Journal of Neuroscience最新文献

{"title":"Targeting the HMGB1-TLR4 Axis Alleviates Neuropathic Pain-Associated Cognitive Deficits.","authors":"Junhua Li, Yafang Liu, Zhaoxia Liao, Dong Cao, Cong Zeng, Jiachong Han, Zhiwen Shen, Yi Wu","doi":"10.1523/JNEUROSCI.2250-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2250-25.2026","url":null,"abstract":"<p><p>Cognitive deficits associated with chronic pain pose a significant burden on a patient's quality of life. Emerging evidence indicates that Toll-like receptor 4 (TLR4), a pattern recognition receptor implicated in neuroinflammatory signaling that can disrupt synaptic plasticity and memory processes. However, the specific involvement of TLR4 in the development of neuropathic pain-related cognitive deficits has not been fully elucidated. In this investigation, we observed an upregulation of TLR4 expression within hippocampal neurons in male mice subjected to chronic constriction injury (CCI) relative to sham group. Notably, in separate experimental cohorts, TLR4-knockout and neuron-specific TLR4-knockdown mice exhibited improved cognitive function compared to wild-type controls, alongside attenuated neuroinflammatory responses, reduced neuronal apoptosis, and enhanced preservation of hippocampal neuroplasticity. Concurrently, elevated concentrations of high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, were detected in the sciatic nerve, serum, and hippocampal tissues following CCI. Furthermore, increased co-localization of HMGB1 with TLR4 was evident in the hippocampus. Exogenous administration of HMGB1 augmented HMGB1 and TLR4 levels in the hippocampus and worsened memory functions that depend on hippocampal integrity. Conversely, inhibition of HMGB1 with glycyrrhizin, which subsequently attenuates TLR4 activation, ameliorated cognitive impairments induced by CCI. Collectively, these results support a model in which HMGB1, elevated during chronic neuropathic pain, contributes to cognitive deficits via a TLR4-dependent mechanism, triggering downstream inflammatory and apoptotic cascades and impairing synaptic plasticity.<b>Significance Statement</b> Chronic neuropathic pain is frequently accompanied by debilitating cognitive deficits, yet the underlying mechanisms linking peripheral nerve injury to central nervous system dysfunction remain poorly understood, hindering the development of targeted therapies. This study identifies the HMGB1/ TLR4 signaling axis as a critical mediator driving these cognitive impairments. We demonstrate that HMGB1, released after nerve injury, activates hippocampal TLR4, triggering neuroinflammation, neuronal apoptosis, and synaptic deficits. Importantly, genetic deletion or neuronal-specific knockdown of TLR4, as well as pharmacological inhibition of the HMGB1/TLR4 interaction, rescues cognitive function. These findings elucidate a precise molecular pathway connecting peripheral neuropathic pain to cognitive decline and establish the HMGB1/TLR4 axis as a promising therapeutic target for preventing or treating pain-associated cognitive dysfunction.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histamine originating from the BNST modulates corticostriatal synaptic transmission during early postnatal development.","authors":"Ricardo Márquez-Gómez, Yasmin Cras, Brenna Parke, Thomas De Backer, L Sophie Gullino, Parastoo Hashemi, Tommas Ellender","doi":"10.1523/JNEUROSCI.1230-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1230-25.2026","url":null,"abstract":"<p><p>The neuromodulator histamine regulates key processes in many circuits of the adult and developing brain, including striatum. However, striatal innervation by histaminergic afferents is very sparse making the physiological sources of histamine unclear. Here sources of striatal histamine were investigated during early postnatal development and specifically during the second postnatal week in mice of either sex. Firstly, a combination of patch-clamp recording and optogenetic stimulation in brain slices demonstrates that during this period exogenously applied histamine modulates both the intrinsic properties of developing D₁ and D₂ striatal spiny projection neurons (SPNs) and synaptic transmission at afferents coming from the mPFC and visual cortex. Secondly, immunohistochemistry for histamine reveals a brain region adjacent to the caudal striatum densely innervated by histaminergic axons and corresponding to the oval nucleus of bed nucleus of stria terminalis (ovBNST). Thirdly, electrical stimulation of the ovBNST leads to significant and detectable levels of histamine in striatum, as assessed by fast scan cyclic voltammetry and fluorescent histamine sensors in brain slices as well as in vivo. Lastly, electrical stimulation of the ovBNST nucleus, at frequencies mimicking normal active histamine neurons, can release sufficient levels of histamine to modulate excitatory synaptic transmission from mPFC onto striatal SPNs through histamine H₃ receptors. Together, these results provide evidence for the existence of the ovBNST as an extrastriatal source of histamine during early brain development and postulates a new view of the modus operandi of histamine in that it can cross anatomical and functional boundaries and act as a paracrine neuromodulator.<b>Significance statement</b> The neuromodulator histamine is synthesized by neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus and is released from their axons in many brain regions. There the histaminergic system regulates many key processes, and has been shown to be dysregulated in a variety of neurological and neurodevelopmental disorders. Key to understanding the physiological roles of histamine and to generate possible interventions when dysregulated is to know both the local sources of histamine and its mode of action. Using the striatum as an exemplar we provide here the first evidence that sources of histamine may lie outside of anatomical boundaries and that histamine can act as a paracrine neuromodulator during early brain development contrasting with many other neuromodulators.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy is required for dopaminergic axon development and confers their responsiveness to guidance cues.","authors":"Marcos Schaan Profes, Charles Gora, Flavie Lavoie-Cardinal, Armen Saghatelyan, Martin Lévesque","doi":"10.1523/JNEUROSCI.1224-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1224-25.2026","url":null,"abstract":"<p><p>Midbrain dopamine (mDA) neurons play a wide range of brain functions, but the molecular mechanisms driving the formation of mDA circuits remain largely unknown. Here, we show that autophagy, the main cellular recycling pathway, is present in the growth cones of developing mDA neurons, and its level changes dynamically in response to guidance cues. To characterize the role of autophagy in mDA axon growth and guidance, we knocked out essential autophagy genes (Atg12, Atg5) specifically in mDA neurons in mice of either sex. Autophagy-deficient mDA axons exhibit axonal swellings and reduced branching both <i>in vitro</i> and in vivo. Strikingly, deletion of autophagy-related genes completely blunted the response of mDA neurons to both chemorepulsive and chemoattractive guidance cues. Our data demonstrate that autophagy plays a central role in regulating mDA neuron development by orchestrating axonal growth and guidance.<b>Significance Statement</b> Midbrain dopaminergic neurons form circuits essential for movement, motivation, and cognition, yet the intracellular mechanisms controlling their axon growth and guidance remain poorly understood. Here we show that autophagy, a major cellular recycling pathway, operates locally in dopaminergic growth cones and is dynamically regulated by guidance cues. Using neuron-specific deletion of core autophagy genes, we demonstrate that autophagy is required for proper axonal morphology, branching, and responsiveness to both chemoattractive and chemorepulsive signals. These findings identify autophagy as a key regulator of dopaminergic circuit formation and reveal a previously unrecognized mechanism linking intracellular degradation pathways to axon guidance during brain development.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory monocyte-derived macrophages drive pain via their production of nerve growth factor after peripheral nerve injury in mice.","authors":"Maxime Kusik, Alexandre Paré, Felipe Da Gama Monteiro, Sylvain Nadeau, Juliette Ferry, Isabelle Pineau, Martine Lessard, Nadia Fortin, Nicolas Vallières, Bradley Kerr, Steve Lacroix","doi":"10.1523/JNEUROSCI.1897-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1897-25.2026","url":null,"abstract":"<p><p>Immune cells are vital to regeneration and repair processes in the nervous system. We previously reported that myeloid cells play a critical role in nerve regeneration and locomotor recovery after peripheral nerve injury (PNI) by facilitating the clearance of inhibitory myelin debris, promoting angiogenesis, and producing neurotrophins (NTs) such as nerve growth factor (NGF), brain-derived neurotrophic factor, NT-3 and NT-4/5. Here, we show that NTs are synthesized by various types of myeloid cells after PNI, including neutrophils, macrophages and dendritic cells. Notably, we found that within the first week of PNI in male and female mice, monocyte-derived Cd11b⁺Cd68⁺Ly6B⁺Ly6C^hi macrophages infiltrate the sciatic nerve in an interleukin (IL)-1-dependent but CCR2-independent manner, and then locally produce mature NGF. Accordingly, depletion of circulating monocytes using PLX73086, a CSF1R inhibitor unable to cross blood-nervous system barriers, reduced NGF mRNA levels in the sciatic nerve distal stump. When polarized toward a proinflammatory phenotype <i>in vitro</i>, mouse macrophages rapidly release the cleaved form of NGF. Further analysis revealed that systemic administration of an anti-NGF neutralizing antibody reduced mechanical pain in mice with PNI. Together with our previous work, these results suggest that infiltrating monocyte-derived macrophages release NGF, thereby promoting both peripheral nerve regeneration and pain following injury.<b>Significance statement</b> We unveil a pivotal role for nerve growth factor (NGF) in the modulation of pain following peripheral nerve injury (PNI). Our comprehensive investigation traces augmented NGF mRNA and protein levels during the initial week post-PNI, pinpointing the involvement of macrophages with a distinct immunophenotypic signature in NGF production. Strategic depletion experiments demonstrate monocyte-derived macrophage production of NGF in the nerve distal stump. Cultured macrophages, when polarized toward a proinflammatory phenotype, release mature NGF. Moreover, systemic NGF neutralization alleviates pain sensitivity post-PNI. This research identifies key molecular intricacies governing NGF expression and release by inflammatory macrophages, offering promising targets for therapeutics in pain management and peripheral nerve regeneration after injury.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Roles of CaMKII in Synaptic Vesicle Dynamics at Zebrafish Retinal Rod Bipolar Ribbon Synapses.","authors":"Johane M Boff, Sivatharshan Sivakumar, Nirujan Rameshkumar, Moumita Khamrai, Jayaraman Seetharaman, Cindy Lorena Olmos-Carreño, Nabeel Chudasama, Takeshi Yoshimatsu, David Zenisek, Steven J Tavalin, Thirumalini Vaithianathan","doi":"10.1523/JNEUROSCI.1495-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1495-25.2026","url":null,"abstract":"<p><p>Calcium (Ca²⁺) not only serves as a fundamental trigger for neurotransmitter release but also participates in shaping neurotransmitter release (NTR) during prolonged presynaptic stimulation via multiple Ca²⁺-dependent processes. The Ca²⁺/calmodulin (CaM)-dependent protein kinase II (CaMKII) is enriched at various presynaptic terminals, including ribbon synapses, where it associates with synaptic ribbons and thus may contribute to the modulation of Ca²⁺-dependent NTR. This could arise via its ability to influence one or more steps that control either the Ca²⁺ signal, the release process, or synaptic vesicle dynamics, affecting available pools. Yet, recent studies have yielded conflicting results regarding the ability of CaMKII to influence NTR at rod bipolar cell (RBC) ribbon synapses. To address this, we acutely manipulated CaMKII activity in synaptic terminals of zebrafish RBCs from both sexes by infusion of either inhibitory peptides targeting CaMKII or CaM, or a constitutively active CaMKII, while using a combination of imaging and electrophysiological approaches. Neither inhibiting nor enhancing CaMKII activity affects presynaptic Ca²⁺ channel activity. However, capacitance measurements revealed that inhibition of either CaMKII or CaM reduces exocytosis. CaMKII inhibition also reduces synaptic vesicle replenishment. Surprisingly, elevation of CaMKII activity also diminished vesicle fusion, similar to the effect of CaMKII inhibition, suggesting that CaMKII activity naturally exists at optimal levels to support neurotransmitter release. In contrast to CaMKII inhibition, CaMKII activity elevation did not impair vesicle replenishment. Collectively, these data suggest that distinct synaptic vesicle populations are differentially reliant on the level of CaMKII activity.<b>Significant Statement</b> CaMKII is well-recognized for its postsynaptic participation in multiple forms of synaptic plasticity, yet it is well-documented to be prevalent in presynaptic compartments, where it may control NTR. The specific functions of CaMKII in synaptic vesicle dynamics remain poorly understood. While using a combination of imaging and electrophysiology approaches, we acutely manipulated CaMKII activity in presynaptic terminals by infusion of inhibitory peptides or constitutively active CaMKII. These manipulations revealed that deviations in CaMKII levels, in either direction, impair neurotransmitter release, suggesting that CaMKII is optimally present at these synapses. Yet CaMKII activity appears required for synaptic vesicle replenishment, suggesting that distinct aspects of synaptic vesicle dynamics are under differential control by CaMKII.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illusory causal impression attenuates the detection of event boundaries.","authors":"Jieyun Li, Fuying Chen, Yi Hu","doi":"10.1523/JNEUROSCI.1889-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1889-25.2026","url":null,"abstract":"<p><p>The art of film editing bridges the transitions between discrete events to build a coherent, immersive experience for viewers. However, how the brain integrates seemingly separate moments into a coherent whole remains poorly understood. We hypothesized that causal impression-even when illusory-acts as a powerful heuristic to attenuate the neural representation of event boundaries, thereby facilitating a smoother transition across events. Using high-resolution EEG, we presented 34 participants (24 women) with a sequence of images sourced from concatenated visual clips, where action-outcome continuity across the event boundary was manipulated to induce or break illusory causality. Behaviorally, we found that illusory causal impression delayed the detection of event boundaries. Neurally, this boundary attenuation effect was marked by a reduced N2 amplitude, indicating mitigated cognitive conflict associated with a context shift. Multivariate analyses further showed that this causal impression reshaped the event representation by increasing neural similarity between generic cross-boundary states, thereby overcoming the typical boundary-induced impairment of cross-event association. Critically, this neural representational change was linked to behavior: the greater and more stable the neural separability in posterior brain regions across the boundary, the faster participants detected the event change. These findings suggest that illusory causal impression mitigates event segmentation by maintaining more coherent neural patterns across the boundary, providing a neuroscientific basis for intuitive editing techniques used in filmmaking.<b>Significance statement</b> The human brain naturally segments the continuous flow of experience into distinct events. Yet, in cinema, continuity editing can make us perceive separate shots as a single, coherent reality. How the brain bridges these gaps is a fundamental question. Our study reveals that causal impression is a key heuristic for integrating discrete episodes. We show that when one action appears to cause an outcome across a visual cut-even if the link is illusory-the brain bridges the two moments, attenuating the perceptual boundary between them. These findings provide the neuroscientific basis for intuitive filmmaking techniques and uncover a core principle of how the brain constructs a seamless narrative from discrete pieces of information.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ih Shapes Pathway-Specific Inhibition in Substantia Nigra Pars Reticulata.","authors":"Ya E Gao, Xiaoyang Ma, Jianan Jian, Alison L Barth, Jonathan E Rubin, Aryn H Gittis","doi":"10.1523/JNEUROSCI.1413-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1413-25.2026","url":null,"abstract":"<p><p>The substantia nigra pars reticulata (SNr) functions as the principal inhibitory output of the basal ganglia, with the timing of its spikes critically controlling downstream disinhibition required for movement initiation. The external globus pallidus (GPe) and D1-expressing medium spiny neurons (D1-MSNs) in the striatum provide GABAergic inputs to the SNr that differ in their amplitude and kinetic properties. How these inputs interact with the intrinsic membrane currents that determine SNr firing is only partially understood. Using optogenetics, computational modeling, and electrophysiology in acute mouse brain slices, 47 animals of either sex were used for measurements, and we found an unexpected interaction between GABAergic inputs and hyperpolarization-activated currents (Ih) that tunes inhibitory efficacy in a pathway-specific manner. GPe inputs evoke fast, large IPSCs that transiently suppress SNr firing within a narrow window but whose rapid decay enables depolarization from Ih to restore firing after only a brief pause. In contrast, the slower decay kinetics of striatal IPSCs enables more sustained inhibition that counters the depolarizing drive from Ih to produce longer pauses, despite their lower conductance amplitudes. Pharmacological blockade of Ih with ZD7288 eliminated the rapid recovery of firing after GPe inhibition and equalized the inhibitory efficacy between GPe and striatal pathways. These findings establish an important interplay between synaptic kinetics and intrinsic membrane conductances in establishing pathway-specific inhibitory balance in the basal ganglia.<b>Significant statement</b> Our study reveals that inhibitory pathways to the substantia nigra pars reticulata are differentially shaped by the interplay between synaptic kinetics and intrinsic membrane conductances. Using optogenetics, electrophysiology, and modeling, we showed that fast-decaying GABAergic inputs from the external globus pallidus are rapidly overcome by Ih, producing only brief pauses in SNr firing, whereas slower striatal inputs generate longer-lasting inhibition. Blocking Ih abolishes this difference, demonstrating that intrinsic currents tune inhibitory efficacy in a pathway-specific manner. These results identify a biophysical mechanism that helps set the balance of basal ganglia output essential for movement control.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The S1-insula Circuit Differentially Modulates Alcohol Drinking and Aversive Behavior in Mice.","authors":"Tatiyana L Adkins, Amanda L Salazar, Jincy R Little, Ellen C Howard, Samuel W Centanni","doi":"10.1523/JNEUROSCI.1588-25.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1588-25.2026","url":null,"abstract":"<p><p>Sensory processing assigns salience to environmental and internal stimuli, shaping behavior through learned associations. In alcohol use disorder (AUD), sensory cue processing is dysregulated, driving problematic drinking patterns and hyperkatifeia in abstinence. While visual, olfactory, and taste cues are known to influence AUD progression, the neurocircuit mechanisms that regulate sensory information in addiction remain poorly understood. The primary somatosensory cortex (S1) encodes tactile, thermal, proprioceptive, and nociceptive inputs, and projects to higher-order regions involved in motor and emotional processing. One such target is the insula, a hub for interoceptive integration and affective regulation. We previously identified that insula neurons receiving S1 projections in turn extend into the extended amygdala, implicating this projection in emotional processing. Here, we map S1-insula collateralizations in downstream motor and sensory processing regions, suggesting a unique role for this circuit in AUD-related behavior. Using chemogenetics, fiber photometry, and two complementary models of AUD- binge-like drinking and chronic drinking with forced abstinence- we demonstrate that the S1-insula circuit is selectively recruited during ethanol drinking and aversive behaviors in female mice. Chronic ethanol exposure disrupts this circuit's engagement, suggesting a maladaptive shift in sensory-affective integration. Notably, S1-insula neurons show both immediate and delayed activity increases in response to an ethanol lick, indicating temporally distinct roles. These findings reveal a unique cortico-cortical mechanism by which somatosensory signaling modulates external cue reactivity and internal affective states in AUD. This work underscores the role of sensory networks in addiction and identifies a potential circuit-level target for future diagnostic and therapeutic strategies.<b>Significance statement</b> Alcohol use disorder (AUD) is characterized by a shift in sensory processing of visual, olfactory, and taste cues, bidirectionally impacting internal and external stimuli integration and driving relapse in many individuals. This study used a circuit-based approach in mouse models to characterize the unique role of sensory and affective network nodes in AUD-related behavior. We examined the primary somatosensory cortex (S1) projection to the insula to test the hypothesis that this sensory-affective circuit encodes both external and internal stimuli, promoting ethanol consumption and negative affective behavior. This pathway is dynamically engaged by ethanol drinking, and chronic ethanol drinking disrupts pathway functionality. We reveal a unique AUD-sensitive somatosensory circuit that can be targeted for future diagnostic and therapeutic strategies.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural and Behavioral Correlates of Rapid Familiarization to Novel Taste.","authors":"Daniel A Svedberg, Avi P Patel, Donald B Katz","doi":"10.1523/JNEUROSCI.0201-26.2026","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0201-26.2026","url":null,"abstract":"<p><p>Gustatory cortex (GC) plays a pivotal role in taste perception, expressing neural ensemble dynamics that reflect, in sequence, taste quality and hedonics, and that influence taste-guided behavior. The circuitry underlying these responses has traditionally been described as fixed and hard-wired in adult rodents, although GC taste responses are known to change across multiple time-scales of experience, including between sessions of novel taste exposure. Here, we show that responses change on an even smaller time-scale-that in fact rapid, experience-dependent changes in GC responses occur across the first handful of taste exposure trials. Specifically, we show that the first 6-9 responses to novel taste stimuli in experimentally-naïve female lab rats are distinct from later trials in the same session: these earliest responses show less \"stereotypical\" dynamics and encode both taste identity and palatability less reliably than later responses; the oft-described rat taste responses are not pre-existing, but rather develop across the first several minutes of taste exposure. This phenomenon, which is not taste-specific, is nonexistent (or nearly so) in later sessions. Furthermore, this rapid neural response plasticity is paralleled in changing licking behavior in response to the same stimuli. Together, these results provide novel insights into the real-time dynamics of sensory processing across novel-taste familiarization, essentially demonstrating that the taste system, rather than being hard-wired, becomes \"tuned up\" by use.<b>Significance Statement</b> It is ubiquitously assumed that adult sensory systems process incoming stimuli normally starting with the first delivery-a property of hard-wired circuits. Here we leverage our understanding of single-trial taste-response dynamics to demonstrate that this is not the case, showing that gustatory cortical (GC) sensory responses \"tune up\" over the initial 9-10 trials of novel taste delivery; these initial responses carry less stimulus and palatability-related content, and fail to show the \"mature\" dynamics described in many previous papers. Further testing revealed this process to be functional, in that normal preferences for palatable tastes develop across this same time period, in a process analogous to but faster than attenuation of neophobia. It appears that rats must learn to taste.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving Emotion Control in Social Anxiety by Targeting Rhythmic Brain Circuits.","authors":"Sjoerd Meijer, Bob Bramson, Ivan Toni, Karin Roelofs","doi":"10.1523/JNEUROSCI.0769-25.2026","DOIUrl":"10.1523/JNEUROSCI.0769-25.2026","url":null,"abstract":"<p><p>Social avoidance is a hallmark of social anxiety disorder. Difficulties in controlling avoidance behavior are the core maintaining factor of this impairing condition, hampering the efficacy of existing therapies. This preregistered study tested a physiologically grounded noninvasive enhancement of control over social approach and avoidance behavior in socially anxious individuals. Participants received dual-site phase-coupled electrical stimulation aimed at enhancing endogenous interregional theta-gamma phase-amplitude coupling between prefrontal and sensorimotor cortex, a mechanism known to support emotional action control in nonanxious individuals. We measured behavioral and fMRI BOLD responses during in-phase, anti-phase, and sham stimulations, while participants of either sex performed a social approach-avoidance task, involving either automatic or controlled emotional actions. In-phase stimulation selectively enhanced control over approach-avoidance actions. Notably, in-phase stimulation modulated neural responses in the same prefrontal region where target engagement increased as a function of trait anxiety. These findings illustrate how human neurophysiological connectivity can be leveraged to improve control over social avoidance, opening the way for mechanistically grounded clinical interventions of persistent avoidance in anxiety disorders.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}