Journal of Neuroscience最新文献

{"title":"Memory boost for recurring emotional events is driven by initial amygdala response promoting stable neocortical patterns across repetitions.","authors":"Valentina Krenz, Arjen Alink, Benno Roozendaal, Tobias Sommer, Lars Schwabe","doi":"10.1523/JNEUROSCI.2406-23.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2406-23.2025","url":null,"abstract":"<p><p>Emotionally arousing events are typically vividly remembered, which is generally adaptive but may contribute to mental disorders such as posttraumatic stress disorder. Previous research on emotional memory focused primarily on events that were experienced only once, leaving the memory mechanisms underlying repeatedly encountered emotional events largely unexplored. Here, we aimed to elucidate the brain mechanisms associated with memory for recurring emotional events. Specifically, we sought to determine whether the memory enhancement for recurring emotional events is linked to more variable neural representations, as predicted by the encoding-variability hypothesis, or to more stable representations across repetitions, as suggested by a memory reinstatement account. To investigate this, healthy men and women were repeatedly presented with images of emotionally negative or neutral scenes during three consecutive runs in an MRI scanner. Subsequent free recall was, as expected, enhanced for emotional compared to neutral images. Neural data showed that this emotional enhancement of memory was linked to (i) activation of the amygdala and anterior hippocampus during the initial encounter of the emotional event and (ii) increased neural pattern similarity in frontoparietal cortices across event repetitions. Most importantly, a multilevel moderated mediation analysis revealed that the impact of neocortical pattern stability across repetitions on emotional memory enhancement was moderated by amygdala activity during the initial exposure to the emotional event. Together, our findings show that the amygdala response during the initial encounter of an emotional event boosts subsequent remembering through a more precise reinstatement of the event representation during subsequent encounters of the same event.<b>Significance statement</b> Despite extensive research on emotional memory, the mechanisms underlying memory formation for recurrent emotional events remain elusive. We show that amygdala and anterior hippocampal activity is most prominent during the initial exposure to an aversive stimulus and decreases markedly with repeated exposure. Neocortical representation patterns of subsequently recalled emotional events, however, are more stable across the repeated encounters of emotional (vs. neutral) events, in line with a memory reinstatement account. Notably, this increased neocortical pattern stability was driven by the amygdala response during the initial exposure to an emotional event. These findings provide novel insights into the mechanisms involved in memory formation for recurrent emotional events, with potential implications for complex post-traumatic stress disorder characterized by multiple traumatic exposures.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Serotonergic Dorsal Raphe Promotes Emergence from Propofol Anesthesia in Zebrafish.","authors":"Xiaoxuan Yang, Shan Zhu, Miaoyun Xia, Le Sun, Sha Li, Peishan Xiang, Funing Li, Qiusui Deng, Lijun Chen, Wei Zhang, Ying Wang, Qiang Li, Zhuochen Lyu, Xufei Du, Jiulin Du, Qianzi Yang, Yan Luo","doi":"10.1523/JNEUROSCI.2125-23.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.2125-23.2025","url":null,"abstract":"<p><p>The mechanisms through which general anesthetics induce loss of consciousness remain unclear. Previous studies have suggested that dorsal raphe nucleus serotonergic (DRN^5-HT) neurons are involved in inhalational anesthesia, but the underlying neuronal and synaptic mechanisms are not well understood. In this study, we investigated the role of DRN^5-HT neurons in propofol-induced anesthesia in larval zebrafish (sex undetermined at this developmental stage) using a combination of in vivo single-cell calcium imaging, two-photon laser ablation, optogenetic activation, in vivo glutamate imaging and in vivo whole-cell recording. We found that calcium activity of DRN^5-HT neurons reversibly decreased during propofol perfusion. Ablation of DRN^5-HT neurons prolonged emergence from 30 μM propofol anesthesia, while induction times were not affected under concentrations of 1 μM, 3 μM, and 30 μM. Additionally, optogenetic activation of DRN^5-HT neurons strongly promoted emergence from propofol anesthesia. Propofol application to DRN^5-HT neurons suppressed both spontaneous and current injection-evoked spike firing, abolished spontaneous excitatory postsynaptic currents, and decreased membrane input resistance. Presynaptic glutamate release events in DRN^5-HT neurons were also abolished by propofol. Furthermore, the hyperpolarization of DRN^5-HT neurons caused by propofol was abolished by picrotoxin, a GABA_A receptor antagonist, which shortened emergence time from propofol anesthesia when locally applied to the DRN. Our results reveal that DRN^5-HT neurons in zebrafish are involved in the emergence from propofol anesthesia by inhibiting presynaptic excitatory glutamate inputs and inducing GABA_A receptor-mediated hyperpolarization.<b>Significance Statement</b> The neural mechanisms of general anesthesia remain unclear. We studied the role of the dorsal raphe nucleus serotonergic (DRN^5-HT) neurons in propofol anesthesia using larval zebrafish, employing in vivo calcium imaging at single-neuron resolution, two-photon ablation, optogenetic activation, and in vivo whole-cell recording. We found that the DRN^5-HT neurons are involved in emergence from anesthesia, but not induction. Propofol suppresses DRN^5-HT activity by inhibiting the activity of DRN^5-HT neurons via GABA_A receptors and blocking presynaptic excitatory glutamate inputs. These findings further support larval zebrafish as an ideal model for investigating the mechanisms of general anesthesia.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416075","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":"Stimulus-dependent expression of <i>Bdnf</i> is mediated by ATF2, MYT1L, and EGR1 transcription factors.","authors":"Eli-Eelika Esvald, Andra Moistus, Karin Lehe, Annela Avarlaid, Anastassia Šubina, Liis Kuusemets, Jürgen Tuvikene, Tõnis Timmusk","doi":"10.1523/JNEUROSCI.0313-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0313-24.2025","url":null,"abstract":"<p><p>Neurotrophins like BDNF have a key role in the proper functioning of the central nervous system, influencing numerous processes like memory formation and behavior. An imbalance in BDNF levels can lead to a wide range of diseases, including depression and neurodevelopmental disorders. While the potential therapeutic effects of BDNF are well-recognized, there is a knowledge gap in understanding the mechanisms governing BDNF expression levels. Here, we focused on the regulation of <i>Bdnf</i> gene expression in response to different stimuli, specifically studying the effects of neuronal activity and BDNF-TrkB signaling on <i>Bdnf</i> transcription in cultured neurons from rats of either sex. We used <i>in vitro</i> DNA pulldown combined with mass spectrometry to determine transcription factors that interact with the <i>Bdnf</i> promoters upon different stimuli and validated numerous known regulators, such as USF and AP1 family, and novel candidate regulators using reporter assays. We show that the USF family of transcription factors is specifically recruited after membrane depolarization, whereas the AP1 family participates in <i>Bdnf</i> regulation only after BDNF-TrkB signaling. We further describe ATF2, MYT1L and EGR family as novel regulators of <i>Bdnf</i> expression by demonstrating their direct binding to <i>Bdnf</i> promoters using chromatin immunoprecipitation assays both <i>in vitro</i> and in vivo, showing their functional role in <i>Bdnf</i> gene expression, and ultimately identifying their regulatory <i>cis</i>-elements in <i>Bdnf</i> promoters. Furthermore, our results show competition between ATF2, CREB, and AP1 family in regulating <i>Bdnf</i> levels. Collectively, our results provide insight into the regulation of <i>Bdnf</i> expression upon different stimuli.<b>Significance statement</b> Membrane depolarization and neurotrophin BDNF (brain-derived neurotrophic factor) signaling via its receptor TrkB (tropomyosin receptor kinase B) are critical processes for proper neuronal functions. Here, we studied how these two stimuli regulate the expression of two main <i>Bdnf</i> transcripts - <i>Bdnf</i> exon I- and IV-containing transcripts. Our results reveal a remarkable overlap of regulators that are recruited to both <i>Bdnf</i> promoters I and IV and after both stimuli. Overall, our results shed light to the complex regulation of <i>Bdnf</i> expression highlighting a dynamic interplay of cooperative and competitive mechanisms among transcription factors. Understanding the regulatory mechanisms beyond single transcription factors and considering the combinatorial effects could pave the way for specifically modulating <i>Bdnf</i> levels as therapeutic interventions.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416074","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":"Neurophysiology of perceptual decision-making and its alterations in attention-deficit hyperactivity disorder (ADHD).","authors":"Mana Biabani, Kevin Walsh, Shou-Han Zhou, Joseph Wagner, Alexandra Johnstone, Julia Paterson, Natasha Matthews, Beth P Johnson, Gerard M Loughnane, Redmond G O'Connell, Mark A Bellgrove","doi":"10.1523/JNEUROSCI.0469-24.2025","DOIUrl":"https://doi.org/10.1523/JNEUROSCI.0469-24.2025","url":null,"abstract":"<p><p>Despite the prevalence of ADHD, efforts to develop a detailed understanding of the neuropsychology of this neurodevelopmental condition are complicated by the diversity of interindividual presentations and the inability of current clinical tests to distinguish between its sensory, attentional, arousal or motoric contributions. Identifying objective methods that can explain the diverse performance profiles across individuals diagnosed with ADHD has been a long-held goal. Achieving this could significantly advance our understanding of etiological processes and potentially inform the development of personalized treatment approaches. Here, we examine key neuropsychological components of ADHD within an electrophysiological (EEG) perceptual decision-making paradigm that is capable of isolating distinct neural signals of several key information processing stages necessary for sensory-guided actions from attentional selection to motor responses. Using a perceptual decision-making task (random dot motion), we evaluated the performance of 79 children (aged 8 to 17 years) and found slower and less accurate responses, along with a reduced rate of evidence accumulation (drift rate parameter of drift diffusion model), in children with ADHD (n = 37; 13 female) compared to typically developing peers (n = 42; 18 female). This was driven by the atypical dynamics of discrete electrophysiological signatures of attentional selection, the accumulation of sensory evidence, and strategic adjustments reflecting urgency of response. These findings offer an integrated account of decision-making in ADHD and establish discrete neural signals that might be used to understand the wide range of neuropsychological performance variations in individuals with ADHD.<b>Significance Statement</b> The efficacy of diagnostic and therapeutic pathways in ADHD is limited by our incomplete understanding of its neurological basis. One promising avenue of research is the search for basic neural mechanisms that may contribute to the variety of cognitive challenges associated with ADHD. We developed a mechanistic account of differences in a fundamental cognitive process by integrating across neurocognitive, neurophysiological (i.e., EEG), and computational levels of analysis. We detected distinct neural changes in ADHD that explained altered performance (e.g., slowed and less accurate responses). These included changes in neural patterns of attentional selection, sensory information processing, and response preparation. These findings enhance our understanding of the neurophysiological profile of ADHD and may offer potential targets for more effective, personalized interventions.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416073","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 stress impairs VTA coordination of BLA network and behavioral states.","authors":"Bradly T Stone, Pantelis Antonoudiou, Eric Teboul, Garrett Scarpa, Grant Weiss, Jamie L Maguire","doi":"10.1523/JNEUROSCI.0088-24.2025","DOIUrl":"10.1523/JNEUROSCI.0088-24.2025","url":null,"abstract":"<p><p>Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states - and whether ELS impacts VTA-mediated network communication - remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and entrainment of mPFC activity in mice, and that ELS weakens the ability of the VTA to coordinate BLA network states, while also impairing dopaminergic signaling between VTA and BLA. Optogenetic stimulation of VTA_BLA terminals decreased social interaction in ELS mice, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.<b>Significance Statement</b> It is well established that oscillatory states in the basolateral amygdala (BLA) govern behavioral states. However, a gap in our knowledge exists regarding the mechanisms mediating transitions between BLA network states. Here we demonstrate a novel mechanism modulating BLA network states involving dopamine inputs from the VTA. Further, we demonstrate that early life stress, a major risk factor for psychiatric illnesses, impairs the ability of dopaminergic inputs from the VTA to coordinate BLA and mPFC network states. Thus, this study provides a novel mechanism mediating transitions between oscillatory states in the BLA which are well documented to govern behavioral states and demonstrates pathological perturbations in the ability of the VTA to coordinate BLA network states following early life stress.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416048","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":"Erratum: Dubal et al., \"Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice\".","authors":"","doi":"10.1523/JNEUROSCI.0069-25.2025","DOIUrl":"10.1523/JNEUROSCI.0069-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025482","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":"Attention Rhythmically Shapes Sensory Tuning.","authors":"Laurie Galas, Ian Donovan, Laura Dugué","doi":"10.1523/JNEUROSCI.1616-24.2024","DOIUrl":"10.1523/JNEUROSCI.1616-24.2024","url":null,"abstract":"<p><p>Attention is key to perception and human behavior, and evidence shows that it periodically samples sensory information (<20 Hz). However, this view has been recently challenged due to methodological concerns and gaps in our understanding of the function and mechanism of rhythmic attention. Here we used an intensive ∼22 h psychophysical protocol combined with reverse correlation analyses to infer the neural representation underlying these rhythms. Participants (male/female) performed a task in which covert spatial (sustained and exploratory) attention was manipulated and then probed at various delays. Our results show that sustained and exploratory attention periodically modulate perception via different neural computations. While sustained attention suppresses distracting stimulus features at the alpha (∼12 Hz) frequency, exploratory attention increases the gain around task-relevant stimulus feature at the theta (∼6 Hz) frequency. These findings reveal that both modes of rhythmic attention differentially shape sensory tuning, expanding the current understanding of the rhythmic sampling theory of attention.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015257","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":"Cell-Type-Specific Splicing of Transcription Regulators and <i>Ptbp1</i> by <i>Rbfox1/2/3</i> in the Developing Neocortex.","authors":"Xiangbin Ruan, Kaining Hu, Yalan Yang, Runwei Yang, Elizabeth Tseng, Bowei Kang, Aileen Kauffman, Rong Zhong, Xiaochang Zhang","doi":"10.1523/JNEUROSCI.0822-24.2024","DOIUrl":"10.1523/JNEUROSCI.0822-24.2024","url":null,"abstract":"<p><p>How master splicing regulators cross talk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq analyses of the developing neocortex uncover variable expression of the Rbfox1/2/3 genes and enriched alternative splicing events in transcription regulators, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glial progenitors induces neuronal splicing events preferentially in transcription regulators such as <i>Meis2</i> and <i>Tead1</i> Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon in <i>Ptbp1</i> Simultaneous ablation of <i>Rbfox1/2/3</i> in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform of <i>Meis2</i> promotes <i>Tgfb3</i> transcription, while the <i>Meis2</i> neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex. (The sex has not been reported to affect cortical neurogenesis in mice, and embryos of both sexes were studied without distinguishing one or the other.).</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631426","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":"Common Neocortical and Hippocampal Correlates of Performance Errors in a Timing Task.","authors":"Matthew R Gielow, Drew B Headley, Mohammad M Herzallah, Denis Paré","doi":"10.1523/JNEUROSCI.2003-23.2024","DOIUrl":"10.1523/JNEUROSCI.2003-23.2024","url":null,"abstract":"<p><p>We aimed to identify the neuronal correlates of performance errors in a difficult timing task. Male rats were trained to seek rewards and avoid shocks depending on the position of photic conditioned stimuli (CS-R and CS-S, respectively). Then, they were exposed to conflict trials where they had to time the interval between the CS-R and CS-S to obtain rewards while avoiding footshocks. There were pronounced individual differences in behavioral strategies on conflict trials. When presented with a CS-S, some rats quickly left the shock sector, forsaking the option of earning a reward, and rarely got shocked. Others earned rewards by delaying avoidance based on the interval between the CS-R and CS-S but were shocked more often. The probability rats would fail a given trial was not stable across trials as rats engaged in incorrect trial runs that were longer than expected by chance. Since this finding suggested that rats shift between two quasi-stable processing modes, we next examined the neuronal correlates of errors. Incorrect trials coincided with reduced firing rates in CA1 and sensory cortical neurons. Moreover, trial-to-trial variations in the firing rates of simultaneously recorded neurons were more strongly correlated on error than correct trials. Last, the power of low-frequency local field potential oscillations was higher during incorrect trials. The finding that the neuronal correlates of correct and error trials are similar in the hippocampus and neocortex lead us to hypothesize that they depend on changes in the activity of common afferents, such as neuromodulatory inputs.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967151","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":"Adolescent Cerebellar Nuclei Manipulation Alters Reversal Learning and Perineuronal Net Intensity Independently in Male and Female Mice.","authors":"Tristan T Lyle, Jessica L Verpeut","doi":"10.1523/JNEUROSCI.2182-23.2024","DOIUrl":"10.1523/JNEUROSCI.2182-23.2024","url":null,"abstract":"<p><p>The cerebellum, identified to be active during cognitive and social behavior, has multisynaptic connections through the cerebellar nuclei (CN) and thalamus to cortical regions, yet formation and modulation of these pathways are not fully understood. Perineuronal nets (PNNs) respond to changes in local cellular activity and emerge during development. PNNs are implicated in learning and neurodevelopmental disorders, but their role in the CN during development is unknown. Connectivity deficits, specifically between lateral CN (LCN) and cortical regions have been found in autism spectrum disorder with patients displaying reduced cognitive flexibility. To examine the role of LCN on cognition, neural activity was perturbed in both male and female mice using designer receptors exclusively activated by designer drugs (DREADDs) from postnatal day 21 to 35. We found that while an adolescent LCN disruption did not alter task acquisition, correct choice reversal performance was dependent on DREADD manipulation and sex. Inhibitory DREADDs improved reversal learning in males (5 d faster to criteria), and excitatory DREADDs improved female reversal learning (10 d faster to criteria) compared with controls. Interestingly, the DREADD manipulation in females regardless of direction reduced PNN intensity, whereas in males, only the inhibitory DREADDs reduced PNNs. This suggests a chronic adolescent LCN manipulation may have sex-specific compensatory changes in PNN structure and LCN output to improve reversal learning. This study provides new evidence for LCN in nonmotor functions and sex-dependent differences in behavior and CN plasticity.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928703","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}