Journal of Neuroscience最新文献

{"title":"Social Reward Learning Deficits and Concordant Brain Alterations in Rats Overexpressing Disrupted-In-Schizophrenia 1 (DISC1).","authors":"José Dören,Yuliya Kupriyanova,Sandra Schäble,Svenja Troßbach,Brodie McGuire,Anthony C Vernon,Michael Roden,Carsten Korth,Tobias Kalenscher","doi":"10.1523/jneurosci.1067-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1067-25.2025","url":null,"abstract":"Social deficits are a hallmark of schizophrenia, often characterized by impairments in processing and integrating socially transmitted information. However, translational models that accurately capture these deficits remain scarce. The Disrupted-in-Schizophrenia 1 gene (DISC1), a key susceptibility factor implicated in the etiology of psychiatric disorders, has been shown to cause DISC1-protein aggregation and dysfunctional signaling when modestly overexpressed, ultimately resulting in aberrant dopamine homeostasis. In this study, we employed a transgenic rat model overexpressing human DISC1 (tgDISC1 rats) to investigate social reward learning and microstructural integrity in the brain. Using a modified Social Transmission of Food Preference (STFP) task, we report that male tgDISC1 rats failed to update reward preferences based on social information, despite intact non-social reward learning-suggesting a specific deficit in social reward learning. Diffusion tensor imaging (DTI) in a behaviorally naïve cohort revealed reduced fractional anisotropy (FA) in key subcortical regions, including the nucleus accumbens, amygdala, and substantia nigra, as well as areas mediating cortical-subcortical communication as the thalamus. Structural alterations in corresponding neuroanatomical areas have also been described in DTI of schizophrenia patients. Our findings link aberrant DISC1 signaling with impaired connectivity in parts of the mesolimbic system, critical for integrating social information into decision-making. This model recapitulates both behavioral and structural endophenotypes of schizophrenia and suggests that social impairments may stem from a fine-grained circuit-selective dysfunction rather than a generalized reward processing deficit. The tgDISC1 rat thus offers a translational platform for probing the neural substrates of social dysfunction in psychiatric disorders.Significance Statement Disrupted-in-Schizophrenia-1 (DISC1) is a scaffold-protein regulating various functions related to psychiatric disorders. Its overexpression causes DISC1-protein aggregation and altered signaling, impairing dopamine pathways and behavior. We investigated whether DISC1 overexpression affects social influence on reward valuation using a modified Social Transmission of Food Preference (STFP)-task. Wildtype rats shift preferences after social interaction, favoring an initially non-preferred reward. In contrast, DISC1-overexpressing (tgDISC1) rats did not shift their preference based on social information. In-vivo diffusion-tensor-imaging (DTI) in a behaviorally naïve cohort of tgDISC1 rats revealed structural changes in limbic areas, potentially favoring the deficits in STFP. These findings highlight the importance of DISC1-signaling and related circuits for integrating social cues during decision-making, offering insights into impaired social reward learning in psychiatric disorders.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"51 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035702","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":"Prefrontal Network Mechanisms of Psychiatric Deep Brain Stimulation.","authors":"Nic Glewwe,Nicola M Grissom,Alik S Widge","doi":"10.1523/jneurosci.1944-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1944-24.2025","url":null,"abstract":"Deep brain stimulation (DBS) is an emerging treatment for otherwise treatment-refractory psychiatric disorders. It can produce remarkable clinical results in expert hands, but has not fared as well in controlled, multisite trials. That difficulty with scaling up arises in part because DBS' mechanisms are poorly understood, meaning that it is difficult to objectively identify patients likely to respond and/or to customize stimulation to match individual patients' needs. In the first part of this review, we overview converging anatomic and physiological evidence that psychiatric DBS acts by modulating distributed networks centered on the prefrontal cortex (PFC). We discuss potential physiological mechanisms of that modulation, including mixed excitatory/inhibitory effects, changes in local field potential oscillations, and neuroplastic changes. A major challenge is that mechanistic data from humans are limited and sometimes contradictory, in part because these studies can only be conducted at low N with limited technical replication. Animal models may overcome that challenge, but are challenging themselves because psychiatric disorders are not fully recapitulated in animal models and are defined primarily by self-reports that are unavailable in nonverbal model species. Thus, in the second part, we review paths to more reliable animal models of psychiatric DBS, including putative disease models and models based on cognitive and decision-making impairments. The latter class includes traditional cognitive assays and newer approaches based on computational modeling, both of which also implicate PFC-centric networks. Taken together, these approaches may yield new insights into DBS' mechanisms that can in turn improve its scalability and clinical reliability.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"14 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031955","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":"Organization of Brainwide Inputs to Discrete Lateral Septum Projection Populations.","authors":"Jennifer Isaac, Sonia C Karkare, Hymavathy Balasubramanian, Malavika Murugan","doi":"10.1523/JNEUROSCI.0797-25.2025","DOIUrl":"10.1523/JNEUROSCI.0797-25.2025","url":null,"abstract":"<p><p>The lateral septum (LS) is anatomically positioned to play a critical role in directing information from the hippocampus and cortex to downstream subcortical structures, such as the hypothalamus. Early anatomical tracing studies investigated the organization of hippocampal inputs to the LS and its hypothalamic outputs to begin to understand how its structure might relate to its function. These studies also characterized the cellular anatomy of the LS and the organization of molecular markers within it. However, little is known about the organization of nonhypothalamic projection populations within the LS and what types of input these different projection populations receive. We used retrograde tracing to determine the organization of LS projections to six brain regions that mediate various social behaviors in male mice, specifically, the basolateral amygdala (BLA), bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAc), periaqueductal gray (PAG), ventromedial hypothalamus (vmH), and ventral tegmental area (VTA). We found that these projection populations occupy discrete anatomical compartments within the LS. We then used a monosynaptic rabies tracing strategy in male mice to map brainwide inputs to these six discrete LS projection populations and examine how different brain regions innervate them. We identified unique region-dependent patterns of inputs to individual LS projection populations. In particular, we observed differences in cortical, hippocampal, and thalamic innervation of the six different LS projection populations, while the hypothalamic inputs were largely similar across projection populations. Thus, this study provides insight into the anatomical connectivity that may underlie the functional heterogeneity of the LS.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social Decision Preferences for Close Others are Embedded in Neural and Linguistic Representations.","authors":"João F Guassi Moreira, L Concepción Esparza, Jennifer A Silvers, Carolyn Parkinson","doi":"10.1523/JNEUROSCI.1696-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.1696-24.2025","url":null,"abstract":"<p><p>Humans frequently make decisions that impact close others. Prior research has shown that people have stable preferences regarding such decisions and maintain rich, nuanced mental representations of their close social partners. Yet, if and how such mental representations shape social decisions preferences remains to be seen. Using a combination of functional magnetic resonance imaging (fMRI) and natural language processing (NLP), this study investigated how neural and linguistic representations of close others relate to social decision-making. After nominating a parent and friend, male and female participants (<i>N</i> = 63) rated their characteristics and made hypothetical social decisions while undergoing fMRI. Neural representations of parents and friends, relative to the self, were linked to social decision preferences. Specifically, greater neural similarity between self and parent in the temporoparietal junction (TPJ) and nucleus accumbens (NAcc) was associated with a preference for parents, while greater self-friend similarity in the medial prefrontal cortex (mPFC) was associated with friend-preference. Additionally, linguistic analysis of written descriptions of close others from a separate sample of males and females (<i>N</i> = 1,641) revealed that social decision preferences could be reliably predicted from semantic features of the text. High correspondence between neural and linguistic data in the imaging sample further strengthened the association with social decision preferences. These findings help elucidate the neural and linguistic underpinnings of social decision-making, emphasizing the critical role of mental representations in guiding choices involving familiar others.<b>Significance Statement</b> This study provides novel insights into how mental representations of close others relate to social decision-making. By combining brain imaging and natural language processing, we show that both neural and linguistic representations of familiar individuals (parents and friends), can predict social preferences. We found that neural representations of these close others are linked to the choices people make about these individuals. Additionally, the way people describe their close others in writing are reliably associated with their decision preferences. Our approach, integrating neuroscience and language analysis, significantly advances our understanding of the cognitive mechanisms behind social decision-making, posing implications for fields ranging from psychology to artificial intelligence. These findings highlight the complexity of human relationships and their impact on everyday decisions.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034538","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":"Working Memory Updating in the Macaque Lateral Prefrontal Cortex.","authors":"Yichen Qian, Roger Herikstad, Camilo Libedinsky","doi":"10.1523/JNEUROSCI.1770-24.2024","DOIUrl":"10.1523/JNEUROSCI.1770-24.2024","url":null,"abstract":"<p><p>Working memory updating is an important executive process. Here, we study the single-neuron mechanisms involved in updating versus protecting memory from distractors in the macaque prefrontal cortex. We recorded single-neuron activity from the lateral prefrontal cortex (LPFC) and prearcuate cortex (PAC) while male monkeys performed a task that required them to update their memory of target locations while ignoring distractors. Our findings revealed that neurons in the PAC signaled updated memory locations ∼100 ms after stimulus onset, significantly faster than the ∼400 ms observed in the LPFC. Additionally, PAC neurons exhibited longer encoding of distractor information. Population decoding analyses further indicated that distractor information was maintained in orthogonal subspaces from target information in both regions, minimizing interference. These results demonstrate the distinct temporal dynamics in memory updating processes between the PAC and LPFC and highlight the interplay between robust memory maintenance and updating, suggesting that local neural mechanisms may contribute to these processes.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal Patterns in Cortical Development: Age, Puberty, and Individual Variability from 9 to 13 Years of Age.","authors":"Katherine L Bottenhorn, Jordan D Corbett, Hedyeh Ahmadi, Megan M Herting","doi":"10.1523/JNEUROSCI.1002-24.2025","DOIUrl":"10.1523/JNEUROSCI.1002-24.2025","url":null,"abstract":"<p><p>Human and nonhuman primate studies suggest that timing and tempo of cortical development varies neuroanatomically along a sensorimotor-to-association (S-A) axis. Prior human studies have reported a principal S-A axis across various modalities but largely rely on cross-sectional samples with wide age ranges. Here, we investigate developmental changes and individual variability therein along the S-A axis between the ages of 9-13 years using a large, longitudinal sample (<i>N</i> = 2,487-3,747; 46-50% female) from the Adolescent Brain Cognitive Development Study (ABCD Study). This work assesses multiple aspects of neurodevelopment indexed by changes in cortical thickness, cortical microarchitecture, and resting-state low-frequency oscillations. First, we evaluated S-A organization in age-related changes and then computed individual-level S-A alignment in brain changes and assessing differences therein due to age, sex, and puberty. Age-related brain changes aligned linearly and quadratically with the S-A axis. Yet, these patterns of cortical development were overshadowed by considerable individual variability in S-A alignment. Even within individuals, there was little correspondence between S-A patterning across the different aspects of neurodevelopment investigated (i.e., cortical morphology, microarchitecture, function). Some of the individual variation in developmental patterning of cortical morphology and microarchitecture was explained by age, sex, and pubertal development. Altogether, this work contextualizes prior findings that regional age differences do progress along an S-A axis at a group level while highlighting broad variation in developmental change between individuals and between aspects of cortical development, in part due to sex and puberty.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Properties of the Prefrontal Cortex.","authors":"Nandakumar S Narayanan,James M Hyman,Jeremy Seamans,Erin L Rich","doi":"10.1523/jneurosci.1093-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1093-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"26 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031957","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":"Robustness of Working Memory to Prefrontal Cortex Microstimulation.","authors":"Joana Soldado-Magraner, Yuki Minai, Byron M Yu, Matthew A Smith","doi":"10.1523/JNEUROSCI.2197-24.2025","DOIUrl":"10.1523/JNEUROSCI.2197-24.2025","url":null,"abstract":"<p><p>Delay period activity in the dorsolateral prefrontal cortex (dlPFC) has been linked to the maintenance and control of sensory information in working memory. The stability of working memory-related signals found in such delay period activity is believed to support robust memory-guided behavior during sensory perturbations, such as distractors. Here, we directly probed dlPFC's delay period activity with a diverse set of activity perturbations and measured their consequences on neural activity and behavior. We applied patterned microstimulation to the dlPFC of two male rhesus macaques implanted with multielectrode arrays by electrically stimulating different electrodes in the array while they performed a memory-guided saccade task. We found that the microstimulation perturbations affected spatial working memory-related signals in individual dlPFC neurons. However, task performance remained largely unaffected. These apparently contradictory observations could be understood by examining different dimensions of the dlPFC population activity. In dimensions where working memory-related signals naturally evolved over time, microstimulation impacted neural activity. In contrast, in dimensions containing working memory-related signals that were stable over time, microstimulation minimally impacted neural activity. This dissociation could explain how working memory-related information may be stably maintained in dlPFC despite the activity changes induced by microstimulation. Thus, working memory processes are robust to a variety of activity perturbations in the dlPFC.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orbitofrontal-Hippocampal State Coding Dynamics during Reversal Learning.","authors":"Alyssa N Sanchez, Celia F Ford, Zuzanna Z Balewski, Joni D Wallis","doi":"10.1523/JNEUROSCI.1228-24.2025","DOIUrl":"10.1523/JNEUROSCI.1228-24.2025","url":null,"abstract":"<p><p>To build an understanding of our world, we make inferences about the connections between our actions, experiences, and the environment. This process, state inference, requires an agent to guess the current state of the world given a set of observations. During value-based decision-making, a growing body of evidence implicates the orbitofrontal cortex (OFC) and the hippocampus (HPC) in the process of contextualizing information and identifying links between stimuli, actions, and outcomes. However, the neural mechanisms driving these processes in primates remain unknown. To investigate how OFC and HPC contribute to state inference, we recorded simultaneously from both regions while two male monkeys (<i>Macaca mulatta</i>) performed a probabilistic reversal learning task, where reward contingencies could be captured by two task states. Using population-level decoding, we found neural representations of task state in both OFC and HPC that remained stable within each trial but strengthened with learning as monkeys adapted to reversals. Subjects also appeared to use their understanding of task structure to anticipate reversals, evidenced by anticipatory neural representations of the upcoming task state.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trans-synaptic interaction with mGluR6 contributes to ELFN1 presynaptic enrichment in rod photoreceptors.","authors":"Jaeeun Lee,Robyn V McGowan,Melina A Agosto","doi":"10.1523/jneurosci.0785-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0785-25.2025","url":null,"abstract":"At the glutamatergic synapses between rod photoreceptors and ON-type bipolar cells, neurotransmitter is detected by the postsynaptic metabotropic glutamate receptor mGluR6. This receptor forms trans-synaptic interactions with ELFN1, a presynaptic cell adhesion molecule expressed in rods, and ELFN1 is important for mGluR6 localization at bipolar cell dendritic tips. Here, we show that in mice of either sex lacking mGluR6, the presynaptic localization of ELFN1 is disrupted. In rods of mGluR6 null mice, ELFN1 is still restricted to the axon terminal spherules, but is only partially co-localized with synapses. The ELFN1 localization defect is rescued by expressing mGluR6-EGFP in ON-bipolar cells. In vitro binding experiments demonstrated that the leucine-rich repeat (LRR) and LRR C-terminal cap (LRRCT) regions of the ELFN1 extracellular domain are necessary and sufficient for binding to all of the group III mGluRs, including mGluR6. ELFN1-flag expressed in rods of wild-type mice is correctly localized at presynapses, co-localizing with the postsynaptic marker TRPM1 in the outer plexiform layer. Deletion of the LRRCT domain abolished trafficking of ELFN1-flag to rod spherules, whereas deletion of other parts of the ELFN1 extracellular domain did not prevent axonal trafficking or correct presynaptic localization. Our results demonstrate bidirectional mutual regulation of presynaptic enrichment of ELFN1 and postsynaptic enrichment of mGluR6 at photoreceptor synapses.Significance statement Metabotropic glutamate receptors (mGluRs) play important roles at synapses throughout the central nervous system. The group III mGluRs participate in trans-synaptic interactions with ELFN synaptic adhesion molecules, which regulate synapse formation, mGluR recruitment, and mGluR function. In the retina, mGluR6 detects neurotransmitter at synapses between photoreceptors and depolarizing bipolar cells. Unlike conventional synapses, where postsynaptic ELFN1 interacts with presynaptic mGluRs, ELFN1 is located at presynapses in photoreceptors and interacts with postsynaptic mGluR6. ELFN1 knockout leads to mGluR6 mislocalization. Here, we show that loss of mGluR6 also disrupts ELFN1 localization. These results demonstrate a bidirectional role for the ELFN1-mGluR6 complex in mediating synaptic enrichment of both parties, which may have broad implications for formation and function of excitatory synapses.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"131 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031959","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}