Journal of Neuroscience current issue

This Week in The Journal

Wed, 25 Nov 2009 10:03:10 PST

Correction for Anna Devor et al., Suppressed Neuronal Activity and Concurrent Arteriolar Vasoconstriction May Explain Negative Blood Oxygenation Level-Dependent Signal

Wed, 25 Nov 2009 10:03:10 PST

Synaptic Activity Induces Dramatic Changes in the Geometry of the Cell Nucleus: Interplay between Nuclear Structure, Histone H3 Phosphorylation, and Nuclear Calcium Signaling

Wed, 25 Nov 2009 10:03:10 PST

Synaptic activity initiates many adaptive responses in neurons. Here we report a novel form of structural plasticity in dissociated hippocampal cultures and slice preparations. Using a recently developed algorithm for three-dimensional image reconstruction and quantitative measurements of cell organelles, we found that many nuclei from hippocampal neurons are highly infolded and form unequally sized nuclear compartments. Nuclear infoldings are dynamic structures, which can radically transform the geometry of the nucleus in response to neuronal activity. Action potential bursting causing synaptic NMDA receptor activation dramatically increases the number of infolded nuclei via a process that requires the ERK-MAP kinase pathway and new protein synthesis. In contrast, death-signaling pathways triggered by extrasynaptic NMDA receptors cause a rapid loss of nuclear infoldings. Compared with near-spherical nuclei, infolded nuclei have a larger surface and increased nuclear pore complex immunoreactivity. Nuclear calcium signals evoked by cytosolic calcium transients are larger in small nuclear compartments than in the large compartments of the same nucleus; moreover, small compartments are more efficient in temporally resolving calcium signals induced by trains of action potentials in the theta frequency range (5 Hz). Synaptic activity-induced phosphorylation of histone H3 on serine 10 was more robust in neurons with infolded nuclei compared with neurons with near-spherical nuclei, suggesting a functional link between nuclear geometry and transcriptional regulation. The translation of synaptic activity-induced signaling events into changes in nuclear geometry facilitates the relay of calcium signals to the nucleus, may lead to the formation of nuclear signaling microdomains, and could enhance signal-regulated transcription.

Role of Striatum in Updating Values of Chosen Actions

Kim, H., Sul, J. H., Huh, N., Lee, D., Jung, M. W. — Wed, 25 Nov 2009 10:03:10 PST

The striatum is thought to play a crucial role in value-based decision making. Although a large body of evidence suggests its involvement in action selection as well as action evaluation, underlying neural processes for these functions of the striatum are largely unknown. To obtain insights on this matter, we simultaneously recorded neuronal activity in the dorsal and ventral striatum of rats performing a dynamic two-armed bandit task, and examined temporal profiles of neural signals related to animal's choice, its outcome, and action value. Whereas significant neural signals for action value were found in both structures before animal's choice of action, signals related to the upcoming choice were relatively weak and began to emerge only in the dorsal striatum ~200 ms before the behavioral manifestation of the animal's choice. In contrast, once the animal revealed its choice, signals related to choice and its value increased steeply and persisted until the outcome of animal's choice was revealed, so that some neurons in both structures concurrently conveyed signals related to animal's choice, its outcome, and the value of chosen action. Thus, all the components necessary for updating values of chosen actions were available in the striatum. These results suggest that the striatum not only represents values associated with potential choices before animal's choice of action, but might also update the value of chosen action once its outcome is revealed. In contrast, action selection might take place elsewhere or in the dorsal striatum only immediately before its behavioral manifestation.

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

Wed, 25 Nov 2009 10:03:10 PST

ATP released during hypoxia from the ventrolateral medulla activates purinergic receptors (P2Rs) to attenuate the secondary hypoxic depression of breathing by a mechanism that likely involves a P2Y₁R-mediated excitation of preBötzinger complex (preBötC) inspiratory rhythm-generating networks. In this study, we used rhythmically active in vitro preparations from embryonic and postnatal rats and ATP microinjection into the rostral ventral respiratory group (rVRG)/preBötC to reveal that these networks are sensitive to ATP when rhythm emerges at embryonic day 17 (E17). The peak frequency elicited by ATP at E19 and postnatally was the same (~45 bursts/min), but relative sensitivity was threefold greater at E19, reflecting a lower baseline frequency (5.6 ± 0.9 vs 19.0 ± 1.3 bursts/min). Combining microinjection techniques with ATP biosensors revealed that ATP concentration in the rVRG/preBötC falls rapidly as a result of active processes and closely correlates with inspiratory frequency. A phosphate assay established that preBötC-containing tissue punches degrade ATP at rates that increase perinatally. Thus, the agonist profile [ATP/ADP/adenosine (ADO)] produced after ATP release in the rVRG/preBötC will change perinatally. Electrophysiology further established that the ATP metabolite ADP is excitatory and that, in fetal but not postnatal animals, ADO at A₁ receptors exerts a tonic depressive action on rhythm, whereas A₁ antagonists extend the excitatory action of ATP on inspiratory rhythm. These data demonstrate that ATP is a potent excitatory modulator of the rVRG/preBötC inspiratory network from the time it becomes active and that ATP actions are determined by a dynamic interaction between the actions of ATP at P2 receptors, ectonucleotidases that degrade ATP, and ATP metabolites on P2Y and P1 receptors.

Sensitivity of Newborn Auditory Cortex to the Temporal Structure of Sounds

Wed, 25 Nov 2009 10:03:10 PST

Understanding the rapidly developing building blocks of speech perception in infancy requires a close look at the auditory prerequisites for speech sound processing. Pioneering studies have demonstrated that hemispheric specializations for language processing are already present in early infancy. However, whether these computational asymmetries can be considered a function of linguistic attributes or a consequence of basic temporal signal properties is under debate. Several studies in adults link hemispheric specialization for certain aspects of speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to spectrotemporal features of speech. Applying concurrent electrophysiological (EEG) and hemodynamic (near-infrared spectroscopy) recording to newborn infants listening to temporally structured nonspeech signals, we provide evidence that newborns process nonlinguistic acoustic stimuli that share critical temporal features with language in a differential manner. The newborn brain preferentially processes temporal modulations especially relevant for phoneme perception. In line with multi-time-resolution conceptions, modulations on the time scale of phonemes elicit strong bilateral cortical responses. Our data furthermore suggest that responses to slow acoustic modulations are lateralized to the right hemisphere. That is, the newborn auditory cortex is sensitive to the temporal structure of the auditory input and shows an emerging tendency for functional asymmetry. Hence, our findings support the hypothesis that development of speech perception is linked to basic capacities in auditory processing. From birth, the brain is tuned to critical temporal properties of linguistic signals to facilitate one of the major needs of humans: to communicate.

Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity

Wed, 25 Nov 2009 10:03:10 PST

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D₂/D₃ receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [¹⁸F]fallypride to measure striatal dopamine D₂/D₃ receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D₂/D₃ receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D₂/D₃ receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D₂/D₃ receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D₂/D₃ receptor availability may mediate impulsive temperament and thereby influence addiction.

Adenosine A2A Receptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by {beta}-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

Wed, 25 Nov 2009 10:03:10 PST

Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of β-amyloid peptide (namely Aβ_1-42) and morphologically by an initial loss of nerve terminals. Caffeine consumption prevents memory dysfunction in different models, which is mimicked by antagonists of adenosine A_2A receptors (A_2ARs), which are located in synapses. Thus, we now tested whether A_2AR blockade prevents the early Aβ_1-42-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Aβ_1-42 (2 nmol) in rats or mice caused, 2 weeks later, memory impairment (decreased performance in the Y-maze and object recognition tests) and a loss of nerve terminal markers (synaptophysin, SNAP-25) without overt neuronal loss, astrogliosis, or microgliosis. These were prevented by pharmacological blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261); 0.05 mg · kg^–1 · d^–1, i.p.; for 15 d] in rats, and genetic inactivation of A_2ARs in mice. Moreover, these were synaptic events since purified nerve terminals acutely exposed to Aβ_1-42 (500 nm) displayed mitochondrial dysfunction, which was prevented by A_2AR blockade. SCH58261 (50 nm) also prevented the initial synaptotoxicity (loss of MAP-2, synaptophysin, and SNAP-25 immunoreactivity) and subsequent loss of viability of cultured hippocampal neurons exposed to Aβ_1-42 (500 nm). This A_2AR-mediated control of neurotoxicity involved the control of Aβ_1-42-induced p38 phosphorylation and was independent from cAMP/PKA (protein kinase A) pathway. Together, these results show that A_2ARs play a crucial role in the development of Aβ-induced synaptotoxicity leading to memory dysfunction through a p38 MAPK (mitogen-activated protein kinase)-dependent pathway and provide a molecular basis for the benefits of caffeine consumption in AD.

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D2 Receptor Internalization

Xiao, M.-F., Xu, J.-C., Tereshchenko, Y., Novak, D., Schachner, M., Kleene, R. — Wed, 25 Nov 2009 10:03:10 PST

The dopaminergic system plays an important role in the etiology of schizophrenia, and most antipsychotic drugs exert their functions by blocking dopamine D₂ receptors (D₂Rs). Since the signaling strength mediated by D₂Rs is regulated by internalization and degradation processes, it is crucial to identify molecules that modulate D₂R localization at the cell surface. Here, we show that the neural cell adhesion molecule (NCAM) promotes D₂R internalization/desensitization and subsequent degradation via direct interaction with a short peptide in the third intracellular loop of the D₂R. NCAM deficiency in mice leads to increased numbers of D₂Rs at the cell surface and augmented D₂R signaling as a result of impaired D₂R internalization. Furthermore, NCAM-deficient mice show higher sensitivity to the psychostimulant apomorphine and exaggerated activity of dopamine-related locomotor behavior. These results demonstrate that, in addition to its classical function in cell adhesion, NCAM is involved in regulating the trafficking of the neurotransmitter receptor D₂R as well as receptor-mediated signaling and behavior, thus implicating NCAM as modulator of the dopaminergic system and a potential pharmacological target for dopamine-related neurological and psychiatric disorders.

Cannabidiol, a Nonpsychotropic Component of Cannabis, Inhibits Cue-Induced Heroin Seeking and Normalizes Discrete Mesolimbic Neuronal Disturbances

Ren, Y., Whittard, J., Higuera-Matas, A., Morris, C. V., Hurd, Y. L. — Wed, 25 Nov 2009 10:03:10 PST

There remains debate regarding the impact of cannabis on neuropsychiatric disorders. Here, we examined the effects of cannabidiol (CBD), a nonpsychoactive constituent of cannabis, on heroin self-administration and drug-seeking behavior using an experimental rat model. CBD (5–20 mg/kg) did not alter stable intake of heroin self-administration, extinction behavior, or drug seeking induced by a heroin prime injection. Instead, it specifically attenuated heroin-seeking behavior reinstated by exposure to a conditioned stimulus cue. CBD had a protracted effect with significance evident after 24 h and even 2 weeks after administration. The behavioral effects were paralleled by neurobiological alterations in the glutamatergic and endocannabinoid systems. Discrete disturbances of AMPA GluR1 and cannabinoid type-1 receptor expression observed in the nucleus accumbens associated with stimulus cue-induced heroin seeking were normalized by CBD treatment. The findings highlight the unique contributions of distinct cannabis constituents to addiction vulnerability and suggest that CBD may be a potential treatment for heroin craving and relapse.

Basal Cerebral Metabolism May Modulate the Cognitive Effects of A{beta} in Mild Cognitive Impairment: An Example of Brain Reserve

Wed, 25 Nov 2009 10:03:10 PST

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [¹⁸F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

CK2 Is a Novel Negative Regulator of NADPH Oxidase and a Neuroprotectant in Mice after Cerebral Ischemia

Kim, G. S., Jung, J. E., Niizuma, K., Chan, P. H. — Wed, 25 Nov 2009 10:03:10 PST

NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. In this study, we identified casein kinase 2 (CK2) as a critical modulator of NADPH oxidase and elucidated the role of CK2 as a neuroprotectant after oxidative insults to the brain. We found that the protein levels of the catalytic subunits CK2 and CK2', as well as the total activity of CK2, are significantly reduced after transient focal cerebral ischemia (tFCI). We also found this deactivation of CK2 caused by ischemia/reperfusion increases expression of Nox2 and translocation of p67^phox and Rac1 to the membrane after tFCI. Interestingly, we found that the inactive status of Rac1 was captured by the catalytic subunit CK2 under normal conditions. However, binding between CK2 and Rac1 was immediately diminished after tFCI, and Rac1 activity was markedly increased after CK2 inhibition. Moreover, we found that deactivation of CK2 in the mouse brain enhances production of ROSs and neuronal cell death via increased NADPH oxidase activity. The increased brain infarct volume caused by CK2 inhibition was restored by apocynin, a NADPH oxidase inhibitor. This study suggests that CK2 can be a direct molecular target for modulation of NADPH oxidase activity after ischemic brain injury.

Proneurotrophin-3 Is a Neuronal Apoptotic Ligand: Evidence for Retrograde-Directed Cell Killing

Yano, H., Torkin, R., Martin, L. A., Chao, M. V., Teng, K. K. — Wed, 25 Nov 2009 10:03:10 PST

Although mature neurotrophins are well described trophic factors that elicit retrograde survival signaling, the precursor forms of neurotrophins (i.e., proneurotrophins) can function as high-affinity apoptotic ligands for selected neural populations. An outstanding question is whether target-derived proneurotrophins might affect neuronal survival/death decisions through a retrograde transport mechanism. Since neurotrophin-3 (NT-3) is highly expressed in non-neural tissues that receive peripheral innervation, we investigated the localized actions of its precursor (proNT-3) on sympathetic neurons in the present study. Pharmacological inhibition of intracellular furin proteinase activity in 293T cells resulted in proNT-3 release instead of mature NT-3, whereas membrane depolarization in cerebellar granule neurons stimulated endogenous proNT-3 secretion, suggesting that proNT-3 is an inducible bona fide ligand in the nervous system. Our data also indicate that recombinant proNT-3 induced sympathetic neuron death that is p75^NTR- and sortilin-dependent, with hallmark features of apoptosis including JNK (c-Jun N-terminal kinase) activation and nuclear fragmentation. Using compartmentalized culture systems that segregate neuronal cell bodies from axons, proNT-3, acting within the distal axon compartment, elicited sympathetic neuron death and overrode the survival-promoting actions of NGF. Together, these results raise the intriguing possibility that dysregulation of proneurotrophin processing/release by innervated targets can be deleterious to the neurons projecting to these sites.

Three Stages and Four Neural Systems in Time Estimation

Morillon, B., Kell, C. A., Giraud, A.-L. — Wed, 25 Nov 2009 10:03:10 PST

Gibbon's scalar expectancy theory assumes three processing stages in time estimation: a collating level in which event durations are automatically tracked, a counting level that reads out the time-tracking system, and a comparing level in which event durations are matched to abstract temporal references. Pöppel's theory, however, postulates a dual system for perception of durations below and above 2 s. By testing the neurophysiological plausibility of Gibbon's proposal using functional magnetic resonance imaging, we validate a three-staged model of time estimation and further show that the collating process is duplicated. Although the motor system automatically tracks durations below 2 s, mesial brain regions of the so-called "default mode network" keep track of longer events. Our results further support unique counting and comparing systems, involving prefrontal and parietal cortices in collators' readout, and the temporal cortex in contextual time estimation. These findings provide a coherent neuroanatomical framework for two theories of time perception.

Functional Variation of the Dopamine D2 Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Wed, 25 Nov 2009 10:03:10 PST

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D₂ receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D₂ receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D₂ short, mainly presynaptic, and D₂ long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D₂ signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

Behavioral and Neural Evidence of Incentive Bias for Immediate Rewards Relative to Preference-Matched Delayed Rewards

Luo, S., Ainslie, G., Giragosian, L., Monterosso, J. R. — Wed, 25 Nov 2009 10:03:10 PST

Several theories of self-control [including intertemporal bargaining (Ainslie, 1992) and self-signaling (Bodner and Prelec, 2001)] imply that intertemporal decisions can be more farsighted than would be predicted by the incentive associated with rewards outside a decision context. We examined this hypothesis using behavior and functional neuroimaging. First, subjects expressed preferences between amounts of money delayed by 4 months and smaller amounts available that day. This allowed us to establish "indifference pairs" individualized to each participant: immediate and delayed amounts that were equally preferred. Participants subsequently performed a reaction time functional magnetic resonance imaging task (Knutson et al., 2001a) that provided them with distinct opportunities to win each of the rewards that comprised the indifference pairs. Anatomical region of interest analysis as well as whole-brain analysis indicated greater response recruited by the immediate rewards (relative to the preference-matched delayed rewards) in regions previously implicated as sensitive to incentive value using the same task (including bilateral putamen, bilateral anterior insula, and midbrain). Reaction time to the target was also faster during the immediate relative to delayed reward trials (p < 0.01), and individual differences in reaction time between immediate versus delayed reward trials correlated with variance in magnetic resonance signal in those clusters that responded preferentially to immediate rewards (r = 0.33, p < 0.05). These findings indicate a discrepancy in incentive associated with the immediate versus the preference-matched delayed rewards. This discrepancy may mark the contribution of self-control processes that are recruited during decision-making but that are absent when rewards are individually anticipated.

PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling

Wed, 25 Nov 2009 10:03:10 PST

The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP_6-38 markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance.

Defective Respiratory Rhythmogenesis and Loss of Central Chemosensitivity in Phox2b Mutants Targeting Retrotrapezoid Nucleus Neurons

Wed, 25 Nov 2009 10:03:10 PST

The retrotrapezoid nucleus (RTN) is a group of neurons in the rostral medulla, defined here as Phox2b-, Vglut2-, neurokinin1 receptor-, and Atoh1-expressing cells in the parafacial region, which have been proposed to function both as generators of respiratory rhythm and as central respiratory chemoreceptors. The present study was undertaken to assess these two putative functions using genetic tools. We generated two conditional Phox2b mutations, which target different subsets of Phox2b-expressing cells, but have in common a massive depletion of RTN neurons. In both conditional mutants as well as in the previously described Phox2b^27Ala mutants, in which the RTN is also compromised, the respiratory-like rhythmic activity normally seen in the parafacial region of fetal brainstem preparations was completely abrogated. Rhythmic motor bursts were recorded from the phrenic nerve roots in the mutants, but their frequency was markedly reduced. Both the rhythmic activity in the RTN region and the phrenic nerve discharges responded to a low pH challenge in control, but not in the mutant embryos. Together, our results provide genetic evidence for the essential role of the Phox2b-expressing RTN neurons both in establishing a normal respiratory rhythm before birth and in providing chemosensory drive.

Prostate Stem Cell Antigen Is an Endogenous lynx1-Like Prototoxin That Antagonizes {alpha}7-Containing Nicotinic Receptors and Prevents Programmed Cell Death of Parasympathetic Neurons

Wed, 25 Nov 2009 10:03:10 PST

Vertebrate -bungarotoxin-like molecules of the Ly-6 superfamily have been implicated as balancers of activity and survival in the adult nervous system. To determine whether a member of this family could be involved in the development of the avian ciliary ganglion, we identified 6 Gallus genes by their homology in structure to mouse lynx1 and lynx2. One of these genes, an ortholog of prostate stem cell antigen (psca), is barely detectable at embryonic day (E) 8, before neuronal cell loss in the ciliary ganglion, but increases >100-fold as the number of neurons begins to decline between E9 and E14. PSCA is highly expressed in chicken and mouse telencephalon and peripheral ganglia and correlates with expression of 7-containing nicotinic acetylcholine receptors (7-nAChRs). Misexpressing PSCA before cell death in the ciliary ganglion blocks 7-nAChR activation by nicotine and rescues the choroid subpopulation from dying. Thus, PSCA, a molecule previously identified as a marker of prostate cancer, is a member of the Ly-6 neurotoxin-like family in the nervous system, and is likely to play a role as a modulator of 7 signaling-induced cell death during development.

Switching Retinogeniculate Axon Laterality Leads to Normal Targeting but Abnormal Eye-Specific Segregation That Is Activity Dependent

Rebsam, A., Petros, T. J., Mason, C. A. — Wed, 25 Nov 2009 10:03:10 PST

Partial decussation of sensory pathways allows neural inputs from both sides of the body to project to the same target region where these signals will be integrated. Here, to better understand mechanisms of eye-specific targeting, we studied how retinal ganglion cell (RGC) axons terminate in their thalamic target, the dorsal lateral geniculate nucleus (dLGN), when crossing at the optic chiasm midline is altered. In models with gain- and loss-of-function of EphB1, the receptor that directs the ipsilateral projection at the optic chiasm, misrouted RGCs target the appropriate retinotopic zone in the opposite dLGN. However, in EphB1^–/– mice, the misrouted axons do not intermingle with normally projecting RGC axons and segregate instead into a distinct patch. We also revisited the role of retinal activity on eye-specific targeting by blocking correlated waves of activity with epibatidine into both eyes. We show that, in wild-type mice, retinal waves are necessary during the first postnatal week for both proper distribution and eye-specific segregation of ipsilateral axons in the mature dLGN. Moreover, in EphB1^–/– mice, refinement of ipsilateral axons is perturbed in control conditions and is further impaired after epibatidine treatment. Finally, retinal waves are required for the formation of the segregated patch of misrouted axons in EphB1^–/– mice. These findings implicate molecular determinants for targeting of eye-specific zones that are independent of midline guidance cues and that function in concert with correlated retinal activity to sculpt retinogeniculate projections.

The Timing of Emotional Discrimination in Human Amygdala and Ventral Visual Cortex

Sabatinelli, D., Lang, P. J., Bradley, M. M., Costa, V. D., Keil, A. — Wed, 25 Nov 2009 10:03:10 PST

Models of visual emotional perception suggest a reentrant organization of the ventral visual system with the amygdala. Using focused functional magnetic resonance imaging in humans with a sampling rate of 100 ms, here we determine the relative timing of emotional discrimination in amygdala and ventral visual cortical structures during emotional perception. Results show that amygdala and inferotemporal visual cortex differentiate emotional from nonemotional scenes ~1 s before extrastriate occipital cortex, whereas primary occipital cortex shows consistent activity across all scenes. This pattern of discrimination is consistent with a reentrant organization of emotional perception in visual processing, in which transaction between rostral ventral visual cortex and amygdala originates the identification of emotional relevance.

Peptidyl-Prolyl Isomerase 1 Regulates Protein Phosphatase 2A-Mediated Topographic Phosphorylation of Neurofilament Proteins

Rudrabhatla, P., Albers, W., Pant, H. C. — Wed, 25 Nov 2009 10:03:10 PST

In normal neurons, neurofilament (NF) proteins are phosphorylated in the axonal compartment. However, in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), NF proteins are aberrantly hyperphosphorylated within the cell bodies. The aberrant hyperphosphorylation of NF accumulations found in neurodegeneration could be attributable to either deregulation of proline-directed Ser/Thr kinase(s) activity or downregulation of protein phosphatase(s) activity. In this study, we found that protein phosphatase 2A (PP2A) expression is high in neuronal cell bodies and that inhibition of PP2A activity by okadaic acid (OA), microcystin LR (mLR), or fostriecin (Fos) leads to perikaryal hyperphosphorylation of NF. Peptidyl-prolyl isomerase Pin1 inhibits the dephosphorylation of NF by PP2A in vitro. In cortical neurons, Pin1 modulates the topographic phosphorylation of the proline-directed Ser/Thr residues within the tail domain of NF proteins by inhibiting the dephosphorylation by PP2A. Inhibition of Pin1 inhibits OA-induced aberrant perikaryal phosphorylation of NF. Treatment of cortical neurons with OA or Fos prevents the general anterograde transport of transfected green fluorescent protein–high-molecular-mass (NF-H) into axons caused by hyperphosphorylation of NF-H, and inhibition of Pin1 rescues this effect. Furthermore, inhibition of Pin1 inhibits the OA- or Fos-induced neuronal apoptosis. We show that OA-induced hyperphosphorylation of NF is a consequence of dephosphorylation of NF and is independent of c-Jun N-terminal protein kinase, extracellular signal-regulated kinase, and cyclin-dependent kinase-5 pathways. This study highlights a novel signaling role of PP2A by Pin1 and implicates Pin1 as a therapeutic target to reduce aberrant phosphorylation of NF proteins in neurodegenerative disorders such as AD, PD, and ALS.

Combining Peripheral Nerve Grafts and Chondroitinase Promotes Functional Axonal Regeneration in the Chronically Injured Spinal Cord

Wed, 25 Nov 2009 10:03:10 PST

Because there currently is no treatment for spinal cord injury, most patients are living with long-standing injuries. Therefore, strategies aimed at promoting restoration of function to the chronically injured spinal cord have high therapeutic value. For successful regeneration, long-injured axons must overcome their poor intrinsic growth potential as well as the inhibitory environment of the glial scar established around the lesion site. Acutely injured axons that regenerate into growth-permissive peripheral nerve grafts (PNGs) reenter host tissue to mediate functional recovery if the distal graft–host interface is treated with chondroitinase ABC (ChABC) to cleave inhibitory chondroitin sulfate proteoglycans in the scar matrix. To determine whether a similar strategy is effective for a chronic injury, we combined grafting of a peripheral nerve into a highly relevant, chronic, cervical contusion site with ChABC treatment of the glial scar and glial cell line-derived neurotrophic factor (GDNF) stimulation of long-injured axons. We tested this combination in two grafting paradigms: (1) a peripheral nerve that was grafted to span a chronic injury site or (2) a PNG that bridged a chronic contusion site with a second, more distal injury site. Unlike GDNF–PBS treatment, GDNF–ChABC treatment facilitated axons to exit the PNG into host tissue and promoted some functional recovery. Electrical stimulation of axons in the peripheral nerve bridge induced c-Fos expression in host neurons, indicative of synaptic contact by regenerating fibers. Thus, our data demonstrate, for the first time, that administering ChABC to a distal graft interface allows for functional axonal regeneration by chronically injured neurons.

The Dorsomedial Striatum Reflects Response Bias during Learning

Kimchi, E. Y., Laubach, M. — Wed, 25 Nov 2009 10:03:10 PST

Previous studies have established that neurons in the dorsomedial striatum track the behavioral significance of external stimuli, are sensitive to contingencies between actions and outcomes, and show rapid flexibility in representing task-related information. Here, we describe how neural activity in the dorsomedial striatum changes during the initial acquisition of a Go/NoGo task and during an initial reversal of stimulus-response contingencies. Rats made nosepoke responses over delay periods and then received one of two acoustic stimuli. Liquid rewards were delivered after one stimulus (S+) if the rats made a Go response (entering a reward port on the opposite wall of the chamber). If a Go response was made to other stimulus (S–), rats experienced a timeout. On 10% of trials, no stimulus was presented. These trials were used to assess response bias, the animals' tendency to collect reward independent of the stimulus. Response bias increased during the reversal, corresponding to the animals' uncertainty about the stimulus-response contingencies. Most task-modulated neurons fired during the response at the end of the delay period. The fraction of response-modulated neurons was correlated with response bias and neural activity was sensitive to the behavioral response made on the previous trial. During initial task acquisition and initial reversal learning, there was a remarkable change in the percentages of neurons that fired in relation to the task events, especially during withdrawal from the nosepoke aperture. These results suggest that changes in task-related activity in the dorsomedial striatum during learning are driven by the animal's bias to collect rewards.

Dopamine-Stimulated Dephosphorylation of Connexin 36 Mediates AII Amacrine Cell Uncoupling

Kothmann, W. W., Massey, S. C., O'Brien, J. — Wed, 25 Nov 2009 10:03:10 PST

Gap junction proteins form the substrate for electrical coupling between neurons. These electrical synapses are widespread in the CNS and serve a variety of important functions. In the retina, connexin 36 (Cx36) gap junctions couple AII amacrine cells and are a requisite component of the high-sensitivity rod photoreceptor pathway. AII amacrine cell coupling strength is dynamically regulated by background light intensity, and uncoupling is thought to be mediated by dopamine signaling via D₁-like receptors. One proposed mechanism for this uncoupling involves dopamine-stimulated phosphorylation of Cx36 at regulatory sites, mediated by protein kinase A. Here we provide evidence against this hypothesis and demonstrate a direct relationship between Cx36 phosphorylation and AII amacrine cell coupling strength. Dopamine receptor-driven uncoupling of the AII network results from protein kinase A activation of protein phosphatase 2A and subsequent dephosphorylation of Cx36. Protein phosphatase 1 activity negatively regulates this pathway. We also find that Cx36 gap junctions can exist in widely different phosphorylation states within a single neuron, implying that coupling is controlled at the level of individual gap junctions by locally assembled signaling complexes. This kind of synapse-by-synapse plasticity allows for precise control of neuronal coupling, as well as cell-type-specific responses dependent on the identity of the signaling complexes assembled.

Functional But Not Structural Networks of the Human Laryngeal Motor Cortex Show Left Hemispheric Lateralization during Syllable But Not Breathing Production

Simonyan, K., Ostuni, J., Ludlow, C. L., Horwitz, B. — Wed, 25 Nov 2009 10:03:10 PST

The laryngeal motor cortex (LMC) is indispensible for the vocal motor control of speech and song production. Patients with bilateral lesions in this region are unable to speak and sing, although their nonverbal vocalizations, such as laughter and cry, are preserved. Despite the importance of the LMC in the control of voluntary voice production in humans, the literature describing its connections remains sparse. We used diffusion tensor probabilistic tractography and functional magnetic resonance imaging-based functional connectivity analysis to identify LMC networks controlling two tasks necessary for speech production: voluntary voice as repetition of two different syllables and voluntary breathing as controlled inspiration and expiration. Peaks of activation during all tasks were found in the bilateral ventral primary motor cortex in close proximity to each other. Functional networks of the LMC during voice production but not during controlled breathing showed significant left-hemispheric lateralization (p < 0.0005). However, structural networks of the LMC associated with both voluntary voice production and controlled breathing had bilateral hemispheric organization. Our findings indicate the presence of a common bilateral structural network of the LMC, upon which different functional networks are built to control various voluntary laryngeal tasks. Bilateral organization of functional LMC networks during controlled breathing supports its indispensible role in all types of laryngeal behaviors. Significant left-hemispheric lateralization of functional networks during simple but highly learned voice production suggests the readiness of the LMC network for production of a complex voluntary behavior, such as human speech.

Brain Mechanisms Supporting Discrimination of Sensory Features of Pain: A New Model

Oshiro, Y., Quevedo, A. S., McHaffie, J. G., Kraft, R. A., Coghill, R. C. — Wed, 25 Nov 2009 10:03:10 PST

Pain can be very intense or only mild, and can be well localized or diffuse. To date, little is known as to how such distinct sensory aspects of noxious stimuli are processed by the human brain. Using functional magnetic resonance imaging and a delayed match-to-sample task, we show that discrimination of pain intensity, a nonspatial aspect of pain, activates a ventrally directed pathway extending bilaterally from the insular cortex to the prefrontal cortex. This activation is distinct from the dorsally directed activation of the posterior parietal cortex and right dorsolateral prefrontal cortex that occurs during spatial discrimination of pain. Both intensity and spatial discrimination tasks activate highly similar aspects of the anterior cingulate cortex, suggesting that this structure contributes to common elements of the discrimination task such as the monitoring of sensory comparisons and response selection. Together, these results provide the foundation for a new model of pain in which bidirectional dorsal and ventral streams preferentially amplify and process distinct sensory features of noxious stimuli according to top-down task demands.

BDNF-Hypersecreting Human Mesenchymal Stem Cells Promote Functional Recovery, Axonal Sprouting, and Protection of Corticospinal Neurons after Spinal Cord Injury

Wed, 25 Nov 2009 10:03:10 PST

Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). We transplanted MSCs derived from human bone marrow (hMSCs) to study their potential therapeutic effect in SCI in the rat. In addition to hMSCs, we used gene-modified hMSCs to secrete brain-derived neurotrophic factor (BDNF-hMSCs). After a dorsal transection lesion was induced at T9, cells were microinjected on each side of the transection site. Fluorogold (FG) was injected into the epicenter of the lesion cavity to identify transected corticospinal tract (CST) neurons. At 5 weeks after transplantation, the animals were perfused. Locomotor recovery improvement was observed for the BDNF-hMSC group, but not in the hMSC group. Structurally there was increased sprouting of injured corticospinal tract and serotonergic projections after hMSC and BDNF-hMSC transplantation. Moreover, an increased number of serotonergic fibers was observed in spinal gray matter including the ventral horn at and below the level of the lesion, indicating increased innervation in the terminal regions of a descending projection important for locomotion. Stereological quantification was performed on the brains to determine neuronal density in primary motor (M1) cortex. The number of FG backfilled cells demonstrated an increased cell survival of CST neurons in M1 cortex in both the hMSC and BDNF-hMSC groups at 5 weeks, but the increase for the BDNF-hMSC group was greater. These results indicate that transplantation of hMSCs hypersecreting BDNF results in structural changes in brain and spinal cord, which are associated with improved functional outcome in acute SCI.

Distinct Muscarinic Acetylcholine Receptor Subtypes Contribute to Stability and Growth, But Not Compensatory Plasticity, of Neuromuscular Synapses

Wed, 25 Nov 2009 10:03:10 PST

Muscarinic acetylcholine receptors (mAChRs) modulate synaptic function, but whether they influence synaptic structure remains unknown. At neuromuscular junctions (NMJs), mAChRs have been implicated in compensatory sprouting of axon terminals in paralyzed or denervated muscles. Here we used pharmacological and genetic inhibition and localization studies of mAChR subtypes at mouse NMJs to demonstrate their roles in synaptic stability and growth but not in compensatory sprouting. M₂ mAChRs were present solely in motor neurons, whereas M₁, M₃, and M₅ mAChRs were associated with Schwann cells and/or muscle fibers. Blockade of all five mAChR subtypes with atropine evoked pronounced effects, including terminal sprouting, terminal withdrawal, and muscle fiber atrophy. In contrast, methoctramine, an M_2/4-preferring antagonist, induced terminal sprouting and terminal withdrawal, but no muscle fiber atrophy. Consistent with this observation, M₂^–/– but no other mAChR mutant mice exhibited spontaneous sprouting accompanied by extensive loss of parental terminal arbors. Terminal sprouting, however, seemed not to be the causative defect because partial loss of terminal branches was common even in the M₂^–/– NMJs without sprouting. Moreover, compensatory sprouting after paralysis or partial denervation was normal in mice deficient in M₂ or other mAChR subtypes. We also found that many NMJs of M₅^–/– mice were exceptionally small and reduced in proportion to the size of parental muscle fibers. These findings show that axon terminals are unstable without M₂ and that muscle fiber growth is defective without M₅. Subtype-specific muscarinic signaling provides a novel means for coordinating activity-dependent development and maintenance of the tripartite synapse.

Cleavage of proBDNF to BDNF by a Tolloid-Like Metalloproteinase Is Required for Acquisition of In Vitro Eyeblink Classical Conditioning

Keifer, J., Sabirzhanov, B. E., Zheng, Z., Li, W., Clark, T. G. — Wed, 25 Nov 2009 10:03:10 PST

The tolloid/bone morphogenetic protein-1 family of metalloproteinases have an important role in the regulation of embryonic pattern formation and tissue morphogenesis. Studies suggest that they participate in mechanisms of synaptic plasticity in adults, but very little is known about their function. Recently, we isolated a reptilian ortholog of the tolloid gene family designated turtle tolloid-like gene (tTll). Here, we examined the role of tTLL in an in vitro model of eyeblink classical conditioning using an isolated brainstem preparation to assess its role in synaptic plasticity during conditioning. Analysis by real-time reverse transcription-PCR shows that an extracellularly secreted form of tTLL, tTLLs, is transiently expressed in the early stages of conditioning during conditioned response acquisition, whereas a cytosolic form, tTLLc, is not. Short interfering RNA (siRNA)-directed gene knockdown and rescue of tTLL expression demonstrate that it is required for conditioning. Significantly, we show that tTLLs cleaves the precursor proBDNF into mature BDNF in cleavage assay studies, and application of recombinant tTLLs protein alone to preparations results in induction of mature BDNF expression. The mature form of BDNF is minimally expressed in preparations treated with anti-tTLL siRNA, and the synaptic incorporation of both GluR1- and GluR4-containing AMPA receptors is significantly reduced, resulting in suppression of conditioning. This is the first study to demonstrate that expression of an extracellularly secreted tolloid-like metalloproteinase is regulated in the early stages of classical conditioning and functions in the conversion of proBDNF to mature BDNF. The mature form of BDNF is required for synaptic delivery of AMPA receptors and acquisition of conditioned responses.

Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis

Soulika, A. M., Lee, E., McCauley, E., Miers, L., Bannerman, P., Pleasure, D. — Wed, 25 Nov 2009 10:03:10 PST

Axonal loss is the principal cause of chronic disability in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). In C57BL/6 mice with EAE induced by immunization with myelin oligodendrocyte glycoprotein peptide 35–55, the first evidences of axonal damage in spinal cord were in acute subpial and perivascular foci of infiltrating neutrophils and lymphocytes and included intra-axonal accumulations of the endovesicular Toll-like receptor TLR8, and the inflammasome protein NAcht leucine-rich repeat protein 1 (NALP1). Later in the course of this illness, focal inflammatory infiltrates disappeared from the spinal cord, but there was persistent activation of spinal cord innate immunity and progressive, bilaterally symmetric loss of small-diameter corticospinal tract axons. These results support the hypothesis that both contact-dependent and paracrine interactions of systemic inflammatory cells with axons and an innate immune-mediated neurodegenerative process contribute to axonal loss in this multiple sclerosis model.

Superior Parietal Cortex Is Critical for the Manipulation of Information in Working Memory

Koenigs, M., Barbey, A. K., Postle, B. R., Grafman, J. — Wed, 25 Nov 2009 10:03:10 PST

In recent years, theoretical perspectives on posterior parietal function have evolved beyond the traditional visuospatial processing models to include more diverse cognitive operations, such as long-term and working memory. However, definitive neuropsychological evidence supporting the superior parietal lobule's purported role in working memory has been lacking. Here, we studied human brain lesion patients to determine whether the superior parietal lobule is indeed necessary for working memory. We assessed a wide range of memory functions in three participant groups: superior parietal lesions (n = 19), lesions not involving superior parietal cortex (n = 146), and no brain lesions (n = 55). Superior parietal damage was reliably associated with deficits on tests involving the manipulation and rearrangement of information in working memory, but not on working memory tests requiring only rehearsal and retrieval processes, nor on tests of long-term memory. These results indicate that superior parietal cortex is critically important for the manipulation of information in working memory.

Fornix Microstructure Correlates with Recollection But Not Familiarity Memory

Wed, 25 Nov 2009 10:03:10 PST

The fornix is the main tract between the medial temporal lobe (MTL) and medial diencephalon, both of which are critical for episodic memory. The precise involvement of the fornix in memory, however, has been difficult to ascertain since damage to this tract in human amnesics is invariably accompanied by atrophy to surrounding structures. We used diffusion-weighted imaging to investigate whether individual differences in fornix white matter microstructure in neurologically healthy participants were related to differences in memory as assessed by two recognition tasks. Higher microstructural integrity in the fornix tail was found to be associated with significantly better recollection memory. In contrast, there was no significant correlation between fornix microstructure and familiarity memory or performance on two non-mnemonic tasks. Our findings support the idea that there are distinct MTL–diencephalon pathways that subserve differing memory processes.

Robust Coding of Ego-Motion in Descending Neurons of the Fly

Wertz, A., Gaub, B., Plett, J., Haag, J., Borst, A. — Wed, 25 Nov 2009 10:03:10 PST

In many species, motion-sensitive neurons responding to optic flow at higher processing stages are well characterized; however, less is known how this representation of ego-motion is further transformed into an appropriate motor response. Here, we analyzed in the blowfly Calliphora vicina the visuomotor transformation from motion-sensitive neurons in the lobula plate [V2 and vertical system (VS) cells] onto premotor descending neurons [descending neurons of the ocellar and vertical system (DNOVS) cells] feeding into the motor circuit of the fly thoracic ganglion. We found that each of these cells is tuned to rotation of the fly around a particular body axis. Comparing the responses of presynaptic and postsynaptic cells revealed that DNOVS cells have approximately the same tuning widths as V2 and VS cells. However, DNOVS signals cells are less corrupted by fluctuations arising from the spatial structure of the visual input than their presynaptic elements. This leads to a more robust representation of ego-motion at the level of descending neurons. Thus, when moving from lobula plate cells to descending neurons, the selectivity for a particular optic flow remains unaltered, but the robustness of the representation increases.

Inhibition of Adult Rat Retinal Ganglion Cells by D1-Type Dopamine Receptor Activation

Wed, 25 Nov 2009 10:03:10 PST

The spike output of neural pathways can be regulated by modulating output neuron excitability and/or their synaptic inputs. Dopaminergic interneurons synapse onto cells that route signals to mammalian retinal ganglion cells, but it is unknown whether dopamine can activate receptors in these ganglion cells and, if it does, how this affects their excitability. Here, we show D_1a receptor-like immunoreactivity in ganglion cells identified in adult rats by retrogradely transported dextran, and that dopamine, D₁-type receptor agonists, and cAMP analogs inhibit spiking in ganglion cells dissociated from adult rats. These ligands curtailed repetitive spiking during constant current injections and reduced the number and rate of rise of spikes elicited by fluctuating current injections without significantly altering the timing of the remaining spikes. Consistent with mediation by D₁-type receptors, SCH-23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] reversed the effects of dopamine on spikes. Contrary to a recent report, spike inhibition by dopamine was not precluded by blocking I_h. Consistent with the reduced rate of spike rise, dopamine reduced voltage-gated Na⁺ current (I_Na) amplitude, and tetrodotoxin, at doses that reduced I_Na as moderately as dopamine, also inhibited spiking. These results provide the first direct evidence that D₁-type dopamine receptor activation can alter mammalian retinal ganglion cell excitability and demonstrate that dopamine can modulate spikes in these cells by a mechanism different from the presynaptic and postsynaptic means proposed by previous studies. To our knowledge, our results also provide the first evidence that dopamine receptor activation can reduce excitability without altering the temporal precision of spike firing.

A Rapamycin-Sensitive Signaling Pathway Is Essential for the Full Expression of Persistent Pain States

Wed, 25 Nov 2009 10:03:10 PST

Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of A-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.