Journal of Neuroscience最新文献

{"title":"The orbitofrontal cortex underlies consolidation of Pavlovian anticipatory arousal responses in macaque monkeys.","authors":"Jaewon Hwang,Pamela L Noble,Mary K L Baldwin,Elisabeth A Murray","doi":"10.1523/jneurosci.0619-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0619-25.2025","url":null,"abstract":"Altered arousal is characteristic of many mental health disorders, including major depressive disorder (MDD). Several studies link neural activity in orbitofrontal cortex (OFC) with anticipation of reward, including anticipatory sympathetic arousal, which is blunted in MDD. We therefore studied acquisition and consolidation of appetitive Pavlovian memories in two groups of adult male rhesus monkeys: unoperated controls (N = 4) and those with selective neurotoxic lesions of OFC (N = 4). The dependent measure was conditioned sympathetic arousal as indexed by differential pupil dilation, and the key comparison was dilation in response to a visual cue that predicted the delivery of a large fluid reward (CS+) vs. a cue that predicted no reward (CS-). Control procedures ruled out global effects of the lesion on pupil dilation. All four unoperated controls and all four monkeys with OFC lesions acquired a conditioned increase in pupil size in response to the CS+. However, three of the four monkeys in the lesion group failed to consolidate the memory underlying this response. In contrast to this impairment, monkeys with OFC lesions acquired and consolidated an operant visual discrimination for the same reward and did so at the same rate as controls. These findings point to a specialized role for OFC in consolidating memories underlying positive affective responses, which further implicates OFC dysfunction in the blunted positive affect characteristic of MDD and suggests therapeutic approaches involving enhanced consolidation and/or reconsolidation of associative memories.Significance statement Blunted anticipation of positive events is characteristic of many mental health disorders, including major depressive disorder (MDD). Cortical circuits underlying anticipatory responses have been identified in rodent models, but it is likely that different mechanisms operate in anthropoid primates, the clade that includes humans and monkeys. Anthropoids have cortical areas that rats and mice lack, and here we show that-in a macaque monkey model-some of these areas are necessary for consolidating memories that produce autonomic arousal in anticipation of rewards. Specifically, the integrity of granular orbitofrontal cortex (OFC)-the part of OFC specific to primates-is essential for macaque monkeys to consistently generate arousal in response to visual cues that predict positive events.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"59 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720304","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":"Phase consistency dynamics of memory encoding.","authors":"Ryan A Colyer, Michael J Kahana","doi":"10.1523/JNEUROSCI.2077-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2077-24.2025","url":null,"abstract":"<p><p>Human and animal studies implicate theta and alpha oscillations in memory function. We tested whether theta, alpha, and beta phase consistency predicts memory encoding dynamics in neurosurgical patients performing delayed free recall tasks with either unrelated (N=188: 99 male, 89 female) or categorized words (N=157: 88 male, 69 female). We observed widespread post-stimulus phase consistency (3-21 Hz) and, crucially, identified distinct frequency-specific patterns predictive of successful encoding. Specifically, increased early-list item recall was significantly correlated across subjects with increased theta (3-7 Hz) phase consistency. Subsequent recall analyses, controlling for serial position, revealed distinct frequency signatures for successfully encoded items: theta (3-6 Hz) and alpha (9-14 Hz) for unrelated lists, and theta (3-6 Hz) and beta (14-19 Hz) for categorized lists. Regional analyses for unrelated lists highlighted the lateral temporal cortex for theta effects and the prefrontal cortex for both theta and alpha consistency. These findings provide novel evidence for the frequency-specific presence of increased phase consistency during episodic encoding, revealing its sensitivity to both item context and temporal position within a learning sequence.<b>Significance statement</b> Neural oscillations are implicated in memory encoding, but their precise roles are still being defined. Our study leverages large-scale intracranial EEG from participants undergoing word recall experiments, and introduces analytical innovations for robustly quantifying phase consistency with differing numbers of recalled versus forgotten items. This methodology reveals that phase consistency across different frequency bands (theta, alpha, beta) predicts memory formation. We demonstrate a role for theta consistency in encoding early list items and show that the brain recruits different oscillatory patterns (alpha or beta alongside theta) depending on item context (unrelated vs. categorized lists). These findings advance our understanding of the frequency-specific neural mechanisms supporting human episodic memory, revealing how the brain adapts its encoding strategies based on informational structure.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144734993","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":"Isolating brain mechanisms of expectancy effects on pain: Cue-based stimulus expectancies versus placebo-based treatment expectancies.","authors":"Elizabeth A Necka,Titilola Akintola,Qingbao Yu,Carolyn M Amir,Olga Oretsky,Lauren Y Atlas","doi":"10.1523/jneurosci.0050-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0050-25.2025","url":null,"abstract":"Clinical trials, laboratory experiments, and neuroimaging studies provide converging evidence that pain is highly sensitive to expectations, whether based on the psychosocial context surrounding treatment (e.g., placebo analgesia) or transient cues that provide information about painful events (e.g., pain-predictive cues). We asked whether placebo analgesia and pain-predictive cues modulate pain through the same mechanisms or dissociable brain pathways. Forty healthy volunteers of both sexes rated pain in response to noxious heat during functional magnetic resonance imaging (fMRI) scanning. We crossed pain-predictive cues, which induce expectations for high or low pain on a trial-by-trial basis, with administration of an inert placebo cream or a control cream. Behavioral analyses revealed a significant interaction, such that predictive cues had weaker effects on pain during placebo blocks than control blocks. This interaction was accompanied by interactions in the insula, pons, and other brain regions. We also observed distinct neural substrates when we compared pure cue effects with pure placebo effects, and only predictive cues modulated responses in nociceptive regions and the Neurologic Pain Signature (NPS; (Wager et al., 2013). The only regions that were influenced similarly by both types of expectations were the rostral anterior cingulate and dorsomedial prefrontal cortex. These results indicate that cue-based expectations about stimulus intensity and placebo-based expectations about treatment outcomes are distinct, and that pain researchers should differentiate between sources of expectations. Furthermore, cue-based expectations were associated with more consistent effects than treatment-based expectations, suggesting that clinicians should be particularly mindful of how they present information about impending pain.Significance Statement This study measured the impact of pain-predictive cues and placebo effects on expectations, pain, and brain responses to noxious heat. Expectations were influenced by both cues and placebos, and we observed interactions between the two types of expectations on both pain and pain-related brain responses. We also observed dissociations in the two types of expectancy effects on brain responses and found that placebo effects were more variable than cue effects across individuals. This suggests that different types of expectations are associated with different underlying mechanisms. To maximize patient outcomes, clinicians should carefully frame both information about painful procedures and information about analgesic treatments.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"36 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719908","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":"Locally induced traveling waves generate globally observable traveling waves.","authors":"Kirsten Petras, Laetitia Grabot, Laura Dugué","doi":"10.1523/JNEUROSCI.0089-25.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0089-25.2025","url":null,"abstract":"<p><p>Cortical traveling waves have been proposed as a fundamental mechanism for neural communication and computation. Methodological uncertainties currently limit the interpretability of non-invasive, extracranial traveling wave data, sparking debates about their cortical origin. Studies using EEG or MEG typically report waves that cover large portions of the sensor array which are often interpreted as reflecting long range cortical waves. Meanwhile, invasive, intracranial recordings in humans and animals routinely find both local, mesoscopic waves and large scale, macroscopic waves in cortex. Whether the global sensor-array waves found with EEG/MEG necessarily correspond to macroscopic cortical waves or whether they are merely projections of local dynamics remains unclear. In this study, we made use of the well-established retinotopic organization of early visual cortex to generate traveling waves with known properties in human participants (N=19, 10 female, 9 male) via targeted visual stimulation, while simultaneously recording MEG and EEG. The inducer stimuli were designed to elicit waves whose traveling direction in mesoscopic retinotopic visual areas depends on stimulus direction, while leaving macroscopic activation patterns along the visual hierarchy largely unchanged. We observed that the preferred direction of traveling waves across the sensor array was influenced by that of the visual stimulus, but only at the stimulation frequency. Comparison between single-trial and trial-averaged responses further showed considerable temporal variation in traveling wave patterns across trials. Our results highlight that under tight experimental control, non-invasive, extracranial recordings can recover mesoscopic traveling wave activity, thus making them viable tools for the investigation of spatially constrained wave dynamics.<b>Significance statement</b> Non-invasively obtained time-resolved neuroimaging data is often thought to primarily reflect neural dynamics on the largest spatial scales. In the context of cortical traveling waves, this assumption can lead to a misinterpretation of spatio-temporal patterns observed in the sensor array. We here show that it is in principle possible that the global sensor array data is dominated by spatially constrained, local cortical traveling wave activity. Our findings crucially inform the ongoing discussion about the origin of traveling waves observed in surface recordings.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709719","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":"Motion Processing in Visual Cortex of Maculopathy Patients.","authors":"Célia Michaud, Jade Guénot, Cynthia Faurite, Mathilde Gallice, Christophe Chiquet, Nathalie Vayssière, Isabelle Berry, Yves Trotter, Vincent Soler, Carole Peyrin, Benoit R Cottereau","doi":"10.1523/JNEUROSCI.0283-25.2025","DOIUrl":"10.1523/JNEUROSCI.0283-25.2025","url":null,"abstract":"<p><p>Previous studies on animal models suggested that visual areas involved in motion processing could undergo important cortical reorganizations following retinal damages. This could have major implications for patients suffering from macular degeneration (MD), one leading cause of vision loss. Here, we performed fMRI recordings in a group of maculopathy patients (<i>N</i> = 7, 3 women, including individuals suffering from age-related macular degeneration or from Stargardt's disease) and a control group to characterize the motion processing cortical network in MD patients and determine whether this network is modified following the onset of the scotoma. We used an experimental protocol based on random-dot kinematograms classically employed to characterize motion-selective areas in the brain. To ensure that the visual information processed by the two groups was equivalent, the visual field in each control participant was masked using an artificial scotoma directly derived from clinical measurements in their paired patient. We found that in MD patients, translational motion elicited significant and robust activations in a restricted cortical network which included the human V5/MT+ complex (hMT+), areas V3A and V6, and a portion of primary visual areas (V1, V2, and V3) connected to peripheral vision. Importantly, the same patterns of responses were also observed in control participants. Moreover, the extent and strength of activation within these motion-selective areas did not differ significantly between the two groups. Altogether, these results suggest that in humans, the motion-selective network does not undergo significant large-scale cortical reorganizations following the onset of MD.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227429","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":"Shared and Diverging Neural Dynamics Underlying False and Veridical Perception.","authors":"Joost Haarsma, Dorottya Hetenyi, Peter Kok","doi":"10.1523/JNEUROSCI.1479-24.2025","DOIUrl":"10.1523/JNEUROSCI.1479-24.2025","url":null,"abstract":"<p><p>We often mistake visual noise for meaningful images, which sometimes appear as convincing as veridical percepts. This suggests considerable overlap between the mechanisms that underlie false and veridical perception. Yet, false percepts must arise at least in part from internally generated signals. Here, we apply multivariate analyses to human MEG data to study the overlap between veridical and false perception across two aspects of perceptual inference: discrimination of content (what did I see?) and detection (did I see something?). Male and female participants performed a visual discrimination task requiring them to indicate the orientation of a noisy grating, as well as their confidence in having seen a grating. Importantly, on 50% of trials, only a noise patch was presented. To exclude external signals driving false percepts, noise patches were carefully designed not to contain orientation signal. Still, participants occasionally confidently reported seeing a grating on noise only trials, i.e., false percepts. Decoding analyses revealed a sensory signal reflecting the content of these false percepts, despite no such grating being physically presented. Uniquely, high confidence false, but not veridical, percepts were associated with increased prestimulus high alpha/low beta [11-14 Hz] power, potentially reflecting enhanced reliance on top-down signaling on false percept trials. Later on, a shared neural code reflecting confidence in stimulus presence emerged for both false and veridical percepts. These findings suggest that false percepts arise through neural signals reflecting both sensory content and detection, similar to veridical percepts, with an increase in prestimulus alpha/beta power uniquely contributing to false percepts.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235755","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":"Cholinergic waves have a modest influence on the transcriptome of retinal ganglion cells.","authors":"Rachana Deven Somaiya, Matthew A Po, Marla B Feller, Karthik Shekhar","doi":"10.1523/JNEUROSCI.0165-25.2025","DOIUrl":"10.1523/JNEUROSCI.0165-25.2025","url":null,"abstract":"<p><p>In the early stages of development, correlated activity known as retinal waves causes periodic depolarizations of retinal ganglion cells (RGCs). The β2KO mouse, which lacks the β2 subunit of the nicotinic acetylcholine receptor, serves as a model for understanding the role of the cholinergic waves. β2KO mice have disruptions in several developmental processes of the visual system, including reduced retinotopic and eye-specific refinement of RGC axonal projections to their primary brain targets and an impact on the retinal circuits underlying direction selectivity. However, the effects of this mutation on gene expression in individual functional RGC types remain unclear. Here, we performed single-cell RNA sequencing on RGCs isolated at the end of the first postnatal week from wild-type and β2KO mice of either sex. We found that in β2KO, the programs governing RGC differentiation were not impacted and the magnitude of transcriptional changes was modest compared to those observed during two days of normal postnatal maturation. This contrasts with the substantial transcriptomic changes seen in downstream visual system areas under wave disruption in recent studies. Overall, we identified ∼238 genes whose expression was altered in a type-specific manner. We confirmed this result via <i>in situ</i> hybridization and whole-cell recording by focusing on one of the downregulated genes in αRGCs, <i>Kcnk9</i>, which encodes the two-pore domain leak potassium channel TASK3. Our study reveals a limited transcriptomic impact of cholinergic signaling in the retina and instead of affecting all RGCs uniformly, these waves show subtle modulation of molecular programs in a type-specific manner.<b>Significance statement</b> Spontaneous retinal waves are critical for the development of the mammalian visual system. However, their role in transcriptional regulation in the retina across the diverse retinal ganglion cell (RGC) types that underpin the detection and transmission of visual features is unclear. Using single-cell RNA sequencing, we analyzed RGC transcriptome from wild-type mice and mice with disrupted retinal waves. We identified several genes that show RGC-type-specific regulation in their expression, including multiple neuropeptides and ion channels. However, wave-dependent changes in the transcriptome were more subtle than developmental changes, indicating that spontaneous activity-dependent molecular changes in retinal ganglion cells are not primarily manifested at the transcriptomic level, suggesting that post-transcriptional mechanisms may be involved.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692247","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":"Evidence for an evolutionary continuity in social dominance: Insights from non-human primates tractography.","authors":"Julie Royo,Thomas Orset,Marco Catani,Pierre Pouget,Michel Thiebaut de Schotten","doi":"10.1523/jneurosci.1646-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1646-24.2025","url":null,"abstract":"The dynamics of social dominance play a significant role in regulating access to resources and influencing reproductive success and survival in non-human primates. These dynamics are based on aggressive and submissive interactions which create distinct, hierarchically organised social structures. In humans, whose social behaviour is similarly organised, the use of brain imaging based on tractography has identified key neuronal networks of the limbic system underlying social behaviour. Among them, the uncinate fasciculus and the cingulum bundle, have been associated with aggression and some disorders such as psychopathy.In this study, we have used advanced tractography to study the anatomy of connections underlying social dominance in a colony of 15 female squirrel monkeys (Saimiri sciureus). We correlated biostructural properties of the uncinate fasciculus and cingulum with behavioural hierarchy measures while controlling for factors such as age, weight, handedness, brain size, and hormonal influences. The fornix, a limbic connection involved in memory, was also included as control tract. Our findings indicate a significant correlation between the integrity of the right uncinate fasciculus and social dominance measures, including normalised David's scores, aggressive behaviours, and submissive behaviours. Trends observed in the left uncinate fasciculus hint at potential bilateral involvement with a right hemispheric lateralisation. These results are consistent with human studies linking the uncinate fasciculus to social aggression and disorders, suggesting an evolutionary continuity in the neuro-anatomical substrates of social dominance back to at least 35 million yearsSignificance Statement In non-human primates, social dominance determines resource access and impacts survival and reproduction. In this study, we used advanced tractography to study the anatomy of connections related to social dominance focusing on limbic regions such as the uncinate fasciculus and cingulum. We found a strong correlation between the integrity of the right uncinate fasciculus and social dominance measures including hierarchy, aggressive and submissive behaviours. These results suggest an evolutionary continuity in the neuro-anatomical substrates of social dominance back to at least 35 million years.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"110 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677870","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":"Multi-omics analysis reveals miR-7220-5p alleviates N2O addictive behaviors via NR2B/ERK/CREB signaling.","authors":"Tianyi Yang,Yan Chen,Maolin Wang,Ren Ren,Fang Yan,Peng Xu,Bin Di","doi":"10.1523/jneurosci.1410-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1410-24.2025","url":null,"abstract":"Nitrous oxide use Disorder（NUD）has recently received increasing social concern for its sharp rise among young people. However, the underlying mechanisms of NUD remain largely unexplored, which obstructs treatment strategy development and may exacerbate the epidemic of N2O abuse. Thus, specifying the essential mechanisms and targets in NUD are desperately needed. Here we unveiled a series of molecular adaptations regarding N2O reward memory in Nucleus accumbens (NAc) of mice through multi-omics approaches comprising transcriptomics, proteomics, metabolomics approaches. Our miRNA transcriptomics and pull-down proteomics analyzes uncovered that miR-7220-5p regulated N2O-induced conditioned-place preference (CPP) and associated increase of dendritic spine density in NAc of male mice. Our pull-down proteomics and metabolomics analyzes revealed that miR-7220-5p modulated ERK signaling pathway by directly binding with NR2B receptor. In summary, our work confirmed that restoring miR-7220-5p expression in NAc protected against synaptic abnormality via the NR2B/ERK/CREB signaling, thereby attenuating CPP behaviors in NUD. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed a potential therapeutic strategy for NUD and provided comprehensive resources of biological data to support future investigations of NUD treatment.Significance Statement Nitrous oxide Use Disorder (NUD) has recently received tremendously increasing social concern for its sharp rise among young people. Although the neurological consequences and their etiologies of consuming N2O have been well elucidated, the underlying mechanisms of NUD remain largely unexplored, which obstructs the development of clinical treatment strategies and may exacerbate the epidemic of N2O abuse. Our work uncovered the role of miR-7220-5p/NR2B/ERK/CREB signaling against synaptic abnormality/CPP behaviors. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed therapeutic targets for overcoming NUD behaviors and the omics data provided comprehensive biological resources to support future investigations of NUD.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"10 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652683","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":"Disrupted Neurogenesis from Basal Intermediate Precursor Cells Alters the Postnatal Neocortex in the TcMAC21 Mouse model of Down Syndrome.","authors":"Zeynep Atak,Anup Srivastava,Sachin Gandhi,Eunbin Park,Jonathan Williams,Masaaki Torii,Tarik F Haydar","doi":"10.1523/jneurosci.0040-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0040-25.2025","url":null,"abstract":"Cognitive, social behavior, speech, and motor skills are known challenges for people with trisomy 21/Down syndrome (DS) but the precise mechanisms that lead to these impactful changes have not yet been described. Data from human and mouse model fetal brains indicate that alterations in prenatal neurogenesis might account for the neurological phenotypes that manifest after birth. Here, we evaluated key features of cortical neurogenesis in the humanized mouse model of DS (TcMAC21 of undetermined sex) to test whether and how the presence of the human HSA21q transchromosome impacts cortical development. Brain growth measurements throughout the second half of gestation and at several periods of postnatal development show overall that the TcMAC21 brain phenotype is less severe than in other DS mouse models that have less genetic similarity to humans with DS. However, despite the lack of gross changes in brain growth, we uncovered a significant temporally limited neurogenesis defect at mid-gestation that correlates with long-lasting effects on neuronal dispersion and neuronal function in the neocortex. Using Cre/Lox mediated genetic fate mapping we discovered a transient reduction in neocortical basal intermediate neural precursors (bIPCs) and that bIPC neuronal progeny are under-represented in the superficial layers of the neocortex. This change in neuronal production is associated with cortical activity changes after birth. Altogether, our data isolate the cell types associated with a very specific temporal change in cortical formation that, due to the high levels of excitability of bIPC-derived neurons, creates lasting effects on network activity and circuit development in trisomic brains.Significance Statement This study, using a mouse model of Down syndrome (DS) with high genetic relevance to human trisomy 21, suggests that a specific population of excitatory neurons in the cerebral cortex is perturbed during fetal brain development. Production of these neurons, from a group of embryonic progenitor cells called basal intermediate progenitor cells (bIPCs), is decreased in mid-gestation, and the neurons successfully produced from intermediate progenitor cells (IPCs) show altered positioning in the mature cerebral cortex of the DS mouse brain. This change in neurogenesis likely contributes to altered connectivity and electrical activity in the DS brain.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"73 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652898","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}