JNeurosci publishes a broad spectrum of articles reporting important work across areas of neuroscience. Because keeping up with exciting work outside your individual subdiscipline can be difficult, JNeurosci created the Spotlight feature to highlight articles that our reviewers gave the highest marks for both methodological merit and significance. We hope the papers in this year’s Spotlight will be of interest to neuroscientists across areas and at many different levels of experience. Below is the collection of this year’s Spotlight papers and summaries of their key findings. Papers selected for the Spotlight feature in previous years can be found below as well.
2022
Cellular/Molecular
JUN Regulation of Injury-Induced Enhancers in Schwann Cells
After peripheral nerve injury, Schwann cells, which normally form peripheral myelin, undergo large changes in gene expression that allow them to instead clear debris and guide regenerating axons. This change in genetic programming involves epigenetic modifications that determine whether specific genes can be transcribed. Ramesh et al. examined epigenetic modifications in Schwann cells of healthy peripheral nerves to determine whether repair genes are associated with modifications that poise them to be activated quickly after nerve injury. The answer was no. Instead, the authors suggest that the transcription factor c-Jun, which is strongly upregulated immediately after nerve injury, binds to enhancer elements of repair genes and promotes the epigenetic modifications required for gene expression. This bolsters the hypothesis that c-Jun upregulation is critical for driving Schwann cells toward a repair phenotype.
Development/Plasticity/Repair
Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins
Neural activity leads to changes in synaptic structure and neuronal function by inducing changes in gene expression and protein synthesis. Single-cell transcriptome profiling has identified numerous genes that are regulated by neural activity. Changes in gene transcription do not necessarily lead to proportional changes in synthesis of the encoded protein, however. Moreover, neural activity can have different effects on protein translation in different cell types. Therefore, Schiapparelli et al. developed a technique to tag nascent proteins in defined cell types. Specifically, they expressed a mutant form of methionine tRNA synthetase (MetRS) selectively in pyramidal neurons in mice, then administered a noncanonical methionine analog that is incorporated into nascent proteins by this mutant MetRS. Newly synthesized proteins could then be selectively tagged for detection and quantification using mass spectrometry. Using this technique, the authors identified >500 proteins whose synthesis was altered shortly after seizure-associated neural activity.
Systems/Circuits
Temporal Dynamics of Neural Responses in Human Visual Cortex
Sensory stimuli and neural responses to these stimuli vary over time. Many studies have investigated the temporal dynamics of neural responses to visual stimuli, but most of these have focused on a single stimulus parameter (e.g. contrast) in 1-2 visual cortical regions and used different computational models to explain the data. To obtain a more comprehensive understanding of the temporal dynamics of neural responses to visual stimuli, Groen et al. used electrocorticography to measure activity in several lower and higher visual areas while presenting stimuli that varied systematically in duration, contrast, and interstimulus interval. A single, relatively simple computational model was able to explain the complex temporal dynamics of neural responses across areas and stimuli using the same set of model parameters. One important conclusion from the work is that a shared mechanism, modeled with a divisive normalization parameter, explains why neural responses decrease both when stimulus contrast is reduced and when stimuli are presented repeatedly.
Systems/Circuits
Cortico-Striatal Control over Adaptive Goal-Directed Responding Elicited by Cues Signaling Sucrose Reward or Punishment
Animals readily learn to identify sensory stimuli that signal the opportunity for reward or the threat of injury and to make appropriate responses when such cues are present. Animals can also learn to suppress actions when conflicting cues are present or when a particular cue is no longer a reliable predictor of an outcome. The ability of sensory information to drive appropriate behavior depends partly on the prelimbic (PL) and infralimbic (IL) areas of the medial prefrontal cortex and their respective targets in the core and shell regions of the nucleus accumbens (NAc). Much work has suggested that PL promotes approach or avoidance responses to cues signaling reward or punishment, whereas IL inhibits these responses when the cues lose predictive value. Hamel et al. extended this work with evidence that both L and IL regulate behavior when conflicting cues are present. Rats learned to press a lever to receive sucrose when a light flashed and to withhold lever presses to avoid shock when a tone played. After training, inactivating either PL or IL reduced lever pressing in response to the light cue and increased lever pressing in response to the sound cue, regardless of whether the sucrose or shock continued to be delivered. This suggests rats were less able to choose the appropriate action in response to conflicting cues.
Behavioral/Cognitive
Contingent Amygdala Inputs Trigger Heterosynaptic LTP at Hippocampus-To-Accumbens Synapses
After an animal learns to associate a particular sensory stimulus with a reward or threat, the animal will be motivated to make appropriate behavioral responses when it encounters the stimulus in the future. The ability of cues to motivate behavior depends on medium spiny neurons in the nucleus accumbens. These neurons receive convergent input from the basolateral amygdala, which conveys information about valence states, and the ventral hippocampus, which conveys contextual information. By using optogenetic techniques to activate these inputs in brain slices, Yu et al. found that co-activation caused long-term potentiation of hippocampal inputs without affecting amygdala inputs. The effects required the activation of D1-type dopamine receptors. Thus, this work suggests a plausible mechanism by which neutral cues may acquire the ability to motivate action.
Behavioral/Cognitive
Distinct Progressions of Neuronal Activity Changes Underlie the Formation and Consolidation of a Gustatory Associative Memory
In gustatory cortex, tastes are represented by distinct spatiotemporal patterns of activity across ensembles of broadly tuned neurons. This population activity encodes both the identity and the valence of tastes. Therefore, ensemble activity is altered during the development of conditioned taste aversion (CTA). Because this learning is mediated by changes in synaptic strength between individual cells in ensembles, Arieli et al. how changes at the single-cell level relate to changes in population dynamics. Single-unit recordings revealed that individual neurons' responses changed in different directions (increases and decreases) and at different times to produce an overall increase in firing during the acquisition and consolidation phases of CTA. The work suggests that taste learning involves continuous adjustments in the activity of individual neurons to achieve the desired changes in network state.
Behavioral/Cognitive
Oxytocin and the Punitive Hub—Dynamic Spread of Cooperation in Human Social Networks
Cooperation among unrelated individuals is essential for large societies to function. To ensure cooperation, groups often punish freeloaders. Remarkably, oxytocin, a neuropeptide produced by the hypothalamus not only increases people’s willingness to cooperate, but also makes them more likely to punish those who fail to cooperate. Using economic games and computer simulations, Li et al. found that administering oxytocin to a few well-connected people in a group increased cooperation throughout the group. Surprisingly this effect did not stem from an increase in willingness to cooperate, per se, but rather from increasing the tendency to punish those who acted selfishly.
Neurobiology of Disease
STAT1 Contributes to Microglial/Macrophage Inflammation and Neurological Dysfunction in a Mouse Model of Traumatic Brain Injury
After traumatic brain injury (TBI), microglia and macrophages become activated in various ways to promote inflammation and tissue repair. Although initially beneficial, proinflammatory microglia and macrophages can cause secondary tissue damage and worsen recovery prospects. Therefore, selectively reducing the number of proinflammatory cells may improve outcomes after TBI. Zhao, Ma, et al. did this by administering fludarabine, which inhibits STAT1, a transcription factor that promotes proinflammatory phenotypes in peripheral macrophages and is upregulated in the brain after traumatic injury. Administering fludarabine after TBI in mice reduced the number of proinflammatory microglia and macrophages in the brain and increased the number of prorepair cells. It also reduced brain levels of inflammatory cytokines, tissue loss, and axonal damage, and it sped recovery of sensorimotor function. These findings suggest that fludarabine may improve functional recovery in patients with traumatic brain injury.
2021
Cellular/Molecular
Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains
Binding of GABA to GABAA receptors opens chloride-selective ion channels. The direction of chloride movement through these channels depends largely on the intracellular chloride concentration ([Cl–]i). In most adult neurons, [Cl–]i is relatively low, so activation of GABA receptors leads to net chloride influx, which hyperpolarizes the cell. However, chloride movement is also influenced by large intracellular anionic polymers (proteins and nucleic acids), which repel chloride ions. The effects of these anions are typically ignored, likely because their concentration doesn’t vary much over time. Importantly, however, anionic polymers such as cytoskeletal proteins are not uniformly distributed within neurons. Moreover, Rahmati et al. provided evidence that within dendrites of single hippocampal pyramidal neurons, actin filaments create microdomains with different [Cl–]i. Consequently, the effects of GABA might vary across dendrites within single cells.
Cellular/Molecular
Comparison of Ciliary Targeting of Two Rhodopsin-Like GPCRs: Role of C-Terminal Localization Sequences in Relation to Cilium Type
Nearly all cells have a primary cilium—an antenna-like protrusion for detecting extracellular signals. This function requires selective trafficking of G-protein-coupled receptors (GPCRs) to the cilium, guided by ciliary localization sequences present in the receptors’ intracellular domains. Chadha et al. found that trafficking of ciliary GPCRs can differ across cell types. In particular, rhodopsin is more efficiently transported to the primary cilium in rod photoreceptors (in which the cilium is markedly modified to house the phototransduction machinery in the outer segment) than in other cell types. They also found a novel ciliary localization sequence in somatostatin receptor 3, a rhodopsin-like GPCR. Their results suggest that specialized sorting machinery is used to localize different GPCRs to the primary cilium of different cell types.
Development/Plasticity/Repair
CNS Hypomyelination Disrupts Axonal Conduction and Behavior in Larval Zebrafish
Myelin speeds axon potential propagation along the axon, protects axons from damage, and supplies nutrients to axons. Therefore, loss of myelin slows axonal conduction and leads to axon degeneration, both of which may contribute to impaired neural function. Studying all these effects simultaneously is challenging, but larval zebrafish, with their transparent bodies and well-characterized locomotor behavior, may provide a way to meet this challenge. Indeed, Madden et al. demonstrated that a genetic mutation that causes hypomyelination of reticulospinal neurons led to slowed action potential conduction and a corresponding increase in the latency to initiate behavioral responses to auditory stimuli. This study provides a foundation for future work studying how changes in myelination affect neuronal function and behavior in living animals over time.
Systems/Circuits
Supervised Multisensory Calibration Signals Are Evident in VIP But Not MSTd
Sensory information can be noisy and hard to interpret. Therefore, animals typically integrate information from multiple sensory modalities to guide behavior. To judge their direction of movement, for example, animals combine vestibular and visual information. Importantly, if information conveyed by one sensory modality becomes unreliable because of changes in the environment or in the sensory organs, animals must recalibrate their algorithms for combining sensory information or interpreting the integrated information to make accurate decisions. Zaidel et al. asked where such multisensory plasticity occurred. They focused on two cortical areas that respond to multisensory information about heading direction: the relatively low-level dorsal medial superior temporal area (MSTd) and the higher-level ventral intraparietal area (VIP), which shows decision-related, as well as stimulus-related activity. The authors recorded neurons in these areas as monkeys judged their heading direction based on sometimes-unreliable visual or vestibular input. Recalibration of judgments (as indicated by behavioral responses) when one modality provided inaccurate information was reflected by changes in neural activity in VIP, but not MSTd.
Systems/Circuits
From Receptive to Perceptive Fields: Size-Dependent Asymmetries in Both Negative Afterimages and Subcortical On and Off Post-Stimulus Responses
If you stare at a stationary image for several seconds then look at a blank screen, you will see a negative afterimage. The production of dark afterimages by bright stimuli is thought to depend on the activation of OFF cells in the lateral geniculate nucleus, which respond to decreases in light intensity within their receptive fields. Conversely, dark stimuli are thought to produce bright afterimages because their offset activates ON cells. Notably, the strength of afterimages is related to the strength of responses to the initial stimuli. Specifically, dark stimuli produce greater responses and stronger and longer-lasting afterimages than bright stimuli of similar contrast. Liu et al. found that this asymmetry in afterimage strength was influenced by the size of stimuli, as a consequence of the antagonistic surrounds of ON and OFF receptive fields. Modeling work confirmed that surround suppression was weaker and sustained responses to offset of antagonistic stimuli were stronger in ON cells than OFF cells in the LGN.
Systems/Circuits
Dissociated Role of Thalamic and Cortical Input to the Lateral Amygdala for Consolidation of Long-Term Fear Memory
Nociceptive information and information about auditory stimuli converge in the basolateral amygdala, driving the formation of associative memories that underlie conditioned fear responses. Like other memories, fear memories must be consolidated for the conditioned responses to persist. Lee et al. used optogenetics to investigate the role of projections to the basolateral amygdala from the auditory cortex and auditory thalamus in the consolidation of auditory fear memories. They found that silencing projections from thalamus immediately after fear conditioning had no effect on fear responses elicited by the conditioned stimulus 1 h after training, but silencing these projections resulted in reduced fear responses when tested 24 h or 20 d later. In contrast, silencing thalamic projections projections 3 h after the initial conditioning session had no effect on conditioned fear responses at any subsequent time point. Silencing projections from auditory cortex had no effect on conditioned fear responses when tested after 24 h, but it reduced fear responses tested after 20 d. These results suggest that immediately after training, activation of projections to the basolateral amygdala from both the auditory thalamus and the auditory cortex contribute to consolidation of fear memories, with the cortical projections being important primarily for the formation of remote memory.
Behavioral/Cognitive
Neural Responses to Heartbeats Detect Residual Signs of Consciousness during Resting State in Postcomatose Patients
Although we are not usually consciously aware of our heartbeats, they evoke neural responses that can be detected by averaging EEG activity time-locked to heartbeats. Notably, heartbeat-evoked responses increase when one is thinking about oneself, and greater responses are associated with better detection of visual and somatosensory stimuli. Such findings have led to the hypothesis that heartbeat-evoked responses contribute to consciousness of oneself. Candia-Rivera et al. extended this hypothesis, proposing that heartbeat-evoked responses could be used to detect residual consciousness in patients who do not exhibit overt behavior or neural responses to verbal instructions. They provided support for this hypothesis by comparing heartbeat-evoked responses measured with EEG to the level of consciousness indicated by resting-state brain glucose uptake. In support of their hypothesis, the magnitude of heartbeat-evoked responses could distinguish patients with unresponsive wakefulness syndrome from those in a minimally conscious state with 87% accuracy. Therefore, heartbeat-evoked responses might be useful for inferring the level of consciousness in unresponsive patients.
Behavioral/Cognitive
Prior Cocaine Exposure Increases Firing to Immediate Reward While Attenuating Cue and Context Signals Related to Reward Value in the Insula
Plasticity in many brain areas contributes to the development of drug addiction and the propensity to relapse. One such area is the insula; in particular, increased activity in the insula is thought to contribute to relapse. To understand the insula’s contribution to drug-related behavior better, Pribut et al. recorded from this area as rats performed a task in which, guided by previously learned cues, they chose between two sucrose-reward sites that differed in either the size of reward or the wait time before receiving the reward. Rats usually chose the larger or the immediate reward, and these preferences were stronger and were indicated more quickly in rats that had received cocaine for 12 d preceding the test than in controls. Most notably, fewer insula neurons responded to reward-predictive cues and more responded to reward delivery in cocaine-experienced rats than in controls. Furthermore, insula neurons showed less sustained firing during delay periods in cocaine-experienced rats than in controls. Thus, cocaine experience followed by abstinence changes how insula neurons respond to rewards, associated cues, and delayed gratification in a way that may enhance drug seeking.
Neurobiology of Disease
Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia
Genetic manipulations in rodents and other animals have enabled researchers to make great progress in understanding human diseases and conditions. But genes don’t act in isolation and even conditions caused by alteration of a single gene are tempered by the carrier’s other genes. Consequently, animal models often don’t fully recapitulate disease phenotypes found in humans. For example, a heterozygous three-nucleotide deletion in TOR1A, encoding Torsin A, causes a form of dystonia (DYT1) in people, but produces minimal motor deficits in mice. Generating neurons from induced pluripotent stem cells (IPSCs) derived from patient fibroblasts offers a path for understanding the cellular effects of a mutation in a more realistic genetic background. Ding et al. used this approach to determine how the dystonia-causing TOR1A deletion affects neurons. They found that the mutation led to mislocalization of Lamin B1, an intermediate filament that helps form the nuclear lamina, and thus caused neurons to have nuclei with fewer nuclear pore complexes, which impaired export of mRNA from the nucleus. Given that the nuclear lamin participates in most nuclear functions, including DNA replication, transcription, chromatin organization, and cell-cycle regulation, numerous neuronal functions are likely to be disrupted in people with DYT1.
Neurobiology of Disease
Estradiol Regulation of the Prelimbic Cortex and the Reinstatement of Cocaine Seeking in Female Rats
Women who are addicted to cocaine report more intense craving and are more prone to relapse than men. Notably, craving varies across the menstrual cycle, suggesting gonadal hormones influence craving. A similar phenomenon occurs in rats, in which reinstatement of cocaine-seeking after extinction is more readily induced by a single cocaine dose in females than in males, and this sensitivity to drug-induced reinstatement varies across the estrous cycle. Notably, estradiol injection increases cocaine-primed reinstatement in ovariectomized female rats, and injecting estradiol into the prelimbic prefrontal cortex of these rats promotes cocaine seeking, supporting a role for estrogens in some aspects of relapse. Doncheck et al. discovered that estradiol exerts its effects in the prelimbic prefrontal cortex by acting on estrogen receptor β and G-protein-coupled estrogen receptor 1 (GPER1) along with downstream reduction in the frequency of GABAA-receptor-dependent miniature IPSCs in layer 5/6 pyramidal cells. The decrease in GABAergic inhibition may impair prefrontal cortical regulation of drug seeking.
2020
Development/Plasticity/Repair
Simultaneous Requirements for Hes1 in Retinal Neurogenesis and Optic Cup–Stalk Boundary Maintenance
Throughout embryonic development, the balance of stem-cell proliferation and differentiation is tightly regulated to ensure that the proper number of each cell type is produced. One important regulator of proliferation and differentiation is Notch signaling, which acts partly via the transcriptional repressor Hes1. Bosze et al. studied the role of Notch and Hes1 in the developing retina and discovered Hes1 not only promotes proliferation and hinders formation of retinal ganglion cells, but also promotes formation of cone photoreceptors. The work highlights the complexity of Notch signaling and transcriptional regulation during development.
Behavioral/Cognitive
Sleep Spindles Promote the Restructuring of Memory Representations in Ventromedial Prefrontal Cortex through Enhanced Hippocampal–Cortical Functional Connectivity
Brain activity during sleep, particularly the oscillatory pattern called sleep spindles, is important for memory consolidation. How spindle activity shapes circuits representing remembered items is poorly understood, however. Cowan et al. addressed this using functional magnetic resonance imaging in humans. They found that greater spindle activity during sleep was associated with both greater overlap in neural representations of studied items and stronger interactions between the hippocampus and prefrontal cortex when items were re-studied the next day. The authors conclude that spindles might participate in the restructuring of memory traces during consolidation.
Behavioral/Cognitive
The Neural Origin of Nociceptive-Induced Gamma-Band Oscillations
A stimulus may be perceived as more or less painful by different people at different times. Therefore, researchers have long sought an objective measure of pain experience. One promising measure is the amplitude of gamma-frequency oscillations recorded in surface electrodes placed over the somatosensory cortex. To pinpoint the source of such oscillations, Yue et al. measured bilateral activity in rat primary somatosensory (S1) and motor (M1) cortex using epidural electrocorticography and intracortical microelectrode recordings. They found evidence that oscillations induced by nociceptive stimulation are generated by firing of interneurons in the superficial layers of S1, supporting the hypothesis that these oscillations reflect the magnitude of pain perception rather than motor preparation.
Systems/Circuits
BNST GluN2D-Containing NMDA Receptors Influence Anxiety- and Depressive-like Behaviors and Modulate Cell-Specific Excitatory/Inhibitory Synaptic Balance
NMDA receptors (NMDARs) are major contributors to neurotransmission throughout the CNS, and their dysfunction contributes to several neurological and psychiatric conditions. Although all NMDARs are glutamate-activated, calcium-permeable cation channels that are subject to voltage-dependent Mg2+ block, their precise electrophysiological properties vary depending on subunit composition. Different subunits have distinct expression patterns and may have unique roles in normal and pathological brain function. Salimando et al. found that in the bed nucleus of the stria terminalis (BNST) of mice, GluN2D subunits were expressed predominantly in neurons that express corticotropin-releasing factor (CRF), an important driver of stress responses. Notably, knocking out GluN2D increased the activity of CRF neurons and increased depression-like behaviors.
Neurobiology of Disease
Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer's Disease
Extracellular accumulation of ß-amyloid is a defining characteristic of Alzheimer’s disease (AD), but treatments targeting amyloid deposits have failed to prevent cognitive decline in AD patients. This disappointment has prompted researchers to search for AD pathology occurring earlier in the disease. Using a mouse model of AD, Caccavano et al. found that hippocampal sharp-wave ripples, which contribute to memory formation, were altered in mice at a time when amyloid deposition and cognitive impairment were minimal. The alterations were attributed to changes in the activity of parvalbumin-expressing inhibitory basket cells and the resulting increase in pyramidal-cell activity. Future work will need to determine whether reversing these abnormalities stabilizes cognitive function.
Cellular/Molecular
D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters
Glutamate can activate NMDA receptors (NMDARs) only when a co-agonist, either glycine or D-serine, is present. Levels of these amino acids therefore influence the extent to which NMDA-dependent synaptic plasticity can be induced. Bodner et al. discovered that D-serine, the predominant NMDAR co-agonist in hippocampal area CA1 and prefrontal cortex, is removed from synapses by the amino acid transporters Slc38a1 and Slc38a2. Notably, these transporters also take up glutamine, which is released by astrocytes. And importantly, increases in extracellular glutamine reduce D-serine uptake, thus increasing the ability of glutamate to activate NMDARs. This provides a mechanism by which astrocytes might modulate synaptic plasticity.
Systems/Circuits
Serial Prefrontal Pathways Are Positioned to Balance Cognition and Emotion in Primates
The dorsolateral prefrontal cortex (DLPFC) is hypothesized to prevent maladaptive responses to threats by dampening activity in ventromedial prefrontal area 25 (A25). Direct connections between DLPFC and A25 are sparse, however. Joyce et al. provided evidence that pregenual anterior cingulate area 32 (A32) acts as an intermediary between these areas: it receives input from superficial layers of DLPFC and densely innervates all layers of A25. Although A32 projections likely increase the activity of pyramidal cells in the superficial layers of A25, they may inhibit A25 output by activating inhibitory interneurons in the deep layers. Reduced activity in these projections might contribute to stress-related psychiatric conditions.
Cellular/Molecular
The Input-Output Relation of Primary Nociceptive Neurons is Determined by the Morphology of the Peripheral Nociceptive Terminals
In the canonical neuron, spikes are initiated near the base of axons and propagate to the terminal arbor to induce transmitter release. In sensory neurons, however, spikes are initiated in the peripheral axon terminals, propagate toward a branch point near the soma, then continue along the central branch to a central terminal arbor in the spinal cord. Notably, nociceptor neurons can have complex peripheral arbors with multiple spike initiating zones. Barkai et al. created a computational model to investigate how all-or-nothing spikes generated in separate peripheral branches are integrated at branch points. Their results revealed that the input–output function of nociceptor neurons is strongly influenced by the morphology of the peripheral arbor—a characteristic that varies considerably across cells.
2019
Systems/Circuits
Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals
Discovering how the nervous system differentiates itchy and painful stimuli has been remarkably challenging, because many neurons are activated by both types of stimuli. Using targeted activation or ablation of spinal neurons that express gastrin-releasing peptide, Albisetti et al. show that these neurons convey itch, but not pain responses, contrary to a previous report. Investigation of these neurons’ synaptic partners should further our understanding of how these two unpleasant sensations are distinguished.
Systems/Circuits
Neuronal Adaptation Reveals a Suboptimal Decoding of Orientation Tuned Populations in the Mouse Visual Cortex
Our sensory systems take in a lot of information, but our brains only use some of it to assess our surroundings. To investigate how sensory information is used when making perceptual judgments, Jin et al. manipulated the responses of primary visual cortical neurons that were activated during an orientation-discrimination task and asked how this manipulation affected perceptual judgments. Although an optimal decoder monitored increases and decreases in the activity of orientation-selective neurons, mice appeared to base their decisions solely on increases in activity. This suboptimal strategy may allow faster decision making.
Systems/Circuits
Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models
Molecular mechanisms of pain differ at many levels of the nervous system in males and females. For example, Avona et al. show that when applied to the dura, calcitonin gene-related peptide, which is released by most nociceptors and is targeted by several migraine medications, reduced facial pain threshold and primed nociceptors in female, but not male rats. This may explain the higher prevalence of migraine in women than in men.
Cellular/Molecular
PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease
Although accumulation of ß-amyloid peptides and tau proteins are the defining pathological characteristics of Alzheimer’s disease (AD), dysfunction of several biological processes likely contributes to synapse loss and neurodegeneration in the disease. Because mitochondrial dysfunction occurs in AD and several other neurodegenerative diseases, Fleck et al. searched exome sequencing data from AD patients and controls for AD-associated variations in mitochondrial genes. They identified PTCD1 (pentatricopeptide repeat-containing protein 1) as a candidate risk gene and showed that loss of PTCD1 reduced ATP production in cultured neurons.
Neurobiology of Disease
Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy
ATP is released from injured cells and contributes to inflammation, which exacerbates damage. ATP acts on ionotropic P2X and metabotropic P2Y receptors. By activating P2X receptors, ATP increases excitability and contributes to seizures. The extent to which P2Y receptors contribute to seizures has been unclear, possibly because, as Alves et al. showed, P2Y receptor agonists and antagonists have opposite effects in mice depending on the time relative to status epilepticus (SE): whereas blocking P2Y receptors before SE increased epileptiform activity, blocking the receptors after the onset of SE reduced such activity.
Cellular/Molecular
Role of Nociceptor Toll-like Receptor 4 (TLR4) in Opioid-Induced Hyperalgesia and Hyperalgesic Priming
Widespread use of opiates to treat pain has led to an epidemic of opioid addiction. Besides being addictive, opiates can actually increase sensitivity to pain, particularly when used at low doses. Araldi et al. showed that this so-called opioid-induced hyperalgesia depends on activation of an immune-system receptor, toll-like receptor 4 (TLR4). Knocking down these receptors in rats blocked opioid-induced hyperalgesia without affecting the analgesic effects of morphine, suggesting a means to reduce this undesirable side effect.
Behavioral/Cognitive
Scene Representations Conveyed by Cortical Feedback to Early Visual Cortex Can Be Described by Line Drawings
Input to primary visual cortex from higher cortical areas helps us interpret what we see. This is especially important when parts of visual scenes are occluded. To learn what kind of information is carried by such feedback, Morgan et al. used functional MRI to measure neural activity while people viewed images of scenes in which one quadrant was occluded. They were able to decode scene and category information based solely on activity in the areas of V1 and V2 that received input from the occluded portion of the visual field, suggesting that this information is provided by feedback from higher areas. Comparing the neural activity to subjects’ line drawings of the missing scenes suggested that such drawings reflect the structure of internal visual models.