Pub Date : 2025-10-25DOI: 10.1016/j.pneurobio.2025.102843
Sigurd L. Alnes , Ellen van Maren , Camille G. Mignardot , Ida Boccalaro , Thea Waldleben , Debora Ledergerber , Lennart H. Stieglitz , Markus Schmidt , Antoine Adamantidis , Lukas L. Imbach , Kaspar Schindler , Maxime O. Baud , Athina Tzovara
Auditory stimulation during non rapid eye movement (NREM) sleep has sparked remarkable interest for neuromodulation of sleep and improvement of memory and cognition. Yet, the electrophysiology of auditory brain responses in sleep remains elusive. Here, we studied auditory processing in the temporal lobe in humans using invasive electroencephalography recordings. We found that the auditory response hierarchy of wakefulness weakens during NREM sleep. NREM sleep instead exhibits two types of responses: (a) intracranial event-related potentials in the lateral and medial temporal lobe that are modulated by slow wave activity and are stronger and faster when sounds occur at or after the peak of local slow waves; (b) high-frequency responses in the temporal cortex, a proxy for neural firing, which are not affected by slow waves. These findings show slow wave resilient and slow wave dependent mechanisms for monitoring the environment during sleep and can drive future interventions based on auditory stimulation.
{"title":"Auditory responses in the temporal lobe are modulated by slow waves of sleep","authors":"Sigurd L. Alnes , Ellen van Maren , Camille G. Mignardot , Ida Boccalaro , Thea Waldleben , Debora Ledergerber , Lennart H. Stieglitz , Markus Schmidt , Antoine Adamantidis , Lukas L. Imbach , Kaspar Schindler , Maxime O. Baud , Athina Tzovara","doi":"10.1016/j.pneurobio.2025.102843","DOIUrl":"10.1016/j.pneurobio.2025.102843","url":null,"abstract":"<div><div>Auditory stimulation during non rapid eye movement (NREM) sleep has sparked remarkable interest for neuromodulation of sleep and improvement of memory and cognition. Yet, the electrophysiology of auditory brain responses in sleep remains elusive. Here, we studied auditory processing in the temporal lobe in humans using invasive electroencephalography recordings. We found that the auditory response hierarchy of wakefulness weakens during NREM sleep. NREM sleep instead exhibits two types of responses: (a) intracranial event-related potentials in the lateral and medial temporal lobe that are modulated by slow wave activity and are stronger and faster when sounds occur at or after the peak of local slow waves; (b) high-frequency responses in the temporal cortex, a proxy for neural firing, which are not affected by slow waves. These findings show slow wave resilient and slow wave dependent mechanisms for monitoring the environment during sleep and can drive future interventions based on auditory stimulation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102843"},"PeriodicalIF":6.1,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145435520","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}
Pub Date : 2025-10-12DOI: 10.1016/j.pneurobio.2025.102842
Alessia Sepe , Matteo Panormita , Qi Zhu , Xiaolian Li , David A. Leopold , Marco Tamietto , Luca Bonini , Wim Vanduffel
The superior colliculus (SC) integrates multisensory inputs from retinal, subcortical, and cortical regions within a map of visual space to support orienting and interactive behaviors. While early models suggested that the SC primarily represents peripheral space for target detection, recent evidence highlights its significant foveal representation, essential for precisely targeting objects. Using ultra-high-resolution phase-encoding fMRI and spatially localized stimuli, we mapped the visuotopic organization of the SC in six macaques up to 40° eccentricity. In addition to confirming previous findings, we identified consistent interhemispheric asymmetries in the fMRI signal. The left SC, unlike the right, displayed a clear eccentricity map with a smooth rostro-caudal progression of responses to stimuli of increasing eccentricity from the fovea to the periphery. Conversely, the right SC showed no evidence of a pronounced eccentricity map and, instead, it exhibited more prominent polar angle maps and spatially broader fMRI responses to peripheral stimuli compared to the left SC. These lateralized responses were consistent across stimulus types and imaging protocols and were mirrored only in the intraparietal sulcus, a major cortical input to the SC. The observed asymmetry may derive from differences in magnification factor, intercollicular or surround inhibition between the left and right SC. Regardless of the underlying mechanism, our results suggest that functional lateralization in nonhuman primates may be more prevalent than previously recognized.
{"title":"Lateralized visuotopic organization in the macaque superior colliculus revealed by fMRI","authors":"Alessia Sepe , Matteo Panormita , Qi Zhu , Xiaolian Li , David A. Leopold , Marco Tamietto , Luca Bonini , Wim Vanduffel","doi":"10.1016/j.pneurobio.2025.102842","DOIUrl":"10.1016/j.pneurobio.2025.102842","url":null,"abstract":"<div><div>The superior colliculus (SC) integrates multisensory inputs from retinal, subcortical, and cortical regions within a map of visual space to support orienting and interactive behaviors. While early models suggested that the SC primarily represents peripheral space for target detection, recent evidence highlights its significant foveal representation, essential for precisely targeting objects. Using ultra-high-resolution phase-encoding fMRI and spatially localized stimuli, we mapped the visuotopic organization of the SC in six macaques up to 40° eccentricity. In addition to confirming previous findings, we identified consistent interhemispheric asymmetries in the fMRI signal. The left SC, unlike the right, displayed a clear eccentricity map with a smooth rostro-caudal progression of responses to stimuli of increasing eccentricity from the fovea to the periphery. Conversely, the right SC showed no evidence of a pronounced eccentricity map and, instead, it exhibited more prominent polar angle maps and spatially broader fMRI responses to peripheral stimuli compared to the left SC. These lateralized responses were consistent across stimulus types and imaging protocols and were mirrored only in the intraparietal sulcus, a major cortical input to the SC. The observed asymmetry may derive from differences in magnification factor, intercollicular or surround inhibition between the left and right SC. Regardless of the underlying mechanism, our results suggest that functional lateralization in nonhuman primates may be more prevalent than previously recognized.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"254 ","pages":"Article 102842"},"PeriodicalIF":6.1,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293400","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}
Pub Date : 2025-10-11DOI: 10.1016/j.pneurobio.2025.102841
Margarita Kapustina , Brianna N. Bristow , Mark S. Cembrowski
Layer 6b (L6b) neurons are a sparse population of deep neocortical neurons that govern both healthy and disordered brain states. L6b neurons have qualitatively been characterized as a thin lamina within the deepest layer of the cerebral cortex, yet the precise cell-type-specific properties and spatial organization of these neurons across the cortical mantle remain unresolved. Here, we combine single-cell RNA sequencing, highly multiplexed fluorescent in situ hybridization, and single-cell spatial transcriptomics to comprehensively characterize L6b cell-type identity, molecular heterogeneity, and spatial organization. In doing so, we identify and spatially resolve multiple distinct L6b subtypes with unique molecular signatures. To investigate the spatial organization of these subtypes across the brain, we generated a single-cell spatial transcriptomics dataset comprising 450,496 cells, offering the most extensive spatial mapping of L6b subtypes to date. Using a data-driven approach to analyze this dataset, we identify that the spatial patterning of L6b varies across the cortical mantle according to a patchwork-like composition of subtypes, which can notably extend beyond the classically defined deep location of L6b for some subtypes. We also find that L6b neurons can be transcriptionally separable but spatially intermingled with Layer 6a neurons, illustrating that a deep location within the cortex is neither sufficient nor necessary for assessing L6b identity. Our work provides the most comprehensive cellular phenotyping of L6b to date, reveals a cell-type-specific spatial-molecular framework for interpreting L6b properties and function, and will guide future investigations on the role of L6b cell subtypes and molecules in brain health and disorder.
{"title":"Distinct Layer 6b transcriptomic subtypes parcellate the cortical mantle","authors":"Margarita Kapustina , Brianna N. Bristow , Mark S. Cembrowski","doi":"10.1016/j.pneurobio.2025.102841","DOIUrl":"10.1016/j.pneurobio.2025.102841","url":null,"abstract":"<div><div>Layer 6b (L6b) neurons are a sparse population of deep neocortical neurons that govern both healthy and disordered brain states. L6b neurons have qualitatively been characterized as a thin lamina within the deepest layer of the cerebral cortex, yet the precise cell-type-specific properties and spatial organization of these neurons across the cortical mantle remain unresolved. Here, we combine single-cell RNA sequencing, highly multiplexed fluorescent <em>in situ</em> hybridization, and single-cell spatial transcriptomics to comprehensively characterize L6b cell-type identity, molecular heterogeneity, and spatial organization. In doing so, we identify and spatially resolve multiple distinct L6b subtypes with unique molecular signatures. To investigate the spatial organization of these subtypes across the brain, we generated a single-cell spatial transcriptomics dataset comprising 450,496 cells, offering the most extensive spatial mapping of L6b subtypes to date. Using a data-driven approach to analyze this dataset, we identify that the spatial patterning of L6b varies across the cortical mantle according to a patchwork-like composition of subtypes, which can notably extend beyond the classically defined deep location of L6b for some subtypes. We also find that L6b neurons can be transcriptionally separable but spatially intermingled with Layer 6a neurons, illustrating that a deep location within the cortex is neither sufficient nor necessary for assessing L6b identity. Our work provides the most comprehensive cellular phenotyping of L6b to date, reveals a cell-type-specific spatial-molecular framework for interpreting L6b properties and function, and will guide future investigations on the role of L6b cell subtypes and molecules in brain health and disorder.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"254 ","pages":"Article 102841"},"PeriodicalIF":6.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286844","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}
Pub Date : 2025-10-08DOI: 10.1016/j.pneurobio.2025.102834
Katrina Lin, Laurence Coutellier
Social interactions are a hallmark of animal behavior and is essential for survival, cooperation, and reproduction. Despite its necessity, the neural mechanisms that drive social behavior, particularly the rewarding nature of social interactions, are not fully understood. Social behaviors are inherently rewarding, and this intrinsic value plays a key role in reinforcing and shaping social engagement. A growing body of work has sought to quantify social reward in rodents using behavioral paradigms such as social conditioned place preference and operant social motivation tasks, offering translational tools to probe underlying circuit mechanisms. Historically, this research has centered on the mesolimbic dopamine pathway, particularly the ventral tegmental area and its projections to the nucleus accumbens. However, emerging evidence supports a complementary role for prefrontal cortical (PFC) circuits in modulating social motivation and reward. The PFC integrates contextual and social information via distinct neuronal populations and exerts top-down control over behavior through its projections to subcortical targets such as the ventral striatum (vSTR). While prior research has implicated the PFC-vSTR pathway in general aspects of social behavior, its specific contribution to the encoding of social reward remains poorly defined. Here, we synthesize existing findings and propose a novel mechanism in which prefrontal parvalbumin (PV) interneurons regulate social reward by modulating PFC-vSTR output. We further consider how neuromodulators such as oxytocin and dopamine interact with this circuit to further influence social behavior. Elucidating the microcircuit-level control of social reward has significant implications for neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, where social motivation and reward processing are often disrupted.
{"title":"Evidence for the involvement of a fronto-striatal pathway in the processing of social reward","authors":"Katrina Lin, Laurence Coutellier","doi":"10.1016/j.pneurobio.2025.102834","DOIUrl":"10.1016/j.pneurobio.2025.102834","url":null,"abstract":"<div><div>Social interactions are a hallmark of animal behavior and is essential for survival, cooperation, and reproduction. Despite its necessity, the neural mechanisms that drive social behavior, particularly the rewarding nature of social interactions, are not fully understood. Social behaviors are inherently rewarding, and this intrinsic value plays a key role in reinforcing and shaping social engagement. A growing body of work has sought to quantify social reward in rodents using behavioral paradigms such as social conditioned place preference and operant social motivation tasks, offering translational tools to probe underlying circuit mechanisms. Historically, this research has centered on the mesolimbic dopamine pathway, particularly the ventral tegmental area and its projections to the nucleus accumbens. However, emerging evidence supports a complementary role for prefrontal cortical (PFC) circuits in modulating social motivation and reward. The PFC integrates contextual and social information via distinct neuronal populations and exerts top-down control over behavior through its projections to subcortical targets such as the ventral striatum (vSTR). While prior research has implicated the PFC-vSTR pathway in general aspects of social behavior, its specific contribution to the encoding of social reward remains poorly defined. Here, we synthesize existing findings and propose a novel mechanism in which prefrontal parvalbumin (PV) interneurons regulate social reward by modulating PFC-vSTR output. We further consider how neuromodulators such as oxytocin and dopamine interact with this circuit to further influence social behavior. Elucidating the microcircuit-level control of social reward has significant implications for neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, where social motivation and reward processing are often disrupted.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"254 ","pages":"Article 102834"},"PeriodicalIF":6.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275791","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}
Understanding the precise mechanisms underlying anxiety and anxiety disorders is crucial for identifying novel interventions. In this study, we report a histaminergic circuit targeting the bed nucleus of the stria terminalis (BNST) that mediates anxiety-like behavior in mice. First, we observed a significant decrease in both histamine signaling and histaminergic fiber activity in the BNST when mice entered an anxious environment. Selective modulation of the BNST-projecting histaminergic circuit mediated state-dependent anxiety behaviors: activation directly induced an anxiogenic effect on naive mice, while inhibition produced a significant anxiolytic effect in mice in an anxious state rather than normal state. Pharmacological intervention revealed that the inhibition of histamine H3 receptors (H3Rs), rather than histamine H1 receptors (H1Rs) or histamine H2 receptors (H2Rs), in the BNST abolished the anxiogenic effect of histaminergic circuit activation. Finally, through optogenetic manipulation of spatial-specific H3Rs, we identified a critical role for anxiety regulation by post-synaptic H3Rs in the BNST GABAergic neurons, rather than pre-synaptic H3Rs from upstream inputs. Together, our results revealed a histaminergic circuit targeting the BNST that mediates state-dependent anxiety-like behaviors through post-synaptic H3Rs. These findings provide new insights into the mechanism of anxiety and offer promising avenues for discovering novel pharmacological targets for the treatment of anxiety disorders.
{"title":"BNST-projecting histaminergic circuits mediate state-dependent anxiety behavior through post-synaptic histamine H3 receptors on GABAergic neurons","authors":"Wenkai Lin , Xinyan Zhu , Xuemin Yu , Qinyan Xia , Mengqi Yan, Yulan Li, Yanrong Zheng, Yi Wang, Heming Cheng, Zhong Chen","doi":"10.1016/j.pneurobio.2025.102833","DOIUrl":"10.1016/j.pneurobio.2025.102833","url":null,"abstract":"<div><div>Understanding the precise mechanisms underlying anxiety and anxiety disorders is crucial for identifying novel interventions. In this study, we report a histaminergic circuit targeting the bed nucleus of the stria terminalis (BNST) that mediates anxiety-like behavior in mice. First, we observed a significant decrease in both histamine signaling and histaminergic fiber activity in the BNST when mice entered an anxious environment. Selective modulation of the BNST-projecting histaminergic circuit mediated state-dependent anxiety behaviors: activation directly induced an anxiogenic effect on naive mice, while inhibition produced a significant anxiolytic effect in mice in an anxious state rather than normal state. Pharmacological intervention revealed that the inhibition of histamine H3 receptors (H3Rs), rather than histamine H1 receptors (H1Rs) or histamine H2 receptors (H2Rs), in the BNST abolished the anxiogenic effect of histaminergic circuit activation. Finally, through optogenetic manipulation of spatial-specific H3Rs, we identified a critical role for anxiety regulation by post-synaptic H3Rs in the BNST GABAergic neurons, rather than pre-synaptic H3Rs from upstream inputs. Together, our results revealed a histaminergic circuit targeting the BNST that mediates state-dependent anxiety-like behaviors through post-synaptic H3Rs. These findings provide new insights into the mechanism of anxiety and offer promising avenues for discovering novel pharmacological targets for the treatment of anxiety disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102833"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221806","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}
Pub Date : 2025-10-01DOI: 10.1016/j.pneurobio.2025.102832
Marion Silvana Fernandez-Berrocal , Dagny Sanden Døskeland , Vidar Langseth Saasen , Anna Maria Bugaj , Nicolas Kunath , Mina Heggedal , Mouzuna Munir , Robert Christoffer Marthinsen , Milan Dekovic Ekeli , Katja Scheffler , Magnar Bjørås , Jing Ye
The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV+ interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.
{"title":"NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV+ interneurons","authors":"Marion Silvana Fernandez-Berrocal , Dagny Sanden Døskeland , Vidar Langseth Saasen , Anna Maria Bugaj , Nicolas Kunath , Mina Heggedal , Mouzuna Munir , Robert Christoffer Marthinsen , Milan Dekovic Ekeli , Katja Scheffler , Magnar Bjørås , Jing Ye","doi":"10.1016/j.pneurobio.2025.102832","DOIUrl":"10.1016/j.pneurobio.2025.102832","url":null,"abstract":"<div><div>The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, <em>Gabra2</em> showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV<sup>+</sup> interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102832"},"PeriodicalIF":6.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182219","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}
Pub Date : 2025-09-17DOI: 10.1016/j.pneurobio.2025.102831
D. Ávila-González , J. Lugo-Baca , F. Camacho-Barrios , A.E. Castro , D.M. Arzate , R. Paredes-Guerrero , N.F. Díaz , W. Portillo
Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (Microtus ochrogaster), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, > 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.
伴侣结合是一种稳定的从属关系，具有深刻的行为和生理优势。草原田鼠（Microtus ochrogaster）是为数不多的社会一夫一妻制哺乳动物之一，为解剖社会互动的神经生物学基础提供了一个易于处理的模型。我们之前的研究表明，社会同居与交配（SCM）会增加心室下区（SVZ）和齿状回（DG）的细胞增殖和神经元分化，暗示成年神经发生与结合形成有关。在这里，我们通过对SVZ、DG和伏隔核（NAc）在SCM或分离（对照）房后48和120小时两个时间点的大量rna测序来表征潜在的分子程序。在18000个表达基因中，雌性SVZ出现286个差异表达基因（deg），雌性DG出现540个差异表达基因（deg） （120h vs 48h SCM），而雄性生态位表现出明显较少的转录变化，证实了明显的两性二态性。基因本体论分析显示，线粒体和氧化磷酸化模块在120h时持续上调，同时神经发生、突触可塑性和细胞迁移途径下调。体外，雌性svz衍生的神经球反映了这些特征：SCM在48小时增加了球数，但神经元输出在120小时后正常化，表明短暂的神经源性激增。大量锌指转录本和未注释的长非编码rna也受到调控，暗示存在田鼠特异性表观遗传控制。引人注目的是，bb100度与人类精神疾病风险位点相对应。自闭症谱系（ADS）和精神分裂症相关同源物（如GRIN2A/B， KMT2A, UBE3A）在女性中在键巩固过程中主要下调，而分离在两性中升高了重度抑郁症（MDD）标记物（如CACNA1H）。这些数据表明，配对键的形成招募了与神经精神疾病的遗传结构重叠的转录网络，而社会隔离则引发了相反的、与疾病相关的特征。总之，我们的研究结果确定了性别特异性的、暂时分阶段的分子途径，这些途径将成人神经发生、能量代谢和精神疾病风险基因网络结合起来，以建立持久的社会纽带。
{"title":"Transcriptomic shifts in Microtus ochrogaster neurogenic niches reveal psychiatric-risk pathways engaged by pair-bond formation","authors":"D. Ávila-González , J. Lugo-Baca , F. Camacho-Barrios , A.E. Castro , D.M. Arzate , R. Paredes-Guerrero , N.F. Díaz , W. Portillo","doi":"10.1016/j.pneurobio.2025.102831","DOIUrl":"10.1016/j.pneurobio.2025.102831","url":null,"abstract":"<div><div>Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (<em>Microtus ochrogaster</em>), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, > 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102831"},"PeriodicalIF":6.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092316","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}
Pub Date : 2025-09-08DOI: 10.1016/j.pneurobio.2025.102823
Serdar Akkol , Akash Mishra , Noah Markowitz , Elizabeth Espinal , Menoua Keshishian , Nima Mesgarani , Charles Schroeder , Ashesh D. Mehta , Stephan Bickel
Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. However, the characteristics of this entrainment process have been shown to be inconsistent across species and experimental paradigms. It is imperative to establish whether neural activity in response to speech is a result of combination of simple evoked responses or of entrainment of neural oscillations in human participants. In this study, 12 participants with intracranial electrodes listened to natural speech and neural entrainment as evidenced by oscillatory activity persisting beyond the evoked responses was assessed. Neural activity was recorded from 165 contacts in Heschl’s gyrus and superior temporal gyrus. First, acoustic edges in the speech envelope induced coherence between speech and auditory cortex activity. Further, entrainment in the theta-alpha band outlasted the acoustic stimulation. This activity exceeded what could be expected from a simple evoked response. These findings suggest that speech has the potential to entrain neural oscillations in the human auditory cortex.
{"title":"Neural entrainment by speech in human auditory cortex revealed by intracranial recordings","authors":"Serdar Akkol , Akash Mishra , Noah Markowitz , Elizabeth Espinal , Menoua Keshishian , Nima Mesgarani , Charles Schroeder , Ashesh D. Mehta , Stephan Bickel","doi":"10.1016/j.pneurobio.2025.102823","DOIUrl":"10.1016/j.pneurobio.2025.102823","url":null,"abstract":"<div><div>Humans live in an environment that contains rich auditory stimuli, which must be processed efficiently. The entrainment of neural oscillations to acoustic inputs may support the processing of simple and complex sounds. However, the characteristics of this entrainment process have been shown to be inconsistent across species and experimental paradigms. It is imperative to establish whether neural activity in response to speech is a result of combination of simple evoked responses or of entrainment of neural oscillations in human participants. In this study, 12 participants with intracranial electrodes listened to natural speech and neural entrainment as evidenced by oscillatory activity persisting beyond the evoked responses was assessed. Neural activity was recorded from 165 contacts in Heschl’s gyrus and superior temporal gyrus. First, acoustic edges in the speech envelope induced coherence between speech and auditory cortex activity. Further, entrainment in the theta-alpha band outlasted the acoustic stimulation. This activity exceeded what could be expected from a simple evoked response. These findings suggest that speech has the potential to entrain neural oscillations in the human auditory cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102823"},"PeriodicalIF":6.1,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034119","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}
Pub Date : 2025-09-04DOI: 10.1016/j.pneurobio.2025.102822
Kyung Jin Seo , Chan Sol Park , Mi So Park , Won Ho Na , Jee Youn Lee , Tae Young Yune
Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.
{"title":"PDGFR mediates lumbar spinal stenosis-induced neuropathic pain by regulating JAK2/STAT3 signaling in activated macrophages","authors":"Kyung Jin Seo , Chan Sol Park , Mi So Park , Won Ho Na , Jee Youn Lee , Tae Young Yune","doi":"10.1016/j.pneurobio.2025.102822","DOIUrl":"10.1016/j.pneurobio.2025.102822","url":null,"abstract":"<div><div>Lumbar spinal stenosis (LSS) is one of the most common spinal disorders in elderly people and is often accompanied by neuropathic pain. Although our previous studies have demonstrated that infiltrating macrophage contribute to chronic neuropathic pain in LSS rat model, the molecular mechanisms underlying macrophage activation and infiltration have not been fully elucidated. In this study, we examined the critical role of platelet-derived growth factor receptor (PDGFR) signaling pathway in neuropathic pain associated with macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block placed within the epidural spaces of the L5-L6 vertebrae, with neuropathic pain developing four weeks after compression. We found that the PDGFR and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathways were upregulated in infiltrated macrophages at 28 days in the LSS model. Administration of the PDGFR inhibitor imatinib significantly alleviated LSS-induced macrophages activation and infiltration. Imatinib also reduced LSS-induced chronic mechanical allodynia and inhibited the expression of inflammatory mediators including tumor necrosis factor alpha (TNF-α), interleukin beta (IL-1β), interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Furthermore, imatinib significantly alleviated the activation of RAW 264.7 macrophage cell line by lipopolysaccharide (LPS). These findings suggest that PDGFR signaling mediates neuropathic pain by promoting macrophage infiltration and activation following cauda equina compression and may serve as a potential therapeutic target for neuropathic pain in LSS patients.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"253 ","pages":"Article 102822"},"PeriodicalIF":6.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008427","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}
Pub Date : 2025-09-01DOI: 10.1016/j.pneurobio.2025.102821
Pasindu Hansana Singhaarachchi , Peter Antal , Frédéric Calon , Carsten Culmsee , Jean-Christophe Delpech , Martin Feldotto , Jorine Geertsema , Emmy E. Hoeksema , Aniko Korosi , Sophie Layé , Jonathan McQualter , Susanne R. de Rooij , Christoph Rummel , Mary Slayo , Luba Sominsky , Sarah J. Spencer
Alzheimer’s disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to design and test targeted reliable treatments for the disease. Amyloid β plaque accumulation, aggregation of neurofibrillary tangles, neuroinflammation, neurodegeneration, and, of course, cognitive decline, are few of the many observed pathological features associated with AD. However, there is a concern that the animal models of AD that are based on these frameworks may not be accurately representing AD in people. As such, the results from preclinical trials have not historically translated well to the clinic. In this article, we review the current major hypotheses to describe AD; we outline the major strengths and weaknesses of the commonly used rodent models used to replicate features of these hypotheses; and we provide a strategy for the field for future research.
{"title":"Rodent models of Alzheimer's disease: Critical analysis of current hypotheses and pathways for future research","authors":"Pasindu Hansana Singhaarachchi , Peter Antal , Frédéric Calon , Carsten Culmsee , Jean-Christophe Delpech , Martin Feldotto , Jorine Geertsema , Emmy E. Hoeksema , Aniko Korosi , Sophie Layé , Jonathan McQualter , Susanne R. de Rooij , Christoph Rummel , Mary Slayo , Luba Sominsky , Sarah J. Spencer","doi":"10.1016/j.pneurobio.2025.102821","DOIUrl":"10.1016/j.pneurobio.2025.102821","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) was first described over a century ago. However, the mechanisms underlying the disease are not well understood to this day. This has negatively impacted our ability to create animal models to design and test targeted reliable treatments for the disease. Amyloid β plaque accumulation, aggregation of neurofibrillary tangles, neuroinflammation, neurodegeneration, and, of course, cognitive decline, are few of the many observed pathological features associated with AD. However, there is a concern that the animal models of AD that are based on these frameworks may not be accurately representing AD in people. As such, the results from preclinical trials have not historically translated well to the clinic. In this article, we review the current major hypotheses to describe AD; we outline the major strengths and weaknesses of the commonly used rodent models used to replicate features of these hypotheses; and we provide a strategy for the field for future research.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102821"},"PeriodicalIF":6.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925331","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}
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