Journal of Neuroscience最新文献

{"title":"Sensory Deficits in mice with Lateral Spinal Cord Hemisection Mimic the Brown-Sequard Syndrome.","authors":"Melissa Henwood,Junkui Shang,Qiang Li,John Moth,John Henwood,Yang Yi,Dustin Green,Ajay Pal,Joseph Sandoval,Wei Li,Tiffany Dunn,Alfredo Sandoval,Jiewen Zhang,Subo Yuan,Bo Chen","doi":"10.1523/jneurosci.2373-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2373-24.2025","url":null,"abstract":"Spinal cord injury (SCI) often results in permanent sensory deficits, significantly impairing quality of life. These deficits are poorly addressed due to a lack of valid animal models with translational relevance. Here, we utilized a thoracic level 8 lateral hemisection SCI mouse model (including both male and female mice) and applied a battery of behavioral assays requiring supraspinal transmission of sensory information, while also assessing ascending spinal circuits from the lumbar spinal cord to the brain. By 28 days post-SCI, sensory assessments revealed distinct deficits: reduced innocuous sensation in the ipsilateral hindpaw and enhanced sensation in the contralateral hindpaw. Both hindlimbs exhibited disrupted nocifensive behaviors, with chronic neuropathic dysesthesia observed only in the contralateral hindlimb. We provided anatomical evidence to elucidate the neural substrates responsible for these sensory discrepancies. This SCI mouse model mimics key features of human lateral hemisection conditions (Brown-Séquard Syndrome) and offers a robust platform to explore underlying mechanisms and develop new therapeutic strategies.Significance statement We present and validate a T8 lateral hemisection model that reproduces the hallmark sensory syndromes of Brown-Séquard syndrome (BSS). Systematic behavioral testing-spanning light-touch, nocifensive, and dysesthesia assays-combined with viral tracing of ascending pathways demonstrates that this single, reproducible lesion recreates the asymmetric sensory loss and chronic contralateral dysesthesia typical of BSS. By tightly matching clinical observations to pre-clinical read-outs, the model offers a powerful platform for dissecting the mechanisms of SCI-induced sensory deficits and for evaluating targeted therapies.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"38 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071775","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":"Involvement of the Endothelial N-Methyl-D-Aspartate Receptor on Vessel-Associated Positioning and Differentiation of Cortical Oligodendrocytes and on Motor Activity.","authors":"Alexandre Beranger,Morgane Lafenêtre,Sabrina Lacomme,Alexis Lebon,Damien Genty,Mélanie Brosolo,François Janin,Anaïs Leroy,Nicolas Guérout,Denis Vivien,Ludovic Galas,Stéphane Marret,Florent Marguet,Etienne Gontier,Bruno J Gonzalez,Maryline Lecointre","doi":"10.1523/jneurosci.0199-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0199-25.2025","url":null,"abstract":"During cortical development, attachment and detachment of oligodendrocyte precursors (OPC) to microvessels play a crucial role in their positioning and differentiation. In the developing brain, endothelial cells are regionally diverse, and previous studies showed a peak in the expression of cortical endothelial NMDA receptors (eNMDAR) during perinatal life, coinciding with OPC migration along cortical microvessels. This raises the hypothesis that eNMDAR might influence the fate of vessel-associated OPC. In this study, a Grin1lox/lox/VeCadCre mouse model was used to investigate in females and males the effects of endothelial GluN1 invalidation (eNMDAR-/-) on i) positioning and differentiation of cortical oligodendrocytes and myelination, ii) OPC/microvessel association and endothelial MMP9-like activity, and iii) motor activity. Results showed that, from P2 to P15, PDGFRα expression was increased in eNMDAR-/- mice and returned to wild-type levels by P45. CNPase and MBP expression was reduced at P15 and remained low in adult eNMDAR-/- mice. Histological analysis revealed no change in OPC-microvessel association, but positioning was altered with increased density in layers VI and V at P15. Myelination was impaired, as evidenced by thinner corpus callosum, reduced myelin sheath thickness, and higher g-ratio. Axonal mitochondria density was significantly increased. Functional tests revealed that glutamate could not stimulate endothelial MMP9-like activity in eNMDAR-/- mice. Molecular, histological and functional changes were linked to sensorimotor disabilities. At P45, despite the absence of observable myelination defects, locomotor impairments persisted, suggesting that early OPC differentiation disruption contributes to lasting motor dysfunction. These findings offer new insights into OPC vulnerability in human preterm infants.Significance Statement During brain development, oligodendrocyte precursors (OPC) integrate the neocortex by migrating along radial microvessels. Here, we show that targeted invalidation of the endothelial NMDA receptor delays the positioning and the differentiation of OPC in layers of the sensorimotor cortex resulting in sustainable under-expression of MBP, in reduced density of myelinated fibers, thinner myelin sheaths and higher g-ratio values. At a functional level, invalidation of the endothelial NMDAR results in the inability for glutamate to stimulate MMP9-like activity. These molecular, cellular, and functional phenotypes are associated with neonatal and long-term motor impairments. Our findings highlight the contribution of the endothelial NMDA receptor on the differentiation of oligodendrocytes entering the sensorimotor cortex along microvessels.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"5 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071782","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":"Spatio-temporal dynamics of lateral Na+ diffusion in apical dendrites of mouse CA1 pyramidal neurons.","authors":"Joel S E Nelson,Jan Meyer,Niklas J Gerkau,Karl W Kafitz,Ghanim Ullah,Fidel Santamaria,Christine R Rose","doi":"10.1523/jneurosci.0077-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0077-25.2025","url":null,"abstract":"Sodium ions (Na+) are major charge carriers mediating neuronal excitation and play a fundamental role in brain physiology. Glutamatergic synaptic activity is accompanied by large transient Na+ increases, but the spatio-temporal dynamics of Na+ signals and properties of Na+ diffusion within dendrites are largely unknown. To address these questions, we employed multi-photon Na+ imaging combined with whole-cell patch-clamp in dendrites of CA1 pyramidal neurons in tissue slices from mice of both sexes. Fluorescence lifetime microscopy revealed a dendritic baseline Na+ concentration of ∼10 mM. Using intensity-based line-scan imaging we found that local, glutamate-evoked Na+ signals spread rapidly within dendrites, with peak amplitudes decreasing and latencies increasing with increasing distance from the site of stimulation. Spread of Na+ along dendrites was independent of dendrite diameter, order or overall spine density in the ranges measured. Our experiments also show that dendritic Na+ readily invades spines and suggest that spine necks may represent a partial diffusion barrier. Experimental data were well reproduced by mathematical simulations assuming normal diffusion with a diffusion coefficient of DNa+= 600 µm²/s. Modeling moreover revealed that lateral diffusion is key for the clearance of local Na+ increases at early time points, whereas when diffusional gradients are diminished, Na+/K+-ATPase becomes more relevant. Taken together, our study thus demonstrates that Na+ influx causes rapid lateral diffusion of Na+ within spiny dendrites. This results in an efficient redistribution and fast recovery from local Na+ transients which is mainly governed by concentration differences.Significance statement Activity of excitatory glutamatergic synapses generates large Na+ transients in postsynaptic cells. Na+ influx is a main driver of energy consumption and modulates cellular properties by modulating Na+-dependent transporters. Knowing the spatio-temporal dynamics of dendritic Na+ signals is thus critical for understanding neuronal function. To study propagation of Na+ signals within spiny dendrites, we performed fast Na+ imaging combined with mathematical simulations. Our data shows that normal diffusion, based on a diffusion coefficient of 600 µm²/s, is crucial for fast clearance of local Na+ transients in dendrites, whereas Na+ export by the Na+/K+-ATPase becomes more relevant at later time points. This fast diffusive spread of Na+ will reduce the local metabolic burden imposed by synaptic Na+ influx.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"7 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071774","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":"Kappa opioid receptors control a stress-sensitive brain circuit and drive cocaine seeking.","authors":"Valentina Martinez Damonte, Lydia G Bailey, Amit Thakar, Joanna Stralka, Travis E Brown, Julie A Kauer","doi":"10.1523/JNEUROSCI.1233-25.2025","DOIUrl":"10.1523/JNEUROSCI.1233-25.2025","url":null,"abstract":"<p><p>Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABA_A synapses on dopamine neurons (LTP_GABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. In male and female mice we optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTP_GABA Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTP_GABA Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTP_GABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA of male rats facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTP_GABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.<b>Significance statement</b> Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. The VTA is a key brain area for processing aversive and rewarding stimuli. Inhibitory synapses that control the activity of dopamine neurons in this area display plasticity, strengthening or weakening the inhibitory control of dopamine neuron firing. We previously characterized a form of long-term plasticity at GABA_A synapses on dopamine neurons (LTP_GABA). Acute stress activates kappa opioid receptors (kORs) to block LTP_GABA and also triggers kOR-dependent reinstatement of cocaine-seeking. Here we identified specific GABAergic afferents affected by stress, the location of relevant kORs in VTA, and show that VTA kOR activation by itself is sufficient to drive reinstatement of cocaine seeking.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071056","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":"Forewarned Is Forearmed: The single- and dual-brain mechanisms in Detectors from Dyads of Varying Social Distance During Deceptive Outcomes Evaluation.","authors":"Rui Huang,Xiaowei Gao,Chenyu Zhang,Jingyue Liu,Ye Zhang,Yifei Zhong,Yunen Chen,He Wang,Xing Wei,Yingjie Liu","doi":"10.1523/jneurosci.2129-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2129-24.2025","url":null,"abstract":"Preventing deception requires understanding how lie detectors process social information across social distance. Although the outcomes of such information are crucial, how detectors evaluate gains or losses from close versus distant others remains unclear. Using a sender-receiver paradigm and fNIRS hyperscanning, we recruited 66 healthy adult dyads (32 male and 34 female dyads) to investigate how perceived social distance modulates the neural basis in receivers (the detector) during deceptive gain-loss evaluation. The results showed that detectors were more prone to deception in gain contexts, with these differences mediated by connectivity in risk evaluation (Dorsolateral Prefrontal Cortex, DLPFC), reward-processing (Orbitofrontal Cortex, OFC), and intention-understanding regions (Frontal Pole Area, FPA). Hyperscanning analyses revealed that friend dyads exhibited higher interpersonal neural synchrony (INS) in these regions than stranger dyads. In gain contexts, friend dyads showed enhanced INS in the OFC, whereas in loss contexts, enhanced INS was observed in the DLPFC. Trial-level analysis revealed that the INS during the current trial effectively predicted the successful deception of that trial. We constructed a series of regression models and found that INS provides superior predictive power over single-brain measures. The INS-based Support Vector Regression model achieved an accuracy of 86.66% in predicting deception. This indicates that increased trust at closer social distances reduces vigilance and fosters relationship-oriented social information processing. As the first to identify INS as a neural marker for deception from the detector's perspective, this work advances Interpersonal Deception Theory and offers a neuroscientific basis for credit risk management.Significance Statement Using a sender-receiver paradigm and fNIRS hyperscanning, we investigated deception from the detector's perspective across social distances and gain-loss contexts. Our findings reveal that interpersonal neural synchrony (INS) between the dorsolateral and orbitofrontal prefrontal cortices reliably predicts whether deception succeeds. We further analyzed the predictive power of INS at the trial level and found that deception susceptibility was first apparent in the early stages of verbal communication. These results suggest that deception is not solely shaped by individual vigilance but emerges from dynamic neural coupling during interaction. This study identifies INS as a neural signature of deception susceptibility and bridges behavioral models with neural computation, offering implications for deception detection in real-world social contexts.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"46 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068366","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":"Early life injury alters spinal astrocyte development.","authors":"Judy J Yoo,Elizabeth K Serafin,J Matthew Kofron,Mark L Baccei","doi":"10.1523/jneurosci.1197-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1197-25.2025","url":null,"abstract":"Neonatal injury alters synaptic transmission in the spinal superficial dorsal horn (SDH), resulting in aberrant amplification of ascending nociceptive transmission. Astrocytes orchestrate synapse development and function across the CNS and play a critical role in the emergence and maintenance of persistent pain. However, little is currently known about the postnatal development of spinal astrocytes, nor about how the maturation of SDH astrocytes is impacted by early life injury. Here, we used a hindpaw incision model of postsurgical pain in postnatal day (P)3 mice of both sexes to elucidate the effects of neonatal injury on the maturation of SDH astrocytes. Three-dimensional morphological analysis of individual astrocytes revealed that incision elicits age-dependent changes to astrocyte structure. At P4, spinal astrocytes in incised mice show increased size and complexity compared to naïve controls. This is reversed at P10 and P24, as astrocytes from incised mice are smaller and less ramified compared to their naïve counterparts. Transcriptomic analysis of spinal astrocytes revealed acute changes to gene expression after neonatal injury, as 76 differentially expressed genes (DEGs) were identified at P4 (such as Thbs1, Efemp1, Acta1, Acta2, Tpm2 and Fgf14), which included genes related to cell motility and cytoskeletal organization, but very few DEGs were detected at P10 and P24. Lastly, we identified that microglial engulfment of astrocyte material occurs in the developing dorsal horn, and that this process is altered by neonatal incision in a sex-dependent manner. These data illustrate, for the first time, that neonatal injury alters the postnatal development of spinal astrocytes.Significance Statement Neonatal tissue damage persistently remodels synaptic circuits in the spinal superficial dorsal horn (SDH), which has been implicated in the ability of early life injury to \"prime\" developing nociceptive pathways. While astrocytes clearly regulate synapse formation, pruning and function across the CNS, nothing is known about the degree to which neonatal injury modulates the properties of astrocytes within the developing SDH. The present study demonstrates that neonatal hindpaw incision evokes age-dependent transcriptional and morphological plasticity in spinal astrocytes, highlighted by a prolonged reduction in the size and complexity of astrocytes following early life injury. These findings yield new insight into the cellular mechanisms by which neonatal tissue damage can exert long-term effects on spinal nociceptive processing.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"67 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036098","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":"Metallothionein III mediates Ca2+-dependent Zn2+ spikes to inhibit dendritic arborization.","authors":"Lyndsie Salvagio,Chen Zhang,Braden E Rue,Nicole Doris,Ci Koehring,Isabella Tyler,Raul Vargas,Won Chan Oh,Yan Qin","doi":"10.1523/jneurosci.0627-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0627-25.2025","url":null,"abstract":"Zinc is crucial for neuron function, but whether and how labile zinc ion (Zn2+) acts as an intracellular signaling molecule remains unclear. In this work, we investigate the relationship between Ca2+ and Zn2+ dynamics using fluorescence imaging. Our findings reveal that manipulating Ca2+ influx through various pathways induces intracellular acidification, which subsequently elicits Zn2+ spikes that reflect transient increases in cytosolic Zn2+ levels. These Ca2+-dependent Zn2+ spikes have been recorded in both rat (Rattus norvegicus) primary neuron cultures and organotypic mouse (Mus musculus) hippocampal slice cultures prepared from both males and females. They are specific to neurons and astrocytes but are absent in other cell types we tested including HeLa cells, COS-7 cells and fibroblasts. We further identify Metallothionein III (MT3), a Zn2+ buffering protein specifically expressed in brain cells, as the source of these Zn2+ spikes. Reduction in MT3 expression by knockdown with shRNAmiR techniques significantly decreases the amplitude of Zn2+ spikes, while overexpression of MT3 in HeLa and COS-7 cells is sufficient to induce Ca2+-dependent Zn2+ spikes, demonstrating the crucial roles of MT3 in Zn2+ release. Lastly, we explore the biological roles of MT3-mediated Zn2+ spikes in neurons. Suppressing Zn2+ spikes with either MT3 knockdown or mild Zn2+ chelation results in increased dendritic branching in primary rat hippocampal neurons. These results suggest that Zn2+ release from endogenous MT3 acts as a regulatory signal to inhibit dendrite branching and growth, establishing a critical role for Zn2+ spikes in neurite outgrowth and neuronal development.Significance statement Zinc is essential for brain development, primarily known for its role in supporting protein structure and enzymatic activity. However, its function as an intracellular signaling molecule has been debated because labile zinc (Zn2+) concentrations inside cells are typically stable. In this study, we discovered a unique pathway where Ca2+ influx triggers cellular acidification, which subsequently releases Zn2+ from Metallothionein III (MT3), a Zn2+-binding protein highly expressed in the brain. More importantly, we found that depletion of these Zn2+ spikes via MT3 knockdown or chelation increases dendritic arborization, a critical step in forming neural connections. Our findings reveal that Ca2+ influx activates MT3-mediated Zn2+ signaling, which fine-tunes the neuronal network maturation, highlighting previously unrecognized signaling roles of Zn2+ in brain development.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"24 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035701","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":"Largely Intact but Less Reliable and Distributed Neural Representations of Subjective Value in Human Opioid Addiction.","authors":"Francesca M LoFaro,Maëlle C M Gueguen,Ananya Kapoor,Emmanuel E Alvarez,Darla Bonagura,Anna B Konova","doi":"10.1523/jneurosci.0679-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0679-25.2025","url":null,"abstract":"Addiction, particularly opioid use disorder (OUD), is often characterized by heightened propensity for risk-taking. While tolerance for risk and uncertainty varies across individuals, the elevated risk-taking in people with OUD is assumed to stem from altered cognitive decision-making processes beyond differences due to idiosyncratic yet lawful tolerances. Specifically, the prevailing assumption is that people with addiction exhibit impairments in the internal representation and integration of information that should guide decisions and judgements about what is valuable. Using model-based fMRI, we examined how the choice behavior of treatment-engaged male and female participants with chronic OUD aligns with the neural encoding of their inferred subjective value of uncertain (risky and ambiguous) rewards and the evidence for impairment in this neural process. Using both univariate and multivariate analyses, we found that canonical value regions (ventromedial prefrontal cortex, striatum, and posterior cingulate cortex) track the subjective value of uncertain choice options in both participants with OUD and comparison controls, irrespective of their tolerance for uncertainty. This speaks against a fundamentally impaired subjective valuation process in OUD. However, value representations were less reliably decodable in people with OUD in some value regions (ventromedial prefrontal cortex) and throughout the brain, especially within the limbic and salience/ventral-attention networks. Thus, while people with OUD engage a neurocomputationally similar process during risky decision-making to controls, they may differ in the fidelity and distribution of subjective value signals across brain networks.Significance statement A common assumption in addiction neuroscience is that people with substance use disorders have impaired encoding or computation of the value of their options and consequently might engage in risky behaviors over less risky alternatives. Empirical support for this viewpoint however remains lacking, potentially hindering the translation of research into improved understanding and treatment of addiction. This study shows the valuation of risky decisions is largely neurally intact, though less reliable and distributed throughout the brain, in people with opioid use disorder. Thus, rather than impaired valuation, addiction may be associated with a less robust, and spatially more restricted, representation of value. These findings highlight network-level mechanisms that shape decision-making, and suggest new targets for future addiction research and treatment.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"35 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036095","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":"Mediodorsal thalamic input to striatum contributes to early action learning.","authors":"Emily T Baltz,Jialin He,Christina M Gremel","doi":"10.1523/jneurosci.0835-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0835-25.2025","url":null,"abstract":"Action control is hypothesized to be mediated by corticothalamo-basal ganglia loops subserving the acquisition and updating of action contingencies. Within this, the mediodorsal thalamus (MD) is thought to contribute to volitional control over behavior largely through its interactions with prefrontal cortex. However, MD also projects into striatum, the main input nucleus of the basal ganglia, and the contribution of such projections to behavioral control is not known. Using a mouse model of volitional action control in either sex, here we find that MD terminal calcium activity in dorsal medial striatum (MD-DMS) represents action information during initial acquisition of a novel action contingency. This representation of action information decreases with continued experience. Data demonstrate MD-DMS activity is necessary to learn and employ a contingency control over actions. Functional attenuation of MD-DMS activity negated normal exploration, instead biasing repetitive action control, and resulted in mice unable to adapt their initial action strategy upon changes in action contingency. This suggests MD supports plasticity underlying initial action strategy learning used to adjust control given changing contingencies. Overall, these data show that MD projections into striatum contribute to volitional action control that supports acquisition of adaptive behavior.Significance Statement Mediodorsal (MD) thalamus is hypothesized to support volitional action control. However, focus has largely been on MD input into prefrontal cortical regions and the contribution of MD input to striatum has not been explored. Here we show that MD input into dorsal medial striatum supports acquisition of goal-directed strategies and their control over actions.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"14 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035749","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":"Behavioral timing of interictal spikes, but not rate, correlates with impaired working memory performance.","authors":"Justin D Yi,Maryam Pasdarnavab,Laura Kueck,Gergely Tarcsay,Laura A Ewell","doi":"10.1523/jneurosci.0193-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0193-25.2025","url":null,"abstract":"In temporal lobe epilepsy, interictal spikes (IS) - hyper-synchronous bursts of network activity - occur at high rates in between seizures. We sought to understand the influence of IS on working memory by recording hippocampal local field potentials from male epileptic mice while they performed a delayed alternation task. Interestingly, the rate of IS during behavior did not correlate with performance. Instead, we found that IS were correlated with worse performance when they were spatially non-restricted and occurred during running. In contrast, when IS were clustered at reward locations, animals tended to perform well. A machine learning decoding approach revealed that IS at reward sites were larger than IS elsewhere on the maze, and could be classified as occurring at specific reward locations. Finally, a spiking neural network model revealed that spatially clustered IS preserved hippocampal replay, while spatially dispersed IS disrupted replay by causing over-generalization. Together, these results show that the spatial specificity of IS on the maze, but not rate, correlates with working memory deficits.Significance Statement In people with epilepsy, the hippocampus can generate large electrical discharges in the period between seizures called interictal spikes. Previous studies have proposed that interictal spikes cause memory impairments. We use a mouse model of epilepsy and computer simulations to study how interictal spikes impact navigation to remembered rewards. We find that when interictal spikes occur uncontrollably throughout the maze memory performance is worse, and in contrast, when they are sequestered to reward locations memory performance is better. Together our results show that interictal spikes are correlated with corrupted memory depending on when and where they occur during learning.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"16 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035751","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}