wed, 11 Nov 2009 10:02:15 PST

The precise control of movement execution onset is essential for safe and autonomous cortical motor prosthetics. A recent study from the parietal reach region (PRR) suggested that the local field potentials (LFPs) in this area might be useful for decoding execution time information because of the striking difference in the LFP spectrum between the plan and execution states (Scherberger et al., 2005). More specifically, the LFP power in the 0–10 Hz band sharply rises while the power in the 20–40 Hz band falls as the state transitions from plan to execution. However, a change of visual stimulus immediately preceded reach onset, raising the possibility that the observed spectral change reflected the visual event instead of the reach onset. Here, we tested this possibility and found that the LFP spectrum change was still time locked to the movement onset in the absence of a visual event in self-paced reaches. Furthermore, we successfully trained the macaque subjects to use the LFP spectrum change as a "go" signal in a closed-loop brain-control task in which the animals only modulated the LFP and did not execute a reach. The execution onset was signaled by the change in the LFP spectrum while the target position of the cursor was controlled by the spike firing rates recorded from the same site. The results corroborate that the LFP spectrum change in PRR is a robust indicator for the movement onset and can be used for control of execution onset in a cortical prosthesis.

Dynorphin Opioid Peptides Enhance Acid-Sensing Ion Channel 1a Activity and Acidosis-Induced Neuronal Death

Sherwood, T. W., Askwith, C. C. — Wed, 11 Nov 2009 10:02:15 PST

Acid-sensing ion channel 1a (ASIC1a) promotes neuronal damage during pathological acidosis. ASIC1a undergoes a process called steady-state desensitization in which incremental pH reductions desensitize the channel and prevent activation when the threshold for acid-dependent activation is reached. We find that dynorphin A and big dynorphin limit steady-state desensitization of ASIC1a and acid-activated currents in cortical neurons. Dynorphin potentiation of ASIC1a activity is independent of opioid or bradykinin receptor activation but is prevented in the presence of PcTx1, a peptide which is known to bind the extracellular domain of ASIC1a. This suggests that dynorphins interact directly with ASIC1a to enhance channel activity. Inducing steady-state desensitization prevents ASIC1a-mediated cell death during prolonged acidosis. This neuroprotection is abolished in the presence of dynorphins. Together, these results define ASIC1a as a new nonopioid target for dynorphin action and suggest that dynorphins enhance neuronal damage following ischemia by preventing steady-state desensitization of ASIC1a.

This Week in The Journal

Wed, 04 Nov 2009 10:02:51 PST

Deciphering the Interaction of the Corticotropin-Releasing Factor and Serotonin Brain Systems in Anxiety-Related Disorders

Homberg, J. R., Contet, C. — Wed, 04 Nov 2009 10:02:51 PST

Brain Gray Matter Decrease in Chronic Pain Is the Consequence and Not the Cause of Pain

Rodriguez-Raecke, R., Niemeier, A., Ihle, K., Ruether, W., May, A. — Wed, 04 Nov 2009 10:02:51 PST

Recently, local morphologic alterations of the brain in areas ascribable to the transmission of pain were reported in patients suffering from chronic pain. Although some authors discussed these findings as damage or loss of brain gray matter, one of the key questions is whether these structural alterations in the cerebral pain-transmitting network precede or succeed the chronicity of pain. We investigated 32 patients with chronic pain due to primary hip osteoarthritis and found a characteristic gray matter decrease in patients compared with controls in the anterior cingulate cortex (ACC), right insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC), amygdala, and brainstem. We then investigated a subgroup of these patients (n = 10) 6 weeks and 4 months after total hip replacement surgery, monitoring whole brain structure. After surgery, all 10 patients were completely pain free and we observed a gray matter increase in the DLPFC, ACC, amygdala, and brainstem. As gray matter decrease is at least partly reversible when pain is successfully treated, we suggest that the gray matter abnormalities found in chronic pain do not reflect brain damage but rather are a reversible consequence of chronic nociceptive transmission, which normalizes when the pain is adequately treated.

Functional Clustering of Neurons in Motor Cortex Determined by Cellular Resolution Imaging in Awake Behaving Mice

Dombeck, D. A., Graziano, M. S., Tank, D. W. — Wed, 04 Nov 2009 10:02:51 PST

Macroscopic (millimeter scale) functional clustering is a hallmark characteristic of motor cortex spatial organization in awake behaving mammals; however, almost no information is known about the functional micro-organization (~100 µm scale). Here, we optically recorded intracellular calcium transients of layer 2/3 neurons with cellular resolution over ~200-µm-diameter fields in the forelimb motor cortex of mobile, head-restrained mice during two distinct movements (running and grooming). We showed that the temporal correlation between neurons was statistically larger the closer the neurons were to each other. We further explored this correlation by using two separate methods to spatially segment the neurons within each imaging field: K-means clustering and correlations between single neuron activity and mouse movements. The two methods segmented the neurons similarly and led to the conclusion that the origin of the inverse relationship between correlation and distance seen statistically was twofold: clusters of highly temporally correlated neurons were often spatially distinct from one another, and (even when the clusters were spatially intermingled) within the clusters, the more correlated the neurons were to each other, the shorter the distance between them. Our results represent a direct observation of functional clustering within the microcircuitry of the awake mouse motor cortex.

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood-Brain Barrier and Provides Neuroprotection

Wed, 04 Nov 2009 10:02:51 PST

Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood–brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre- or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.

Reliability and Precision of the Mouse Calyx of Held Synapse

Lorteije, J. A. M., Rusu, S. I., Kushmerick, C., Borst, J. G. G. — Wed, 04 Nov 2009 10:02:51 PST

Traditionally, the calyx of Held synapse is viewed as a highly reliable relay in the sound localization circuit of the auditory brainstem, with every presynaptic action potential triggering a postsynaptic action potential in vivo. However, this view is at odds with slice recordings that report large short-term depression (STD). To investigate the reliability and precision of this synapse, we compared slice and in vivo recordings from medial nucleus of the trapezoid body neurons of young adult mice. We show that the extracellularly recorded complex waveform can be used to estimate both presynaptic release and postsynaptic excitability. Whereas under standard slice conditions the synapse underwent large STD, both extracellular and whole-cell recordings indicated that in vivo the size of the EPSPs was independent of recent history. The estimated quantal content was typically <20 in vivo, much lower than in the resting synapse under standard slice conditions. However, due to the large quantal size and summation of EPSPs, the safety factor of this synapse was generally still sufficiently large and postsynaptic failures were observed only infrequently in vivo. When present, failures were typically due to stochastic fluctuations in EPSP size or postsynaptic spike depression. In vivo, the calyx of Held synapse thus functions as a tonic synapse. The price it pays for its low release probability is an increase in jitter and synaptic latency and occasional postsynaptic failures.

From Neurons to Circuits: Linear Estimation of Local Field Potentials

Rasch, M., Logothetis, N. K., Kreiman, G. — Wed, 04 Nov 2009 10:02:51 PST

Extracellular physiological recordings are typically separated into two frequency bands: local field potentials (LFPs) (a circuit property) and spiking multiunit activity (MUA). Recently, there has been increased interest in LFPs because of their correlation with functional magnetic resonance imaging blood oxygenation level-dependent measurements and the possibility of studying local processing and neuronal synchrony. To further understand the biophysical origin of LFPs, we asked whether it is possible to estimate their time course based on the spiking activity from the same electrode or nearby electrodes. We used "signal estimation theory" to show that a linear filter operation on the activity of one or a few neurons can explain a significant fraction of the LFP time course in the macaque monkey primary visual cortex. The linear filter used to estimate the LFPs had a stereotypical shape characterized by a sharp downstroke at negative time lags and a slower positive upstroke for positive time lags. The filter was similar across different neocortical regions and behavioral conditions, including spontaneous activity and visual stimulation. The estimations had a spatial resolution of ~1 mm and a temporal resolution of ~200 ms. By considering a causal filter, we observed a temporal asymmetry such that the positive time lags in the filter contributed more to the LFP estimation than the negative time lags. Additionally, we showed that spikes occurring within ~10 ms of spikes from nearby neurons yielded better estimation accuracies than nonsynchronous spikes. In summary, our results suggest that at least some circuit-level local properties of the field potentials can be predicted from the activity of one or a few neurons.

Dynamic Range Adaptation to Sound Level Statistics in the Auditory Nerve

Wen, B., Wang, G. I., Dean, I., Delgutte, B. — Wed, 04 Nov 2009 10:02:51 PST

The auditory system operates over a vast range of sound pressure levels (100–120 dB) with nearly constant discrimination ability across most of the range, well exceeding the dynamic range of most auditory neurons (20–40 dB). Dean et al. (2005) have reported that the dynamic range of midbrain auditory neurons adapts to the distribution of sound levels in a continuous, dynamic stimulus by shifting toward the most frequently occurring level. Here, we show that dynamic range adaptation, distinct from classic firing rate adaptation, also occurs in primary auditory neurons in anesthetized cats for tone and noise stimuli. Specifically, the range of sound levels over which firing rates of auditory nerve (AN) fibers grows rapidly with level shifts nearly linearly with the most probable levels in a dynamic sound stimulus. This dynamic range adaptation was observed for fibers with all characteristic frequencies and spontaneous discharge rates. As in the midbrain, dynamic range adaptation improved the precision of level coding by the AN fiber population for the prevailing sound levels in the stimulus. However, dynamic range adaptation in the AN was weaker than in the midbrain and not sufficient (0.25 dB/dB, on average, for broadband noise) to prevent a significant degradation of the precision of level coding by the AN population above 60 dB SPL. These findings suggest that adaptive processing of sound levels first occurs in the auditory periphery and is enhanced along the auditory pathway.

Reference Frame of the Ventriloquism Aftereffect

Kopco, N., Lin, I-F., Shinn-Cunningham, B. G., Groh, J. M. — Wed, 04 Nov 2009 10:02:51 PST

Seeing the image of a newscaster on a television set causes us to think that the sound coming from the loudspeaker is actually coming from the screen. How images capture sounds is mysterious because the brain uses different methods for determining the locations of visual versus auditory stimuli. The retina senses the locations of visual objects with respect to the eyes, whereas differences in sound characteristics across the ears indicate the locations of sound sources referenced to the head. Here, we tested which reference frame (RF) is used when vision recalibrates perceived sound locations. Visually guided biases in sound localization were induced in seven humans and two monkeys who made eye movements to auditory or audiovisual stimuli. On audiovisual (training) trials, the visual component of the targets was displaced laterally by 5–6°. Interleaved auditory-only (probe) trials served to evaluate the effect of experience with mismatched visual stimuli on auditory localization. We found that the displaced visual stimuli induced ventriloquism aftereffect in both humans (~50% of the displacement size) and monkeys (~25%), but only for locations around the trained spatial region, showing that audiovisual recalibration can be spatially specific. We tested the reference frame in which the recalibration occurs. On probe trials, we varied eye position relative to the head to dissociate head- from eye-centered RFs. Results indicate that both humans and monkeys use a mixture of the two RFs, suggesting that the neural mechanisms involved in ventriloquism occur in brain region(s) using a hybrid RF for encoding spatial information.

The Responses of Visual Neurons in the Frontal Eye Field Are Biased for Saccades

Lawrence, B. M., Snyder, L. H. — Wed, 04 Nov 2009 10:02:51 PST

Previous research suggests that visually responsive neurons in the frontal eye field (FEF) respond to visual targets even when they are not the goal of a saccadic eye movement. These results raise the possibility that these neurons respond to visual targets independent of the effector that is to be used to acquire the target locations. In the present study, we examined whether a plan to execute a saccade or a reach to a visual target influenced the response to and the representation of targets in the FEF. We recorded single unit responses to the onset of the target, during the delay period, and around the time of the movement, on interleaved saccade and reach trials of a delayed-response task. We found that the responses of approximately equal percentages of visual, visuomovement, and movement neurons (50%, 58%, and 58%, respectively) were greater on saccade trials than on reach trials in at least one interval of the delayed-response task. Converse biases, in favor of reaches, were much less frequent (13%, 10%, and 19%, in visual, visuomovement, and movement neurons respectively). Thus, although visual neurons may not be directly involved in triggering saccadic eye movements, they are nonetheless highly saccade-biased, with percentages comparable to neurons that are directly involved in triggering saccadic eye movements.

Estrogen Attenuates Ischemic Oxidative Damage via an Estrogen Receptor {alpha}-Mediated Inhibition of NADPH Oxidase Activation

Wed, 04 Nov 2009 10:02:51 PST

The goal of this study was to elucidate the mechanisms of 17β-estradiol (E₂) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E₂ during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E₂ neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide production in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor (ER)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/inactivation of Rac1, a factor critical for activation of NOX2 NADPH oxidase. Intriguingly, E₂ nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E₂ deprivation, and this loss was tissue specific because the uterus remained responsive to E₂. Correspondingly, a remarkable loss of ER, but not ERβ, was observed in the CA1 after long-term E₂ deprivation, with no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E₂ provides support and mechanistic insights for a "critical period" of E₂ replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.

Correlating Stimulus-Specific Adaptation of Cortical Neurons and Local Field Potentials in the Awake Rat

von der Behrens, W., Bauerle, P., Kossl, M., Gaese, B. H. — Wed, 04 Nov 2009 10:02:51 PST

Changes in the sensory environment are good indicators for behaviorally relevant events and strong triggers for the reallocation of attention. In the auditory domain, violations of a pattern of repetitive stimuli precipitate in the event-related potentials as mismatch negativity (MMN). Stimulus-specific adaptation (SSA) of single neurons in the auditory cortex has been proposed to be the cellular substrate of MMN (Nelken and Ulanovsky, 2007). However, until now, the existence of SSA in the awake auditory cortex has not been shown. In the present study, we recorded single and multiunits in parallel with evoked local field potentials (eLFPs) in the primary auditory cortex of the awake rat. Both neurons and eLFPs in the awake animal adapted in a stimulus-specific manner, and SSA was controlled by stimulus probability and frequency separation. SSA of isolated units was significant during the first stimulus-evoked "on" response but not in the following inhibition and rebound of activity. The eLFPs exhibited SSA in the first negative deflection and, to a lesser degree, in a slower positive deflection but no MMN. Spike adaptation correlated closely with adaptation of the fast negative deflection but not the positive deflection. Therefore, we conclude that single neurons in the auditory cortex of the awake rat adapt in a stimulus-specific manner and contribute to corresponding changes in eLFP but do not generate a late deviant response component directly equivalent to the human MMN. Nevertheless, the described effect may reflect a certain part of the process needed for sound discrimination.

Reticulon-4A (Nogo-A) Redistributes Protein Disulfide Isomerase to Protect Mice from SOD1-Dependent Amyotrophic Lateral Sclerosis

Yang, Y. S., Harel, N. Y., Strittmatter, S. M. — Wed, 04 Nov 2009 10:02:51 PST

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease inherited in a small subset of patients. The SOD1(G93A) transgenic mouse models this subset of patients, and studies of this strain have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. Here, we demonstrate that the reticulon family of proteins is a novel regulator of the ER chaperone protein disulfide isomerase (PDI), and that through PDI, reticulon-4A (Nogo-A) can protect mice against the neurodegeneration that characterizes ALS. We show that overexpressing reticulon protein induces a punctate redistribution of PDI intracellularly, both in vitro and in vivo. Conversely, reduction of endogenous NogoA expression causes a more homogeneous expression pattern in vivo. These effects occur without induction of the unfolded protein response. To examine the effect of PDI redistribution on ALS disease progression, we conducted survival and behavior studies of SOD1(G93A) mice. Deletion of a single copy of the NogoA,B gene accelerates disease onset and progression, while deletion of both copies further worsens disease. We conclude that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS.

Two Classes of GABAergic Neurons in the Inferior Colliculus

Ito, T., Bishop, D. C., Oliver, D. L. — Wed, 04 Nov 2009 10:02:51 PST

The inferior colliculus (IC) is unique, having both glutamatergic and GABAergic projections ascending to the thalamus. Although subpopulations of GABAergic neurons in the IC have been proposed, criteria to distinguish them have been elusive and specific types have not been associated with specific neural circuits. Recently, the largest IC neurons were found to be recipients of somatic terminals containing vesicular glutamate transporter 2 (VGLUT2). Here, we show with electron microscopy that VGLUT2-positive (VGLUT2⁺) axonal terminals make axosomatic synapses on IC neurons. These terminals contain only VGLUT2 even though others in the IC have VGLUT1 or both VGLUT1 and 2. We demonstrate that there are two types of GABAergic neurons: larger neurons with VGLUT2⁺ axosomatic endings and smaller neurons without such endings. Both types are present in all subdivisions of the IC, but larger GABAergic neurons with VGLUT2⁺ axosomatic terminals are most prevalent in the central nucleus. The GABAergic tectothalamic neurons consist almost entirely of the larger cells surrounded by VGLUT2⁺ axosomatic endings. Thus, two types of GABAergic neurons in the IC are defined by different synaptic organization and neuronal connections. Larger tectothalamic GABAergic neurons are covered with glutamatergic axosomatic synapses that could allow them to fire rapidly and overcome a slow membrane time constant; their axons may be the largest in the brachium of the IC. Thus, large GABAergic neurons could deliver IPSPs to the medial geniculate body before EPSPs from glutamatergic IC neurons firing simultaneously.

Dynamic Encoding of Movement Direction in Motor Cortical Neurons

Rickert, J., Riehle, A., Aertsen, A., Rotter, S., Nawrot, M. P. — Wed, 04 Nov 2009 10:02:51 PST

When we perform a skilled movement such as reaching for an object, we can make use of prior information, for example about the location of the object in space. This helps us to prepare the movement, and we gain improved accuracy and speed during movement execution. Here, we investigate how prior information affects the motor cortical representation of movements during preparation and execution. We trained two monkeys in a delayed reaching task and provided a varying degree of prior information about the final target location. We decoded movement direction from multiple single-unit activity recorded from M1 (primary motor cortex) in one monkey and from PMd (dorsal premotor cortex) in a second monkey. Our results demonstrate that motor cortical cells in both areas exhibit individual encoding characteristics that change dynamically in time and dependent on prior information. On the population level, the information about movement direction is at any point in time accurately represented in a neuronal ensemble of time-varying composition. We conclude that movement representation in the motor cortex is not a static one, but one in which neurons dynamically allocate their computational resources to meet the demands defined by the movement task and the context of the movement. Consequently, we find that the decoding accuracy decreases if the precise task time, or the previous information that was available to the monkey, were disregarded in the decoding process. An optimal strategy for the readout of movement parameters from motor cortex should therefore take into account time and contextual parameters.

Neuroligin-2 Deletion Selectively Decreases Inhibitory Synaptic Transmission Originating from Fast-Spiking but Not from Somatostatin-Positive Interneurons

Gibson, J. R., Huber, K. M., Sudhof, T. C. — Wed, 04 Nov 2009 10:02:51 PST

Neuroligins are cell adhesion molecules involved in synapse formation and/or function. Neurons express four neuroligins (NL1–NL4), of which NL1 is specific to excitatory and NL2 to inhibitory synapses. Excitatory and inhibitory synapses include numerous subtypes. However, it is unknown whether NL1 performs similar functions in all excitatory and NL2 in all inhibitory synapses, or whether they regulate the formation and/or function of specific subsets of synapses. To address this central question, we performed paired recordings in primary somatosensory cortex of mice lacking NL1 or NL2. Using this system, we examined neocortical microcircuits formed by reciprocal synapses between excitatory neurons and two subtypes of inhibitory interneurons, namely, fast-spiking and somatostatin-positive interneurons. We find that the NL1 deletion had little effect on inhibitory synapses, whereas the NL2 deletion decreased (40–50%) the unitary (cell-to-cell) IPSC amplitude evoked from single fast-spiking interneurons. Strikingly, the NL2 deletion had no effect on IPSC amplitude evoked from single somatostatin-positive inhibitory interneurons. Moreover, the frequency of unitary synaptic connections between individual fast-spiking and somatostatin-positive interneurons and excitatory neurons was unchanged. The decrease in unitary IPSC amplitude originating from fast-spiking interneurons in NL2-deficient mice was due to a multiplicative and uniform downscaling of the amplitude distribution, which in turn was mediated by a decrease in both synaptic quantal amplitude and quantal content, the latter inferred from an increase in the coefficient of variation. Thus, NL2 is not necessary for establishing unitary inhibitory synaptic connections but is selectively required for "scaling up" unitary connections originating from a subset of interneurons.

Main Immunogenic Region Structure Promotes Binding of Conformation-Dependent Myasthenia Gravis Autoantibodies, Nicotinic Acetylcholine Receptor Conformation Maturation, and Agonist Sensitivity

Luo, J., Taylor, P., Losen, M., de Baets, M. H., Shelton, G. D., Lindstrom, J. — Wed, 04 Nov 2009 10:02:51 PST

The main immunogenic region (MIR) is a conformation-dependent region at the extracellular apex of 1 subunits of muscle nicotinic acetylcholine receptor (AChR) that is the target of half or more of the autoantibodies to muscle AChRs in human myasthenia gravis and rat experimental autoimmune myasthenia gravis. By making chimeras of human 1 subunits with 7 subunits, both MIR epitopes recognized by rat mAbs and by the patient-derived human mAb 637 to the MIR were determined to consist of two discontiguous sequences, which are adjacent only in the native conformation. The MIR, including loop 1 67–76 in combination with the N-terminal helix 1 1–14, conferred high-affinity binding for most rat mAbs to the MIR. However, an additional sequence corresponding to 1 15–32 was required for high-affinity binding of human mAb 637. A water soluble chimera of Aplysia acetylcholine binding protein with the same 1 MIR sequences substituted was recognized by a majority of human, feline, and canine myasthenia gravis sera. The presence of the 1 MIR sequences in 1/7 chimeras greatly promoted AChR expression and significantly altered the sensitivity to activation. This reveals a structural and functional, as well as antigenic, significance of the MIR.

Autocrine and Paracrine Roles for ATP and Serotonin in Mouse Taste Buds

Huang, Y. A., Dando, R., Roper, S. D. — Wed, 04 Nov 2009 10:02:51 PST

Receptor (type II) taste bud cells secrete ATP during taste stimulation. In turn, ATP activates adjacent presynaptic (type III) cells to release serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE). The roles of these neurotransmitters in taste buds have not been fully elucidated. Here we tested whether ATP or 5-HT exert feedback onto receptor (type II) cells during taste stimulation. Our previous studies showed NE does not appear to act on adjacent taste bud cells, or at least on receptor cells. Our data show that 5-HT released from presynaptic (type III) cells provides negative paracrine feedback onto receptor cells by activating 5-HT_1A receptors, inhibiting taste-evoked Ca²⁺ mobilization in receptor cells, and reducing ATP secretion. The findings also demonstrate that ATP exerts positive autocrine feedback onto receptor (type II) cells by activating P2Y1 receptors and enhancing ATP secretion. These results begin to sort out how purinergic and aminergic transmitters function within the taste bud to modulate gustatory signaling in these peripheral sensory organs.

Selective Targeting of the Dendrites of Corticothalamic Cells by Thalamic Afferents in Area 17 of the Cat

da Costa, N. M., Martin, K. A. C. — Wed, 04 Nov 2009 10:02:51 PST

Pyramidal cells of layer 6 in cat visual cortex are the source of the corticothalamic projection, and their recurrent collaterals provide substantially more excitatory synapses in layer 4 than does the thalamic input. They have predominantly simple receptive fields and can be driven monosynaptically by electrically stimulating thalamic relay cells. Layer 6 cells could thus provide a significant disynaptic amplification of the thalamic input to layer 4, particularly since their synapses facilitate, unlike the thalamic afferents whose synapses depress. However, purely geometric considerations of the relation of their dendritic trees to the thalamic input indicate that they should form a far smaller number of synapses with thalamic afferents than do the simple cells of layer 4. We thus analyzed quantitatively the thalamic input to identified corticothalamic cells by labeling the thalamic afferents and corticothalamic cells in vivo. We made a correlated light and electron microscopic study of 73 "contacts" between thalamic afferents and five corticothalamic cells. The electron microscope revealed that only 24 of the contacts identified at light microscope level were indeed synapses and, contrary to geometric predictions, virtually all were located on spines on the basal dendrites. Our quantitative estimates indicate that the corticothalamic cells form even fewer synapses with the thalamic afferents than predicted by geometric considerations and only 1/10 as many as do the layer 4 simple cells. These data strongly suggest it is the collective computation of cortical neurons, not the monosynaptic thalamic input, that determines the output of the corticothalamic cells.

Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability

Wed, 04 Nov 2009 10:02:51 PST

The effects of lifelong, moderate excess release of glutamate (Glu) in the CNS have not been previously characterized. We created a transgenic (Tg) mouse model of lifelong excess synaptic Glu release in the CNS by introducing the gene for glutamate dehydrogenase 1 (Glud1) under the control of the neuron-specific enolase promoter. Glud1 is, potentially, an important enzyme in the pathway of Glu synthesis in nerve terminals. Increased levels of GLUD protein and activity in CNS neurons of hemizygous Tg mice were associated with increases in the in vivo release of Glu after neuronal depolarization in striatum and in the frequency and amplitude of miniature EPSCs in the CA1 region of the hippocampus. Despite overexpression of Glud1 in all neurons of the CNS, the Tg mice suffered neuronal losses in select brain regions (e.g., the CA1 but not the CA3 region). In vulnerable regions, Tg mice had decreases in MAP2A labeling of dendrites and in synaptophysin labeling of presynaptic terminals; the decreases in neuronal numbers and dendrite and presynaptic terminal labeling increased with advancing age. In addition, the Tg mice exhibited decreases in long-term potentiation of synaptic activity and in spine density in dendrites of CA1 neurons. Behaviorally, the Tg mice were significantly more resistant than wild-type mice to induction and duration of anesthesia produced by anesthetics that suppress Glu neurotransmission. The Glud1 mouse might be a useful model for the effects of lifelong excess synaptic Glu release on CNS neurons and for age-associated neurodegenerative processes.

The Nitric Oxide/cGMP Pathway Tunes the Thermosensitivity of Swimming Motor Patterns in Xenopus laevis Tadpoles

Robertson, R. M., Sillar, K. T. — Wed, 04 Nov 2009 10:02:51 PST

We investigated the role of the nitric oxide (NO)/cGMP pathway in setting thresholds for failure and recovery during hyperthermic stress of the swimming central pattern generator of immobilized Xenopus tadpoles (stage 42). We recorded swimming motor patterns induced by tail skin stimulation (TS) (1 ms current pulse) or by bath application of 50 µm NMDA. Swimming rhythm frequency increased in a linear manner with increasing temperature. In the presence of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), recovery from hyperthermic failure was greatly slowed, often taking longer than the duration of the experiment. Pharmacological activation of the NO/cGMP pathway using SNAP or 8-bromo-cGMP (1) decreased the duration of TS-evoked swim episodes; (2) decreased the temperature threshold for hyperthermic circuit failure; (3) decreased the temperature at which the circuit recovered; and (4) increased the time taken to recover. Pharmacological inhibition of the NO/cGMP pathway using the NO scavenger CPTIO, the nitric oxide synthase (NOS) inhibitor l-NAME or the guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) had the opposite effects. NMDA rhythms were more resistant to hyperthermic failure than TS-evoked swim episodes, but the effects of SNAP on the temperature sensitivity of swimming evoked by NMDA were similar to those on TS-evoked swimming, suggesting that drug effects occur on central pattern-generating networks rather than sensory pathways. We conclude that the NO/cGMP pathway is involved in setting the threshold temperatures for hyperthermic failure and subsequent recovery of fictive swimming in tadpoles, and we suggest that this is part of a variable response to prevent overexcitation during abiotic stress under different environmental conditions.

Decreased Firing of Striatal Neurons Related to Licking during Acquisition and Overtraining of a Licking Task

Wed, 04 Nov 2009 10:02:51 PST

Neurons that fire in relation to licking, in the ventral part of the dorsolateral striatum (DLS), were studied during acquisition and performance of a licking task in rats for 14 sessions (2 h/d). Task learning was indicated by fewer errors of omission of licking and improved movement efficiency (i.e., shorter lick duration) over sessions. Number of licks did not change over sessions. Overtraining did not result in habit formation, as indicated by similar reductions of licking responses following devaluation by satiety in both early and late sessions. Twenty-nine lick neurons recorded and tracked over sessions exhibited a significant linear decrease in average firing rate across all neurons over sessions, correlating with concurrent declines in lick duration. Individually, most neurons (86%) exhibited decreased firing rates, while a small proportion (14%) exhibited increased firing rates, during lick movements that were matched over sessions. Reward manipulations did not alter firing patterns over sessions. Aside from the absence of habit formation, striatal processing during unconditioned movements (i.e., licking) was characterized by high activity of movement-related neurons during early performance and decreased activity of the same neurons during overtraining, similar to our previous report of head movement neurons during acquired, skilled, instrumental head movements that ultimately became habitual (Tang et al., 2007). Decreased activity in DLS neurons may reflect a common neural mechanism underlying improvement in movement efficiency with overtraining. Nonetheless, the decreased striatal firing in relation to a movement that did not become habitual demonstrates that not all DLS changes reflect habit formation.

Stimulus-Induced and State-Dependent Sustained Gamma Activity Is Tightly Coupled to the Hemodynamic Response in Humans

Koch, S. P., Werner, P., Steinbrink, J., Fries, P., Obrig, H. — Wed, 04 Nov 2009 10:02:51 PST

A prompt behavioral response to a stimulus depends both on the salience of the stimulus as well as the subject's preparedness. Thus, both stimulus properties and cognitive factors, such as attention, may determine the strength of neuronal synchronization in the gamma range. For a comprehensive investigation of stimulus–response processing through noninvasive imaging, it is, however, a crucial issue whether both kinds of gamma modulation elicit a hemodynamic response. Here, we show that, in the human visual cortex, stimulus strength and internal state modulate sustained gamma activity and hemodynamic response in close correspondence. When participants reported velocity changes of gratings varying in contrast, gamma activity (35–70 Hz) increased systematically with contrast. For stimuli of constant contrast, the amplitude of gamma activity before the behaviorally relevant velocity change was inversely correlated to the behavioral response latency. This indicates that gamma activity also reflects an overall attentive state. For both sources of variance, gamma activity was tightly coupled to the hemodynamic response measured through optical topography. Because of the close relationship between high-frequency neuronal activity and the hemodynamic signal, we conclude that both stimulus-induced and state-dependent gamma activity trigger a metabolic demand and are amenable to vascular-based imaging.

Phosphorylation of Ezrin/Radixin/Moesin Proteins by LRRK2 Promotes the Rearrangement of Actin Cytoskeleton in Neuronal Morphogenesis

Wed, 04 Nov 2009 10:02:51 PST

Leucine-rich repeat kinase 2 (LRRK2) functions as a putative protein kinase of ezrin, radixin, and moesin (ERM) family proteins. A Parkinson's disease-related G2019S substitution in the kinase domain of LRRK2 further enhances the phosphorylation of ERM proteins. The phosphorylated ERM (pERM) proteins are restricted to the filopodia of growing neurites in which they tether filamentous actin (F-actin) to the cytoplasmic membrane and regulate the dynamics of filopodia protrusion. Here, we show that, in cultured neurons derived from LRRK2 G2019S transgenic mice, the number of pERM-positive and F-actin-enriched filopodia was significantly increased, and this correlates with the retardation of neurite outgrowth. Conversely, deletion of LRRK2, which lowered the pERM and F-actin contents in filopodia, promoted neurite outgrowth. Furthermore, inhibition of ERM phosphorylation or actin polymerization rescued the G2019S-dependent neuronal growth defects. These data support a model in which the G2019S mutation of LRRK2 causes a gain-of-function effect that perturbs the homeostasis of pERM and F-actin in sprouting neurites critical for neuronal morphogenesis.

Retinotopic Mapping Requires Focal Adhesion Kinase-Mediated Regulation of Growth Cone Adhesion

Woo, S., Rowan, D. J., Gomez, T. M. — Wed, 04 Nov 2009 10:02:51 PST

Adhesion controls growth cone motility, yet the effects of axon guidance cues on adhesion site dynamics are poorly understood. Here we show that ephrin-A1 reduces retinal ganglion cell (RGC) axon outgrowth by stabilizing existing adhesions and inhibiting new adhesion assembly. Ephrin-A1 activates focal adhesion kinase (FAK) in an integrin- and Src-dependent manner and the effects of ephrin-A1 on growth cone motility require FAK activation. We also find that FAK is expressed in a high temporal to low nasal gradient in RGCs, similar to EphA receptors, and that balanced FAK activation is necessary for optimal axon outgrowth. Last, we find that FAK is required for proper topographic positioning of retinal axons along the anterior–posterior axis of the optic tectum in both Xenopus and zebrafish, a guidance decision mediated in part by A-type ephrins. Together, our data suggest that ephrin-A1 controls growth cone advance by modulating adhesive point contacts through FAK activation and that graded FAK signaling is an important component of ephrin-A-mediated retinotopic mapping.

Decoding and Reconstructing Color from Responses in Human Visual Cortex

Brouwer, G. J., Heeger, D. J. — Wed, 04 Nov 2009 10:02:51 PST

How is color represented by spatially distributed patterns of activity in visual cortex? Functional magnetic resonance imaging responses to several stimulus colors were analyzed with multivariate techniques: conventional pattern classification, a forward model of idealized color tuning, and principal component analysis (PCA). Stimulus color was accurately decoded from activity in V1, V2, V3, V4, and VO1 but not LO1, LO2, V3A/B, or MT+. The conventional classifier and forward model yielded similar accuracies, but the forward model (unlike the classifier) also reliably reconstructed novel stimulus colors not used to train (specify parameters of) the model. The mean responses, averaged across voxels in each visual area, were not reliably distinguishable for the different stimulus colors. Hence, each stimulus color was associated with a unique spatially distributed pattern of activity, presumably reflecting the color selectivity of cortical neurons. Using PCA, a color space was derived from the covariation, across voxels, in the responses to different colors. In V4 and VO1, the first two principal component scores (main source of variation) of the responses revealed a progression through perceptual color space, with perceptually similar colors evoking the most similar responses. This was not the case for any of the other visual cortical areas, including V1, although decoding was most accurate in V1. This dissociation implies a transformation from the color representation in V1 to reflect perceptual color space in V4 and VO1.

Range-Adapting Representation of Economic Value in the Orbitofrontal Cortex

Padoa-Schioppa, C. — Wed, 04 Nov 2009 10:02:51 PST

While making economic choices, individuals assign subjective values to the available options. Values computed in different behavioral conditions, however, can vary substantially. The same person might choose some times between goods worth a few dollars, and other times between goods worth thousands of dollars, or more. How does the brain system that computes values—the "valuation system"—handle this large variability? Here we show that the representation of value in the orbitofrontal cortex (OFC), an area implicated in value assignment during economic choice, adapts to the behavioral condition of choice and, more specifically, to the range of values available in any given condition. In the experiments, monkeys chose between different juices and their choice patterns provided a measure of subjective value. Value ranges were varied from session to session and, in each session, OFC neurons encoded values in a linear way. Across the population, the neuronal sensitivity (defined as the change in neuronal activity elicited by the increase in one value unit) was inversely proportional to the value range. Conversely, the neuronal activity range did not depend on the value range. This phenomenon of range adaptation complements that of menu invariance observed in a previous study. Indeed, the activity of each neuron adapts to the range values it encodes but does not depend on other available goods. Our results thus suggest that the representation of value in the OFC is at one time instantiative of preference transitivity (menu invariance) and computationally efficient (range adaptation).

Enduring Reversal of Neuropathic Pain by a Single Intrathecal Injection of Adenosine 2A Receptor Agonists: A Novel Therapy for Neuropathic Pain

Wed, 04 Nov 2009 10:02:51 PST

Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A_2ARs) decrease proinflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain and that IL-10 can suppress such pain, we evaluated the effects of intrathecally administered A_2AR agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A_2AR agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680), 10–14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks. Neither drug altered the nociceptive responses of sham-operated controls. An A_2AR antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A_2AR agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4–L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration. Neutralizing IL-10 antibodies administered intrathecally transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A_2ARs after intrathecal administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.

Visual Learning Shapes the Processing of Complex Movement Stimuli in the Human Brain

Jastorff, J., Kourtzi, Z., Giese, M. A. — Wed, 04 Nov 2009 10:02:51 PST

Recognition of actions and complex movements is fundamental for social interactions and action understanding. While the relationship between motor expertise and visual recognition of body movements has received a vast amount of interest, the role of visual learning remains largely unexplored. Combining psychophysics and functional magnetic resonance imaging (fMRI) experiments, we investigated neural correlates of visual learning of complex movements. Subjects were trained to visually discriminate between very similar complex movement stimuli generated by motion morphing that were either compatible (experiments 1 and 2) or incompatible (experiment 3) with human movement execution. Employing an fMRI adaptation paradigm as index of discriminability, we scanned human subjects before and after discrimination training. The results of experiment 1 revealed three different effects as a consequence of training: (1) Emerging fMRI-selective adaptation in general motion-related areas (hMT/V5+, KO/V3b) for the differences between human-like movements. (2) Enhanced of fMRI-selective adaptation already present before training in biological motion-related areas (pSTS, FBA). (3) Changes covarying with task difficulty in frontal areas. Moreover, the observed activity changes were specific to the trained movement patterns (experiment 2). The results of experiment 3, testing artificial movement stimuli, were strikingly similar to the results obtained for human movements. General and biological motion-related areas showed movement-specific changes in fMRI-selective adaptation for the differences between the stimuli after training. These results support the existence of a powerful visual machinery for the learning of complex motion patterns that is independent of motor execution. We thus propose a key role of visual learning in action recognition.

Inositol 1,4,5-Trisphosphate 3-Kinase A Functions As a Scaffold for Synaptic Rac Signaling

Wed, 04 Nov 2009 10:02:51 PST

Activity-dependent alterations of synaptic contacts are crucial for synaptic plasticity. The formation of new dendritic spines and synapses is known to require actin cytoskeletal reorganization specifically during neural activation phases. Yet the site-specific and time-dependent mechanisms modulating actin dynamics in mature neurons are not well understood. In this study, we show that actin dynamics in spines is regulated by a Rac anchoring and targeting function of inositol 1,4,5-trisphosphate 3-kinase A (IP₃K-A), independent of its kinase activity. On neural activation, IP₃K-A bound directly to activated Rac1 and recruited it to the actin cytoskeleton in the postsynaptic area. This focal targeting of activated Rac1 induced spine formation through actin dynamics downstream of Rac signaling. Consistent with the scaffolding role of IP₃K-A, IP₃K-A knock-out mice exhibited defects in accumulation of PAK1 by long-term potentiation-inducing stimulation. This deficiency resulted in a reduction in the reorganization of actin cytoskeletal structures in the synaptic area of dentate gyrus. Moreover, IP₃K-A knock-out mice showed deficits of synaptic plasticity in perforant path and in hippocampal-dependent memory performances. These data support a novel model in which IP₃K-A is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism.

Sleep Deprivation Differentially Impairs Cognitive Performance in Abstinent Methylenedioxymethamphetamine ("Ecstasy") Users

McCann, U. D., Wilson, M. J., Sgambati, F. P., Ricaurte, G. A. — Wed, 04 Nov 2009 10:02:51 PST

Methylenedioxymethamphetamine (MDMA; "Ecstasy") is a popular recreational drug and brain serotonin (5-HT) neurotoxin. Neuroimaging data indicate that some human MDMA users develop persistent deficits in brain 5-HT neuronal markers. Although the consequences of MDMA-induced 5-HT neurotoxicity are not fully understood, abstinent MDMA users have been found to have subtle cognitive deficits and altered sleep architecture. The present study sought to test the hypothesis that sleep disturbance plays a role in cognitive deficits in MDMA users. Nineteen abstinent MDMA users and 21 control subjects participated in a 5 d inpatient study in a clinical research unit. Baseline sleep quality was measured using the Pittsburgh Sleep Quality Inventory. Cognitive performance was tested three times daily using a computerized cognitive battery. On the third day of admission, subjects began a 40 h sleep deprivation period and continued cognitive testing using the same daily schedule. At baseline, MDMA users performed less accurately than controls on a task of working memory and more impulsively on four of the seven computerized tests. During sleep deprivation, MDMA users, but not controls, became increasingly impulsive, performing more rapidly at the expense of accuracy on tasks of working and short-term memory. Tests of mediation implicated baseline sleep disturbance in the cognitive decline seen during sleep deprivation. These findings are the first to demonstrate that memory problems in MDMA users may be related, at least in part, to sleep disturbance and suggest that cognitive deficits in MDMA users may become more prominent in situations associated with sleep deprivation.

This Week in The Journal

Wed, 28 Oct 2009 10:32:16 PDT

Correction for Koichi Obata et al., Suppression of the p75 Neurotrophin Receptor in Uninjured Sensory Neurons Reduces Neuropathic Pain after Nerve Injury

Wed, 28 Oct 2009 10:32:16 PDT

Are the Boundary-Related Cells in the Subiculum Boundary-Vector Cells?

Derdikman, D. — Wed, 28 Oct 2009 10:32:16 PDT

Prelimbic Prefrontal Neurons Drive Fear Expression: A Clue for Extinction-Reconsolidation Interactions

Schiller, D., Johansen, J. — Wed, 28 Oct 2009 10:32:16 PDT

Identification of Two Distinct Macrophage Subsets with Divergent Effects Causing either Neurotoxicity or Regeneration in the Injured Mouse Spinal Cord

Wed, 28 Oct 2009 10:32:16 PDT

Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e., "classically activated" proinflammatory (M1) or "alternatively activated" anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or "alternatively" activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.

Dual Neural Routing of Visual Facilitation in Speech Processing

Arnal, L. H., Morillon, B., Kell, C. A., Giraud, A.-L. — Wed, 28 Oct 2009 10:32:16 PDT

Viewing our interlocutor facilitates speech perception, unlike for instance when we telephone. Several neural routes and mechanisms could account for this phenomenon. Using magnetoencephalography, we show that when seeing the interlocutor, latencies of auditory responses (M100) are the shorter the more predictable speech is from visual input, whether the auditory signal was congruent or not. Incongruence of auditory and visual input affected auditory responses ~20 ms after latency shortening was detected, indicating that initial content-dependent auditory facilitation by vision is followed by a feedback signal that reflects the error between expected and received auditory input (prediction error). We then used functional magnetic resonance imaging and confirmed that distinct routes of visual information to auditory processing underlie these two functional mechanisms. Functional connectivity between visual motion and auditory areas depended on the degree of visual predictability, whereas connectivity between the superior temporal sulcus and both auditory and visual motion areas was driven by audiovisual (AV) incongruence. These results establish two distinct mechanisms by which the brain uses potentially predictive visual information to improve auditory perception. A fast direct corticocortical pathway conveys visual motion parameters to auditory cortex, and a slower and indirect feedback pathway signals the error between visual prediction and auditory input.

Control of On/Off Glomerular Signaling by a Local GABAergic Microcircuit in the Olfactory Bulb

Gire, D. H., Schoppa, N. E. — Wed, 28 Oct 2009 10:32:16 PDT

Odors are coded at the input level of the olfactory bulb by a spatial map of activated glomeruli, reflecting different odorant receptors (ORs) stimulated in the nose. Here we examined the function of local synaptic processing within glomeruli in transforming these input patterns into an output for the bulb, using patch-clamp recordings and calcium imaging in rat bulb slices. Two types of transformations were observed at glomeruli, the first of which produced a bimodal, "on/off" glomerular signal that varied probabilistically depending on olfactory receptor neuron (ORN) input levels. The bimodal response behavior was seen in glomerular synaptic responses, as well as in action potential ("spike") firing, wherein all mitral cells affiliated with a glomerulus either engaged in prolonged spike bursts or did not spike at all. In addition, evidence was obtained that GABAergic periglomerular (PG) cells that surround a glomerulus can prevent activation of a glomerulus through inhibitory inputs targeted onto excitatory external tufted cells. The path of PG cell activation appeared to be confined to one glomerulus, such that ORNs at one glomerulus initiated inhibition of the same glomerulus. The observed glomerular "self-inhibition" provides a mechanism of filtering odor signals that would be an alternative to commonly proposed mechanisms of lateral inhibition between OR-specific glomeruli. In this case, selective suppression of weak odor signals could be achieved based on the difference in the input resistance of PG cells versus excitatory neurons at a glomerulus.

Brain Hemispheres Selectively Track the Expected Value of Contralateral Options

Palminteri, S., Boraud, T., Lafargue, G., Dubois, B., Pessiglione, M. — Wed, 28 Oct 2009 10:32:16 PDT

A main focus in economics is on binary choice situations, in which human agents have to choose between two alternative options. The classical view is that decision making consists of valuating each option, comparing the two expected values, and selecting the higher one. Some neural correlates of option values have been described in animals, but little is known about how they are represented in the human brain: are they integrated into a single center or distributed over different areas? To address this issue, we examined whether the expected values of two options, which were cued by visual symbols and chosen with either the left or right hand, could be distinguished using functional magnetic resonance imaging. The two options were linked to monetary rewards through probabilistic contingencies that subjects had to learn so as to maximize payoff. Learning curves were fitted with a standard computational model that updates, on a trial-by-trial basis, the value of the chosen option in proportion to a reward prediction error. Results show that during learning, left and right option values were specifically expressed in the contralateral ventral prefrontal cortex, regardless of the upcoming choice. We therefore suggest that expected values are represented in a distributed manner that respects the topography of the brain systems elicited by the available options.

A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain

Wed, 28 Oct 2009 10:32:16 PDT

Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC- via Gab1/2/PI₃K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.

Oscillations, Phase-of-Firing Coding, and Spike Timing-Dependent Plasticity: An Efficient Learning Scheme

Masquelier, T., Hugues, E., Deco, G., Thorpe, S. J. — Wed, 28 Oct 2009 10:32:16 PDT

Recent experiments have established that information can be encoded in the spike times of neurons relative to the phase of a background oscillation in the local field potential—a phenomenon referred to as "phase-of-firing coding" (PoFC). These firing phase preferences could result from combining an oscillation in the input current with a stimulus-dependent static component that would produce the variations in preferred phase, but it remains unclear whether these phases are an epiphenomenon or really affect neuronal interactions—only then could they have a functional role. Here we show that PoFC has a major impact on downstream learning and decoding with the now well established spike timing-dependent plasticity (STDP). To be precise, we demonstrate with simulations how a single neuron equipped with STDP robustly detects a pattern of input currents automatically encoded in the phases of a subset of its afferents, and repeating at random intervals. Remarkably, learning is possible even when only a small fraction of the afferents (~10%) exhibits PoFC. The ability of STDP to detect repeating patterns had been noted before in continuous activity, but it turns out that oscillations greatly facilitate learning. A benchmark with more conventional rate-based codes demonstrates the superiority of oscillations and PoFC for both STDP-based learning and the speed of decoding: the oscillation partially formats the input spike times, so that they mainly depend on the current input currents, and can be efficiently learned by STDP and then recognized in just one oscillation cycle. This suggests a major functional role for oscillatory brain activity that has been widely reported experimentally.

Endogenous BDNF in the Dorsolateral Striatum Gates Alcohol Drinking

Jeanblanc, J., He, D.-Y., Carnicella, S., Kharazia, V., Janak, P. H., Ron, D. — Wed, 28 Oct 2009 10:32:16 PDT

We previously found that brain-derived neurotrophic factor (BDNF)-haplodeficient mice exhibit greater ethanol-induced place preference and psychomotor sensitization, and greater ethanol consumption after deprivation, than control mice. We further observed that, in mice, voluntary ethanol intake increases BDNF expression in the dorsal striatum (DS). Here, we determined whether BDNF within the DS regulates ethanol self-administration in Long–Evans rats trained to self-administer a 10% ethanol solution. We observed a greater increase in BDNF expression after ethanol self-administration in the dorsolateral striatum (DLS) than in the dorsomedial striatum (DMS). We further found that downregulation of endogenous BDNF using viral-mediated siRNA in the DLS, but not in the DMS, significantly increased ethanol self-administration. Infusion of exogenous BDNF (0.25 µg/µl/side into the DMS; 0.25 and 0.75 µg/µl/side into the DLS) attenuated responding for ethanol when infused 3 h before the beginning of the self-administration session. Although the decrease in ethanol intake was similar in the DLS and DMS, BDNF infused in the DLS, but not in the DMS, induced an early termination of the drinking episode. Furthermore, the action of BDNF in the DLS was specific for ethanol, as infusion of the neurotrophic factor in the DMS, but not DLS, resulted in a reduction of sucrose intake. Together, these findings demonstrate that the BDNF pathway within the DLS controls the level of ethanol self-administration. Importantly, our results suggest that an endogenous signaling pathway within the same brain region that mediates drug-taking behavior also plays a critical role in gating the level of ethanol intake.

Classical Major Histocompatibility Complex Class I Molecules in Motoneurons: New Actors at the Neuromuscular Junction

Thams, S., Brodin, P., Plantman, S., Saxelin, R., Karre, K., Cullheim, S. — Wed, 28 Oct 2009 10:32:16 PDT

Major histocompatibility complex (MHC) class I molecules have fundamental functions in the immune system. Recent studies have suggested that these molecules may also have non-immune functions in the nervous system, in particular related to synaptic function and plasticity. Because adult motoneurons express mRNAs for MHC class I molecules, we have examined their subcellular expression pattern in vivo and their role for the synaptic connectivity of these neurons. We observed immunoreactivity for classical MHC class I (Ia) protein in motoneuron somata, but the predominant expression was found in axons and presynaptically at neuromuscular junctions (NMJs). Peripheral nerve lesion induced a strong increase of motoneuron MHC class Ia (H2-K^b/D^b) mRNA, indicating a role for MHC class Ia molecules during regeneration. Accordingly, there was an accumulation of MHC class Ia proteins at the cut ends and in growth cones of motor axons after lesion. In K^b–/–D^b–/– mice (lacking MHC class Ia molecules), the time course for recovery of grip ability in reinnervated muscles was significantly delayed. Muscles from K^b–/–D^b–/– mice displayed an increased density and a disturbed distribution of NMJs and fewer terminal Schwann cells/NMJ compared with wild-type mice. A population of Schwann cells in sciatic nerves expressed the paired Ig receptor B, which binds to MHC class I molecules. These results provide the first evidence that neuronal MHC class Ia molecules are present in motor axons, that they are important for organization of NMJs and motor recovery after nerve lesion, and that their actions may be mediated via Schwann cells.

Predicting Language Lateralization from Gray Matter

Josse, G., Kherif, F., Flandin, G., Seghier, M. L., Price, C. J. — Wed, 28 Oct 2009 10:32:16 PDT

It has long been predicted that the degree to which language is lateralized to the left or right hemisphere might be reflected in the underlying brain anatomy. We investigated this relationship on a voxel-by-voxel basis across the whole brain using structural and functional magnetic resonance images from 86 healthy participants. Structural images were converted to gray matter probability images, and language activation was assessed during naming and semantic decision. All images were spatially normalized to the same symmetrical template, and lateralization images were generated by subtracting right from left hemisphere signal at each voxel. We show that the degree to which language was left or right lateralized was positively correlated with the degree to which gray matter density was lateralized. Post hoc analyses revealed a general relationship between gray matter probability and blood oxygenation level-dependent signal. This is the first demonstration that structural brain scans can be used to predict language lateralization on a voxel-by-voxel basis in the normal healthy brain.

Human Reinforcement Learning Subdivides Structured Action Spaces by Learning Effector-Specific Values

Gershman, S. J., Pesaran, B., Daw, N. D. — Wed, 28 Oct 2009 10:32:16 PDT

Humans and animals are endowed with a large number of effectors. Although this enables great behavioral flexibility, it presents an equally formidable reinforcement learning problem of discovering which actions are most valuable because of the high dimensionality of the action space. An unresolved question is how neural systems for reinforcement learning—such as prediction error signals for action valuation associated with dopamine and the striatum—can cope with this "curse of dimensionality." We propose a reinforcement learning framework that allows for learned action valuations to be decomposed into effector-specific components when appropriate to a task, and test it by studying to what extent human behavior and blood oxygen level-dependent (BOLD) activity can exploit such a decomposition in a multieffector choice task. Subjects made simultaneous decisions with their left and right hands and received separate reward feedback for each hand movement. We found that choice behavior was better described by a learning model that decomposed the values of bimanual movements into separate values for each effector, rather than a traditional model that treated the bimanual actions as unitary with a single value. A decomposition of value into effector-specific components was also observed in value-related BOLD signaling, in the form of lateralized biases in striatal correlates of prediction error and anticipatory value correlates in the intraparietal sulcus. These results suggest that the human brain can use decomposed value representations to "divide and conquer" reinforcement learning over high-dimensional action spaces.

Adult-Born Hippocampal Dentate Granule Cells Undergoing Maturation Modulate Learning and Memory in the Brain

Deng, W., Saxe, M. D., Gallina, I. S., Gage, F. H. — Wed, 28 Oct 2009 10:32:16 PDT

Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature DGCs display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory.

Simvastatin Inhibits the Activation of p21ras and Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

Ghosh, A., Roy, A., Matras, J., Brahmachari, S., Gendelman, H. E., Pahan, K. — Wed, 28 Oct 2009 10:32:16 PDT

Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP⁺ induced the activation of p21^ras and nuclear factor-B (NF-B) in mouse microglial cells. Inhibition of MPP⁺-induced activation of NF-B by p21^ras, a dominant-negative mutant of p21^ras, supported the involvement of p21^ras in MPP⁺-induced microglial activation of NF-B. Interestingly, simvastatin attenuated activation of both p21^ras and NF-B in MPP⁺-stimulated microglial cells. Consistently, we found a very rapid activation of p21^ras in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21^ras, attenuated nigral activation of NF-B, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice, but at levels less than simvastatin. Furthermore, both the statins administered 2 d after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters, suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients.

Structural Changes between Seasons in the Songbird Auditory Forebrain

Wed, 28 Oct 2009 10:32:16 PDT

The song control system (SCS) of seasonal songbirds shows remarkable seasonal plasticity. Male starlings (Sturnus vulgaris) sing throughout the year, but in the breeding season, when concentrations of testosterone are elevated, the song is highly sexually motivated. The main goal of this study was to investigate structural seasonal changes in regions involved in auditory processing and in socio-sexual behavior. Using in vivo Diffusion Tensor Imaging (DTI), we measured in breeding and nonbreeding seasons volume and tissue characteristics of several brain regions of nine adult male starlings. We demonstrate that the songbird brain exhibits an extreme seasonal plasticity not merely limited to the SCS. Volumetric analysis showed seasonal telencephalon volume changes and more importantly also a volumetric change in the caudal region of the nidopallium (NCM), a region analogous to the mammalian secondary auditory cortex. Analysis of the DTI data allowed detection of seasonal changes in cellular attributes in NCM and regions involved in social behavior. This study extends our view on a seasonally dynamic avian brain which not only hones its song control system but also auditory and social systems to be prepared for the breeding season.

Spinal Interneurons Differentiate Sequentially from Those Driving the Fastest Swimming Movements in Larval Zebrafish to Those Driving the Slowest Ones

McLean, D. L., Fetcho, J. R. — Wed, 28 Oct 2009 10:32:16 PDT

Studies of neuronal networks have revealed few general principles that link patterns of development with later functional roles. While investigating the neural control of movements, we recently discovered a topographic map in the spinal cord of larval zebrafish that relates the position of motoneurons and interneurons to their order of recruitment during swimming. Here, we show that the map reflects an orderly pattern of differentiation of neurons driving different movements. First, we use high-speed filming to show that large-amplitude swimming movements with bending along much of the body appear first, with smaller, regional swimming movements emerging later. Next, using whole-cell patch recordings, we demonstrate that the excitatory circuits that drive large-amplitude, fast swimming movements at larval stages are present and functional early on in embryos. Finally, we systematically assess the orderly emergence of spinal circuits according to swimming speed using transgenic fish expressing the photoconvertible protein Kaede to track neuronal differentiation in vivo. We conclude that a simple principle governs the development of spinal networks in which the neurons driving the fastest, most powerful swimming in larvae develop first with ones that drive increasingly weaker and slower larval movements layered on over time. Because the neurons are arranged by time of differentiation in the spinal cord, the result is a topographic map that represents the speed/strength of movements at which neurons are recruited and the temporal emergence of networks. This pattern may represent a general feature of neuronal network development throughout the brain and spinal cord.

Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in {alpha}-Synuclein Models of Parkinson's and Lewy Body Diseases

Wed, 28 Oct 2009 10:32:16 PDT

Accumulation of the synaptic protein -synuclein (-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of -syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of -syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of -syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and -syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a -syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of -syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of -syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.

Intrabody Gene Therapy Ameliorates Motor, Cognitive, and Neuropathological Symptoms in Multiple Mouse Models of Huntington's Disease

Southwell, A. L., Ko, J., Patterson, P. H. — Wed, 28 Oct 2009 10:32:16 PDT

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting from the expansion of a glutamine repeat in the huntingtin (Htt) protein. Current therapies are directed at managing symptoms such as chorea and psychiatric disturbances. In an effort to develop a therapy directed at disease prevention we investigated the utility of highly specific, anti-Htt intracellular antibodies (intrabodies). We previously showed that V_L12.3, an intrabody recognizing the N terminus of Htt, and Happ1, an intrabody recognizing the proline-rich domain of Htt, both reduce mHtt-induced toxicity and aggregation in cell culture and brain slice models of HD. Due to the different mechanisms of action of these two intrabodies, we then tested both in the brains of five mouse models of HD using a chimeric adeno-associated virus 2/1 (AAV2/1) vector with a modified CMV enhancer/chicken β-actin promoter. V_L12.3 treatment, while beneficial in a lentiviral model of HD, has no effect on the YAC128 HD model and actually increases severity of phenotype and mortality in the R6/2 HD model. In contrast, Happ1 treatment confers significant beneficial effects in a variety of assays of motor and cognitive deficits. Happ1 also strongly ameliorates the neuropathology found in the lentiviral, R6/2, N171-82Q, YAC128, and BACHD models of HD. Moreover, Happ1 significantly prolongs the life span of N171-82Q mice. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly specific and effective treatment in diverse mouse models of HD.

Molecular Reconstruction of mGluR5a-Mediated Endocannabinoid Signaling Cascade in Single Rat Sympathetic Neurons

Won, Y.-J., Puhl, H. L., Ikeda, S. R. — Wed, 28 Oct 2009 10:32:16 PDT

Endocannabinoids (eCB) such as 2-arachidonylglycerol (2-AG) are lipid metabolites that are synthesized in a postsynaptic neurons and act upon CB₁ cannabinoid receptors (CB₁R) in presynaptic nerve terminals. This retrograde transmission underlies several forms of short and long term synaptic plasticity within the CNS. Here, we constructed a model system based on isolated rat sympathetic neurons, in which an eCB signaling cascade could be studied in a reduced, spatially compact, and genetically malleable system. We constructed a complete eCB production/mobilization pathway by sequential addition of molecular components. Heterologous expression of four components was required for eCB production and detection: metabotropic glutamate receptor 5a (mGluR5a), Homer 2b, diacylglycerol lipase , and CB₁R. In these neurons, application of l-glutamate produced voltage-dependent modulation of N-type Ca²⁺ channels mediated by activation of CB₁R. Using both molecular dissection and pharmacological agents, we provide evidence that activation of mGluR5a results in rapid enzymatic production of 2-AG followed by activation of CB₁R. These experiments define the critical elements required to recapitulate retrograde eCB production and signaling in a single peripheral neuron. Moreover, production/mobilization of eCB can be detected on a physiologically relevant time scale using electrophysiological techniques. The system provides a platform for testing candidate molecules underlying facilitation of eCB transport across the plasma membrane.

Broadband Shifts in Local Field Potential Power Spectra Are Correlated with Single-Neuron Spiking in Humans

Manning, J. R., Jacobs, J., Fried, I., Kahana, M. J. — Wed, 28 Oct 2009 10:32:16 PDT

A fundamental question in neuroscience concerns the relation between the spiking of individual neurons and the aggregate electrical activity of neuronal ensembles as seen in local field potentials (LFPs). Because LFPs reflect both spiking activity and subthreshold events, this question is not simply one of data aggregation. Recording from 20 neurosurgical patients, we directly examined the relation between LFPs and neuronal spiking. Examining 2030 neurons in widespread brain regions, we found that firing rates were positively correlated with broadband (2–150 Hz) shifts in the LFP power spectrum. In contrast, narrowband oscillations correlated both positively and negatively with firing rates at different recording sites. Broadband power shifts were a more reliable predictor of neuronal spiking than narrowband power shifts. These findings suggest that broadband LFP power provides valuable information concerning neuronal activity beyond that contained in narrowband oscillations.

Perceptual Learning of Object Shape

Golcu, D., Gilbert, C. D. — Wed, 28 Oct 2009 10:32:16 PDT

Recognition of objects is accomplished through the use of cues that depend on internal representations of familiar shapes. We used a paradigm of perceptual learning during visual search to explore what features human observers use to identify objects. Human subjects were trained to search for a target object embedded in an array of distractors, until their performance improved from near-chance levels to over 80% of trials in an object-specific manner. We determined the role of specific object components in the recognition of the object as a whole by measuring the transfer of learning from the trained object to other objects sharing components with it. Depending on the geometric relationship of the trained object with untrained objects, transfer to untrained objects was observed. Novel objects that shared a component with the trained object were identified at much higher levels than those that did not, and this could be used as an indicator of which features of the object were important for recognition. Training on an object also transferred to the components of the object when these components were embedded in an array of distractors of similar complexity. These results suggest that objects are not represented in a holistic manner during learning but that their individual components are encoded. Transfer between objects was not complete and occurred for more than one component, regardless of how well they distinguish the object from distractors. This suggests that a joint involvement of multiple components was necessary for full performance.

Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent {beta}-Catenin mRNA Translation in Developing Hippocampal Neurons

Kundel, M., Jones, K. J., Shin, C. Y., Wells, D. G. — Wed, 28 Oct 2009 10:32:16 PDT

Neuronal morphogenesis, the growth and arborization of neuronal processes, is an essential component of brain development. Two important but seemingly disparate components regulating neuronal morphology have previously been described. In the hippocampus, neurotrophins, particularly brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), act to enhance cell growth and branching, while activity-induced branching was shown to be dependent upon intracellular β-catenin. We now describe a molecular link between NT3 stimulation and β-catenin increase in developing neurons and demonstrate that this process is required for the NT3-mediated increase in process branching. Here, we show that β-catenin is rapidly increased specifically in growth cones following NT3 stimulation. This increase in β-catenin is protein synthesis dependent and requires the activity of cytoplasmic polyadenylation element-binding protein-1 (CPEB1), an mRNA-binding protein that regulates mRNA translation. We find that CPEB1 protein binds β-catenin mRNA in a CPE-dependent manner and that both localize to growth cones of developing hippocampal neurons. Both the NT3-mediated rapid increase in β-catenin and process branching are abolished when CPEB1 function is inhibited. In addition, the NT3-mediated increase in β-catenin in growth cones is dependent upon internal calcium and the activity of CaMKII (calcium/calmodulin-dependent kinase II). Together, these results suggest that CPEB1 regulates β-catenin synthesis in neurons and may contribute to neuronal morphogenesis.

Progressive Postnatal Motoneuron Loss in Mice Lacking GDF-15

Wed, 28 Oct 2009 10:32:16 PDT

Growth/differentiation factor-15 (GDF-15) is a widely expressed distant member of the TGF-β superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15-deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a ~20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, whereas sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knock-out phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.

Dendritic Compartment and Neuronal Output Mode Determine Pathway-Specific Long-Term Potentiation in the Piriform Cortex

Wed, 28 Oct 2009 10:32:16 PDT

The apical dendrite of layer 2/3 pyramidal cells in the piriform cortex receives two spatially distinct inputs: one projecting onto the distal apical dendrite in sensory layer 1a, the other targeting the proximal apical dendrite in layer 1b. We observe an expression gradient of A-type K⁺ channels that weakens the backpropagating action potential-mediated depolarization in layer 1a compared with layer 1b. We find that the pairing of presynaptic and postsynaptic firing leads to significantly smaller Ca²⁺ signals in the distal dendritic spines in layer 1a compared with the proximal spines in layer 1b. The consequence is a selective failure to induce long-term potentiation (LTP) in layer 1a, which can be rescued by pharmacological enhancement of action potential backpropagation. In contrast, LTP induction by pairing presynaptic and postsynaptic firing is possible in layer 1b but requires bursting of the postsynaptic cell. This output mode strongly depends on the balance of excitation and inhibition in the piriform cortex. We show, on the single-spine level, how the plasticity of functionally distinct synapses is gated by the intrinsic electrical properties of piriform cortex layer 2 pyramidal cell dendrites and the cellular output mode.

Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Wed, 28 Oct 2009 10:32:16 PDT

We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na⁺-K⁺ ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the ₃ subunit of Na⁺-K⁺ ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation.

Differential Gene Expression in the Developing Lateral Geniculate Nucleus and Medial Geniculate Nucleus Reveals Novel Roles for Zic4 and Foxp2 in Visual and Auditory Pathway Development

Horng, S., Kreiman, G., Ellsworth, C., Page, D., Blank, M., Millen, K., Sur, M. — Wed, 28 Oct 2009 10:32:16 PDT

Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to "rewired" MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.

Proopiomelanocortin Expression in both GABA and Glutamate Neurons

Hentges, S. T., Otero-Corchon, V., Pennock, R. L., King, C. M., Low, M. J. — Wed, 28 Oct 2009 10:32:16 PDT

Proopiomelanocortin (POMC) neurons have been intensively studied because of their essential role in regulating energy balance and body weight. Many effects of POMC neurons can be attributed to their release of cognate neuropeptides from secretory granules in axon terminals. However, these neurons also synaptically release non-peptide neurotransmitters. The aim of this study was to settle the controversy whether there are separate populations of POMC neurons that release GABA or glutamate. Transgenic mice expressing a red fluorescent protein [Discosoma red (DsRed)] driven by Pomc neuronal regulatory elements (POMC–DsRed) were crossed to mice that expressed green fluorescent protein (gfp) in GABAergic neurons (GAD67–gfp). Approximately 40% of POMC neurons in the arcuate nucleus of the double-transgenic mice expressed the GAD67–gfp transgene. In vitro neurotransmitter release was detected using whole-cell electrophysiologic recordings in cultured GAD67–gfp-positive and GAD67–gfp-negative POMC neurons that had formed recurrent synapses (autapses). Autapses from GAD67–gfp-positive neurons were uniformly GABAergic. In contrast, autapses from the GAD67–gfp-negative POMC neurons exclusively exhibited postsynaptic currents mediated by glutamate. Together, these results indicate that there are two subpopulations of POMC neurons in the arcuate nucleus differentiated by their amino acid neurotransmitter phenotype. Whole-cell voltage-clamp recordings from POMC neurons in live brain slices indicated that GABAergic and glutamatergic POMC neurons are under similar presynaptic and postsynaptic regulation, although the GABAergic POMC neurons are smaller and have higher input resistance. GABAergic and glutamatergic POMC neurons may mediate distinct aspects of POMC neuron function, including the regulation of energy homeostasis.

Permanent Functional Reorganization of Retinal Circuits Induced by Early Long-Term Visual Deprivation

Di Marco, S., Nguyen, V. A., Bisti, S., Protti, D. A. — Wed, 28 Oct 2009 10:32:16 PDT

Early sensory experience shapes the functional and anatomical connectivity of neuronal networks. Light deprivation alters synaptic transmission and modifies light response properties in the visual system, from retinal circuits to higher visual centers. These effects are more pronounced during a critical period in juvenile life and are mostly reversed by restoring normal light conditions. Here we show that complete light deprivation, from birth to periods beyond the critical period, permanently modifies the receptive field properties of retinal ganglion cells. Visual deprivation reduced both the strength of light responses in ganglion cells and their receptive field size. Light deprivation produced an imbalance in the ratio of inhibitory to excitatory inputs, with a shift toward larger inhibitory conductances. Ganglion cell receptive fields in visually deprived animals showed a spatial mismatch of inhibitory and excitatory inputs and inhibitory inputs were highly scattered over the receptive field. These results indicate that visual experience early in life is critical for the refinement of retinal circuits and for appropriate signaling of the spatiotemporal properties of visual stimuli, thus influencing the response properties of neurons in higher visual centers and their processing of visual information.

Pattern Motion Selectivity of Spiking Outputs and Local Field Potentials in Macaque Visual Cortex

Khawaja, F. A., Tsui, J. M. G., Pack, C. C. — Wed, 28 Oct 2009 10:32:16 PDT

The dorsal pathway of the primate visual cortex is involved in the processing of motion signals that are useful for perception and behavior. Along this pathway, motion information is first measured by the primary visual cortex (V1), which sends specialized projections to extrastriate regions such as the middle temporal area (MT). Previous work with plaid stimuli has shown that most V1 neurons respond to the individual components of moving stimuli, whereas some MT neurons are capable of estimating the global motion of the pattern. In this work, we show that the majority of neurons in the medial superior temporal area (MST), which receives input from MT, have this pattern-selective property. Interestingly, the local field potentials (LFPs) measured simultaneously with the spikes often exhibit properties similar to that of the presumptive feedforward input to each area: in the high-gamma frequency band, the LFPs in MST are as component selective as the spiking outputs of MT, and MT LFPs have plaid responses that are similar to the spiking outputs of V1. In the lower LFP frequency bands (beta and low gamma), component selectivity is very common, and pattern selectivity is almost entirely absent in both MT and MST. Together, these results suggest a surprisingly strong link between the sensory tuning of cortical LFPs and afferent inputs, with important implications for the interpretation of imaging studies and for models of cortical function.

{beta}-Catenin Signaling Levels in Progenitors Influence the Laminar Cell Fates of Projection Neurons

Mutch, C. A., Funatsu, N., Monuki, E. S., Chenn, A. — Wed, 28 Oct 2009 10:32:16 PDT

The mechanisms underlying the timing of the laminar fate decisions during cortical neurogenesis remain poorly understood. Here we show that β-catenin signaling in cortical neural precursors can regulate the laminar fate of their daughters. In ventricular zone neural precursors, β-catenin signaling is higher when deep-layer neurons are being generated and lower when upper-layer neurons are being generated. Overactivation of β-catenin in cortical precursors midway through corticogenesis increased the relative production of deep-layer neurons, while inhibition of signaling increased the relative production of upper-layer neurons. Furthermore, in late-gestation upper-layer precursors, overactive β-catenin signaling was able to partially restore production of deep-layer neurons. These observations suggest that increased β-catenin signaling can reset the timing of cortical precursors to promote the production of deep-layer neurons, while inhibition of β-catenin signaling advances the timing to promote upper-layer production.

Control of Cortical Axon Elongation by a GABA-Driven Ca2+/Calmodulin-Dependent Protein Kinase Cascade

Wed, 28 Oct 2009 10:32:16 PDT

Ca²⁺ signaling plays important roles during both axonal and dendritic growth. Yet whether and how Ca²⁺ rises may trigger and contribute to the development of long-range cortical connections remains mostly unknown. Here, we demonstrate that two separate limbs of the Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK)–CaMKI cascades, CaMKK–CaMKI and CaMKK–CaMKI, critically coordinate axonal and dendritic morphogenesis of cortical neurons, respectively. The axon-specific morphological phenotype required a diffuse cytoplasmic localization and a strikingly -isoform-specific kinase activity of CaMKI. Unexpectedly, treatment with muscimol, a GABA_A receptor agonist, selectively stimulated elongation of axons but not of dendrites, and the CaMKK–CaMKI cascade critically mediated this axonogenic effect. Consistent with these findings, during early brain development, in vivo knockdown of CaMKI significantly impaired the terminal axonal extension and thereby perturbed the refinement of the interhemispheric callosal projections into the contralateral cortices. Our findings thus indicate a novel role for the GABA-driven CaMKK–CaMKI cascade as a mechanism critical for accurate cortical axon pathfinding, an essential process that may contribute to fine-tuning the formation of interhemispheric connectivity during the perinatal development of the CNS.

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with L-[{beta}-11C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

Wed, 28 Oct 2009 10:32:16 PDT

Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D₂ receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D₂ receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D₂ receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [¹¹C]raclopride and l-[β-¹¹C]DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D₂ receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D₂ receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

What "Works" in Working Memory? Separate Systems for Selection and Updating of Critical Information

Bledowski, C., Rahm, B., Rowe, J. B. — Wed, 28 Oct 2009 10:32:16 PDT

Cognition depends critically on working memory, the active representation of a limited number of items over short periods of time. In addition to the maintenance of information during the course of cognitive processing, many tasks require that some of the items in working memory become transiently more important than others. Based on cognitive models of working memory, we hypothesized two complementary essential cognitive operations to achieve this: a selection operation that retrieves the most relevant item, and an updating operation that changes the focus of attention onto it. Using functional magnetic resonance imaging, high-resolution oculometry, and behavioral analysis, we demonstrate that these two operations are functionally and neuroanatomically dissociated. Updating the attentional focus elicited transient activation in the caudal superior frontal sulcus and posterior parietal cortex. In contrast, increasing demands on selection selectively modulated activation in rostral superior frontal sulcus and posterior cingulate/precuneus. We conclude that prioritizing one memory item over others invokes independent mechanisms of mnemonic retrieval and attentional focusing, each with its distinct neuroanatomical basis within frontal and parietal regions. These support the developing understanding of working memory as emerging from the interaction between memory and attentional systems.