Journal of Neuroscience最新文献

{"title":"Directed Neural Network Dynamics in Sensorimotor Integration: Divergent Roles of Frontal Theta Band Activity Depending on Age.","authors":"Adriana Böttcher,Saskia Wilken,Markus Raab,Sven Hoffmann,Christian Beste","doi":"10.1523/jneurosci.0427-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0427-25.2025","url":null,"abstract":"Sensorimotor integration processes are crucial for daily-life activities, such as grasping objects or driving a car. Theta band activity (TBA) in distributed brain networks is likely essential to perform sensorimotor integration successfully. Directed communication in these brain networks is shaped by brain maturation during adolescence. This study investigates how age-related effects attributable to brain maturation influence directed communication in a theta-associated sensorimotor integration network. We conducted an EEG study with a continuous pursuit-tracking task performed by an adult group (n = 41) and an adolescent group (n = 30), each including both sexes. Both groups show elevated theta-band activity during higher sensorimotor demands. Yet, the adult group outperformed the adolescent group, particularly during higher demands. Further analyses revealed that this is likely due to enhanced directed connectivity between frontal areas and the ventral processing stream in adults, which likely enables effective integration of visual and motor information. Adolescents rely on frontal TBA signaling surprise and prediction error, with no input from ventral stream areas. This might cause lower performance during higher demands. Across age, TBA appears to serve distinct functions during sensorimotor integration. Age-related processes transform the neural processes underlying complex sensorimotor integration.Significance Statement This study shows how brain development affects tasks like grasping or driving, where vision and movement must work together. The results suggest that adults who performed better in sensorimotor integration yield a stronger information transfer between brain regions that integrate visual and motor information, while adolescents lack an input from such areas. This difference in brain communication could explain why adolescents struggle with more complex tasks, highlighting how brain maturation improves sensorimotor integration.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"31 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114119","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":"Learning Modulates Early Encephalographic Responses to Distracting Stimuli: A Combined SSVEP and ERP Study.","authors":"Dock H Duncan, Norman Forschack, Dirk van Moorselaar, Matthias M Müller, Jan Theeuwes","doi":"10.1523/JNEUROSCI.1973-24.2025","DOIUrl":"10.1523/JNEUROSCI.1973-24.2025","url":null,"abstract":"<p><p>Through experience, humans can learn to suppress locations that frequently contain distracting stimuli. However, the neural mechanism underlying learned suppression remains largely unknown. In this study, we combined steady-state visually evoked potentials (SSVEPs) with event-related potentials (ERPs) to investigate the mechanism behind statistically learned spatial suppression. Twenty-four male and female human participants performed a version of the additional singleton search task in which one location contained a distractor stimulus frequently. The search stimuli constantly flickered on-and-off the screen, resulting in steady-state entrainment. Prior to search onset, no differences in the SSVEP response were found, though a post hoc analysis did reveal proactive alpha lateralization. Following search onset, clear evoked differences in both the SSVEP and ERP signals emerged at the suppressed location relative to all other locations. Crucially, the early timing of these evoked modulations suggests that learned distractor suppression occurs at the initial stages of visual processing.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789092","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":"Sensorimotor Transformations for Postural Control in the Vermis of the Cerebellum.","authors":"Robyn L Mildren,Kathleen E Cullen","doi":"10.1523/jneurosci.0249-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0249-25.2025","url":null,"abstract":"The cerebellar vermis plays an essential role in maintaining posture and balance by integrating sensory inputs from multiple modalities to effectively coordinate movement. By transforming convergent sensory information into precise motor commands, it ensures smooth, adaptive motor control, enabling the body to maintain stability in dynamic environments. This review examines recent findings that investigate the distinct neural computations performed by the anterior vermis and posterior vermis (nodulus/uvula). Specifically, we examine how Purkinje cells in these regions integrate vestibular and proprioceptive signals to convert self-motion information from a head-centered to a body-centered reference frame, which is essential for maintaining precise postural control in response to unexpected movements. Additionally, we consider recent findings showing that, during voluntary self-motion, Purkinje cells in the anterior vermis selectively suppress responses in the vestibulospinal pathway by integrating motor inputs with sensory signals. Given the anterior vermis's role in maintaining balance during voluntary behaviors such as locomotion, its suppression prevents counterproductive stabilizing reflexes, enabling goal-directed movement through space. In contrast, the posterior vermis, encompassing the nodulus and uvula, integrates vestibular inputs from both the otoliths and semicircular canals to maintain equilibrium relative to gravitational forces. We thus hypothesize that Purkinje cells in the nodulus/uvula do not generate suppression signals like those observed in the anterior vermis but instead continuously compute our orientation in space, regardless of whether movement is voluntarily generated or unexpected. If our hypothesis is correct, the nodulus/uvula would effectively provide consistent \"ground truth\" information about self-motion relative to gravity.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"135 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114116","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 That Respiratory Phase May Modulate Task-Related Neural Representations of Visual Stimuli.","authors":"Lisa Stetza, Lena Hehemann, Christoph Kayser","doi":"10.1523/JNEUROSCI.2236-24.2025","DOIUrl":"10.1523/JNEUROSCI.2236-24.2025","url":null,"abstract":"<p><p>We investigate how respiration influences cognition by examining the interaction between respiratory phase and task-related brain activity during two visual categorization tasks. While prior research shows that cognitive performance varies along the respiratory cycle, the underlying neurophysiological mechanisms remain poorly understood. Though some studies have shown that large-scale neural activity reflecting for example changes in the excitation-inhibition balance is comodulated with the respiratory cycle, it remains unclear whether respiration directly shapes the neural signatures reflecting the encoding of task-specific external signals. We address this gap by applying single-trial multivariate analyses to EEG data obtained in humans (<i>n</i> = 25, any gender), allowing us to track how respiration relates to the sensory evidence reflected in this neurophysiological signal. Confirming previous studies, our data show that participant's performance varies with the respiratory phase prior and during a trial. Importantly, they suggest that respiration may directly influence the sensory evidence carried by neurophysiological processes emerging ∼300-200 ms prior to participant's responses. Hence, respiration and sensory-cognitive processes are not only highly intertwined but respiration may directly facilitate the representation of behaviorally relevant signals in the brain.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057124","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":"PVN-NAc shell-VP circuit OT and OTR neurons regulate pair bonding via D2R and D1R.","authors":"Lizi Zhang,Yishan Qu,Lu Li,Yahan Sun,Wei Qian,Jiayu Xiao,Kaizhe Huang,Xiao Han,Haiwei Niu,Luoman Li,Jing Liu,Hui Qiao,Rui Jia,Ting Lian,Zhixiong He,Fadao Tai","doi":"10.1523/jneurosci.2061-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2061-24.2025","url":null,"abstract":"Previous studies have found that several neurochemicals are involved in formation of pair bonding. However, circuit mechanisms underlying pair bonding, especially how these chemicals interact in this circuit regulate pair bonding, remains unclear. Using male mandarin voles, the present study shows that cohabitation with a partner increased frequency of spontaneous excitatory postsynaptic current (sEPSC) of paraventricular nucleus (PVN) oxytocin (OT) neurons projecting to nucleus accumbens (NAc) shell. Optogenetic activation of PVN OT neurons projecting to the NAc shell reduced D2 medium spiny neurons (MSNs) activity, but increased activities of D1 MSNs in the NAc shell. Bath application of OT caused a long-term depression (LTD) of evoked excitatory postsynaptic current (eEPSC) in NAc shell D1/D2 MSNs in the no cohabitated male voles. This OT-induced LTD in the NAc shell D1/D2 MSNs was suppressed by 7 days of cohabitation. NAc shell oxytocin receptor (OTR) MSNs projecting to the ventral pallidum (VP) were D1R/D2R positive. Chemogenetic activation or inhibition of OTR MSNs in the NAc shell projecting to the VP facilitated or disrupted the pair bond formation respectively. The facilitatory effects of OTR MSNs activation on pair bond formation could be blocked by D2 antagonist, but not D1 antagonist. These results suggest that OT and OTR neurons in the PVN-NAc shell-VP circuit regulate pair bonding via different activities of D1/D2 MSNs.Significance Statement Pair bond is important for successful reproduction in monogamous species, while the mechanisms by which the neurochemicals interact to regulate formation of pair bonding remain unclear. Using whole cell patch-clamp recordings, we confirmed that cohabitation with opposite sexes alters the synaptic transmission of OT neurons in the PVN and the effects of OT on D1 and D2 MSNs in the NAc. We then unveiled that optogenetic activation of PVN OT neurons influence activities of D1 and D2 MSNs in the NAc shell and manipulation of VP-projecting OTR MSNs in the NAc shell affected pair bonding formation. Our findings identify that OT and dopamine system interact in the PVN-NAc shell-VP neural circuits modulate formation of pair bonding.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"135 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114155","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":"Timing of Speech in Brain and Glottis and the Feedback Delay Problem in Motor Control.","authors":"John P Veillette, Jacob Rosen, Daniel Margoliash, Howard C Nusbaum","doi":"10.1523/JNEUROSCI.2294-24.2025","DOIUrl":"10.1523/JNEUROSCI.2294-24.2025","url":null,"abstract":"<p><p>To learn complex motor skills, an organism must be able to assign sensory feedback events to the actions that caused them. This matching problem would be simple if motor neuron output led to sensory feedback with a fixed, predictable lag. However, nonlinear dynamics in the brain and the body's periphery can decouple the timing of critical events from that of the motor output which caused them. During human speech production, for example, phonation from the glottis (a sound source for speech) begins suddenly when subglottal pressure and laryngeal tension cross a sharp threshold (i.e., a bifurcation). Only if the brain can predict the timing of these discrete peripheral events resulting from motor output, then, would it be possible to match sensory feedback to movements based on temporal coherence. We show that event onsets in the (male and female) human glottal waveform, measured using electroglottography, are reflected in the electroencephalogram during speech production, leading up to the time of the event itself. Conversely, glottal event times can be decoded from the electroencephalogram. After prolonged exposure to delayed auditory feedback, subjects recalibrate their behavioral threshold for detecting temporal auditory-motor mismatches and decoded event times decouple from actual movements. This suggests decoding performance is driven by plastic predictions of peripheral timing, providing a missing component for hindsight credit assignment, in which specific feedback events are associated with the neural activity that gave rise to movements. We discuss parallel findings from the birdsong system suggesting that results may generalize across vocal learning species.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990403","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":"EEG of the Dancing Brain: Decoding Sensory, Motor, and Social Processes during Dyadic Dance.","authors":"Félix Bigand, Roberta Bianco, Sara F Abalde, Trinh Nguyen, Giacomo Novembre","doi":"10.1523/JNEUROSCI.2372-24.2025","DOIUrl":"10.1523/JNEUROSCI.2372-24.2025","url":null,"abstract":"<p><p>Real-world social cognition requires processing and adapting to multiple dynamic information streams. Interpreting neural activity in such ecological conditions remains a key challenge for neuroscience. This study leverages advancements in denoising techniques and multivariate modeling to extract interpretable EEG signals from pairs of (male and/or female) participants engaged in spontaneous dyadic dance. Using multivariate temporal response functions (mTRFs), we investigated how music acoustics, self-generated kinematics, other-generated kinematics, and social coordination uniquely contributed to EEG activity. Electromyogram recordings from ocular, face, and neck muscles were also modeled to control for artifacts. The mTRFs effectively disentangled neural signals associated with four processes: (I) auditory tracking of music, (II) control of self-generated movements, (III) visual monitoring of partner movements, and (IV) visual tracking of social coordination. We show that the first three neural signals are driven by event-related potentials: the P50-N100-P200 triggered by acoustic events, the central lateralized movement-related cortical potentials triggered by movement initiation, and the occipital N170 triggered by movement observation. Notably, the (previously unknown) neural marker of social coordination encodes the spatiotemporal alignment between dancers, surpassing the encoding of self- or partner-related kinematics taken alone. This marker emerges when partners can see each other, exhibits a topographical distribution over occipital areas, and is specifically driven by movement observation rather than initiation. Using data-driven kinematic decomposition, we further show that vertical bounce movements best drive observers' EEG activity. These findings highlight the potential of real-world neuroimaging, combined with multivariate modeling, to uncover the mechanisms underlying complex yet natural social behaviors.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020015","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":"Threonine-53 phosphorylation of dopamine transporter dictates kappa opioid receptor mediated locomotor suppression, aversion, and cocaine reward.","authors":"Durairaj Ragu Varman,Sammanda Ramamoorthy,Lankupalle D Jayanthi","doi":"10.1523/jneurosci.0171-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0171-25.2025","url":null,"abstract":"Dynorphin (DYN)/kappa opioid receptor (KOR) activation contributes to aversion, dysphoria, sedation, depression, and enhanced psychostimulant-rewarding effects by inhibiting dopamine (DA) release. The precise neuronal mechanisms underlying these effects remain unclear, limiting the use of KOR agonists in treating mood and substance use disorders. DYN fibers form synapses with DA terminals that express KOR and dopamine transporter (DAT), which is crucial for regulating DA dynamics and related behaviors. Previously, we demonstrated that KOR agonists upregulate DAT activity via ERK1/2 signaling involving phospho-Thr53 DAT (pT53-DAT). However, it remains unclear whether pT53-DAT is involved in KOR-mediated DAT regulation in vivo and whether such a phenomenon contributes to the behavioral effects of KOR agonism. In this study, we utilized male DAT-Ala53 knock-in mice with non-phosphorylatable Ala at position 53 to investigate the role of pT53-DAT in KOR-mediated DAT regulation and its behavioral effects. KOR agonist U69593 increased KOR antagonist-sensitive DAT activity, DAT Vmax, pT53-DAT, and surface expression in WT but not in DAT-Ala53 mice. KOR agonists caused locomotor suppression, conditioned place aversion (CPA), and enhanced cocaine preference (CPP) in WT but not in DAT-Ala53 mice. Conversely, both WT and DAT-Ala53 mice exhibited similar lithium chloride-induced CPA and morphine-induced CPP. These findings provide the first causal evidence that KOR-mediated locomotor suppression, aversive response, and enhancement of cocaine reward manifest through the modulation of DAT activity via DAT-T53 phosphorylation. This suggests that targeting specific DAT-regulatory motif(s) may help develop new KOR-directed therapeutic strategies devoid of adverse effects.Significance Statement Preclinical and clinical research reveal that cocaine use disorder (CUD) affects mesolimbic dopamine neurotransmission, dopamine transporters (DAT), and DA interactions with the dynorphin (DYN)/kappa opioid receptor (KOR) system. The lack of FDA-approved treatments for CUD highlights a significant gap in our understanding of its neurobiology. While KOR ligands have potential as therapies, their effectiveness is often limited by side effects like aversion, dysphoria. and enhancing cocaine reward. Our study demonstrates that phosphorylation of Thr53 motif in DAT is crucial for KOR-mediated aversion, locomotor suppression, and enhancement of cocaine reward. These findings provide the first neurobiological evidence linking DAT-Thr53 phosphorylation to KOR modulation of DA clearance, highlighting its contribution to adverse behavioral outcomes and opening avenues for effective CUD treatments.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"127 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103741","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":"Modulation of dopamine neurons alters behavior and event encoding in the nucleus accumbens during Pavlovian conditioning.","authors":"Ethan W Herring,Kira B Lear,Sandford Zeng,Elin F B McLaughlin,Tulasi Syamala,Eesha D Patel,Kyle Duffer,Sara E Morrison","doi":"10.1523/jneurosci.0061-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0061-25.2025","url":null,"abstract":"When a cue is located away from its associated reward, some animals will learn to approach the site of reward (goal-tracking behavior) while others will approach the cue (sign-tracking behavior). The acquisition of sign tracking, but not goal tracking, is dependent on dopamine in the nucleus accumbens (NAc), and we have previously demonstrated that reward-evoked activity in the NAc core may reflect different patterns of dopamine release in sign tracker vs. goal tracker individuals. However, a causal relationship among dopamine release, NAc activity, and sign tracking has not been established. Using male and female TH::Cre rats, we expressed inhibitory or excitatory opsins in dopamine neurons of the ventral tegmental area (VTA) and examined the impact of optical manipulation of dopamine neurons on behavior and concurrent NAc neuronal activity. We found that inhibition of VTA dopamine neurons at the time of reward suppressed the acquisition of sign-tracking, but not goal-tracking, behavior. On the other hand, stimulation of dopamine neurons did not alter the acquisition of sign tracking; however, cessation of stimulation impeded further acquisition of sign tracking. Finally, both inhibition and stimulation of VTA dopamine neurons rapidly modulated activity in a subset of NAc neurons and led to changes in cue- and reward-related activity across sessions. Overall, these findings support the ideas that sign tracking and goal tracking are the products of two different learning processes - one dopamine-dependent and one not - and that the impact of VTA dopamine on sign tracking may be mediated by activity in the NAc core.Significance Statement During Pavlovian reward conditioning, activity patterns in the nucleus accumbens (NAc) core appear to reflect differences in dopamine release between sign trackers - individuals who tend to approach reward-paired cues - and goal trackers, who tend to approach the site of reward. Here, we use optogenetics to inhibit or stimulate dopamine neurons at the time of reward during learning. We show that inhibition suppresses the acquisition of sign-tracking behavior but not goal-tracking behavior; meanwhile, stimulation has no overt effect, but cessation of stimulation suppresses further acquisition of sign tracking, but not goal tracking. Finally, by recording from individual neurons concurrent with optical stimulation/inhibition, we show that these effects may be mediated by a small subset of neurons in the NAc core.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"38 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103745","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":"Atypical cadherin FAT2 is required for synaptic integrity and motor behaviors.","authors":"Xiankun Wang,Yadi Pu,Jifei Miao,Li Xie,Liangyu Guan,Yongfei Cui,Jun Wang,Liming Qin,Ying Han,Markus Wöhr,Bo Zhang","doi":"10.1523/jneurosci.2345-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2345-24.2025","url":null,"abstract":"In humans, mutations or deletions of atypical FAT cadherin genes are linked to autism spectrum disorder and cerebellar ataxia. However, their large genomic size and the enormous size of their encoded proteins have hampered functional studies, leaving the roles of FAT cadherins poorly understood. To address this gap, we investigated FAT2-an atypical cadherin selectively expressed in cerebellar granule cells-in murine cerebellar function. We demonstrate that FAT2 directly binds Cbln1, a secreted molecule essential for synapse formation and plasticity at Purkinje cell synapses. Furthermore, Fat2 deletion mice of both sexes selectively weakened the synaptic strength of parallel fiber synapses in the cerebellum and impaired motor behaviors. These findings reveal that FAT2 is indispensable for motor behaviors, likely through regulating Cbln1-dependent synaptic integrity.Significance Statement Abnormal motor behavior is a hallmark of many neurological and psychiatric disorders and a common symptom across numerous diseases. Growing evidence highlights the critical role of the motor system in elucidating the pathophysiology and treatment of mental disorders. Digging behavior-a movement characterized by forefeet scratching and/or hindfeet substrate kicking-is poorly understood at the genetic level. Here, we identify FAT Atypical Cadherin 2 (FAT2) as a binding partner of Cbln1, a synaptic organizer for cerebellar parallel fiber synapses. We demonstrate that deletion of cerebellar granule cell FAT2 impairs synaptic integrity and motor behaviors. These findings establish FAT2 as essential for synaptic integrity and the execution of fine motor and digging behaviors.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"44 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103699","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}