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}
Pub Date : 2025-08-20DOI: 10.1016/j.pneurobio.2025.102820
Jiayu Wang , Rui Zhang , Xingya Cai , Rendong Tang , Zhuoyue Dai , Haidong D. Lu
Binocular rivalry (BR) is a fascinating phenomenon in which the presentation of two different images to each eye leads to alternating perceptual experiences. During BR, cortical activation is influenced by both stimulus-related factors (e.g., image incongruence) and top-down cognitive processes such as attention. Disentangling the contributions of these factors has remained a challenge. Anesthetized animal models offer a unique opportunity to isolate purely stimulus-driven neural activity, eliminating confounds from higher cognitive and behavioral processes. Using two-photon calcium imaging, we recorded neuronal responses to BR stimuli in areas V1 and V2 of anesthetized macaques. We found that under BR stimulation, V1 neurons exhibited ongoing response fluctuations whose magnitude varied across cells and closely resembled activity patterns during physical stimulus alternation (SA). Key characteristics of these fluctuations mirrored those typical of perceptual BR. The strength of fluctuation in individual neurons correlated with their ocular dominance and orientation selectivity. Similar patterns observed in V2 suggest that such rivalry-like activity propagates along the visual hierarchy. Together, these results demonstrate that early sensory mechanisms in V1 can generate BR-like alternations independently of conscious processing.
{"title":"Stimulus-driven rivalry among V1 neurons","authors":"Jiayu Wang , Rui Zhang , Xingya Cai , Rendong Tang , Zhuoyue Dai , Haidong D. Lu","doi":"10.1016/j.pneurobio.2025.102820","DOIUrl":"10.1016/j.pneurobio.2025.102820","url":null,"abstract":"<div><div>Binocular rivalry (BR) is a fascinating phenomenon in which the presentation of two different images to each eye leads to alternating perceptual experiences. During BR, cortical activation is influenced by both stimulus-related factors (e.g., image incongruence) and top-down cognitive processes such as attention. Disentangling the contributions of these factors has remained a challenge. Anesthetized animal models offer a unique opportunity to isolate purely stimulus-driven neural activity, eliminating confounds from higher cognitive and behavioral processes. Using two-photon calcium imaging, we recorded neuronal responses to BR stimuli in areas V1 and V2 of anesthetized macaques. We found that under BR stimulation, V1 neurons exhibited ongoing response fluctuations whose magnitude varied across cells and closely resembled activity patterns during physical stimulus alternation (SA). Key characteristics of these fluctuations mirrored those typical of perceptual BR. The strength of fluctuation in individual neurons correlated with their ocular dominance and orientation selectivity. Similar patterns observed in V2 suggest that such rivalry-like activity propagates along the visual hierarchy. Together, these results demonstrate that early sensory mechanisms in V1 can generate BR-like alternations independently of conscious processing.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"254 ","pages":"Article 102820"},"PeriodicalIF":6.1,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144966530","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 : 2025-08-14DOI: 10.1016/j.pneurobio.2025.102811
Jessica Winne , George Nascimento , Rafael Pedrosa , Margareth Nogueira , Cristiano S. Simões , Klas Kullander , Katarina E. Leão , Richardson N. Leão
The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.
{"title":"Auditory regulation of hippocampal locomotion circuits by a non-canonical reticulo-limbic pathway","authors":"Jessica Winne , George Nascimento , Rafael Pedrosa , Margareth Nogueira , Cristiano S. Simões , Klas Kullander , Katarina E. Leão , Richardson N. Leão","doi":"10.1016/j.pneurobio.2025.102811","DOIUrl":"10.1016/j.pneurobio.2025.102811","url":null,"abstract":"<div><div>The ability to rapidly detect and respond to unexpected auditory stimuli is critical for adaptive behavior, especially during locomotion. Since movement suppresses auditory cortical activity, it remains unclear how salient auditory information influences locomotor circuits. In this work, using in vivo calcium imaging, electrophysiology, chemo- and optogenetics, we investigate the path that relays loud broadband sounds to the dorsal hippocampus (dHPC) and modulates theta oscillations. We demonstrate that noise accelerates theta frequency and decreases its power, effects mediated by entorhinal cortex (EC) and medial septum (MS) inputs while independent of the primary auditory cortex. Activation of dorsal cochlear nucleus (DCN) neurons projecting to the pontine reticular nucleus (PRN) mimics noise-driven hippocampal responses, supporting a brainstem-limbic auditory processing route. Furthermore, noise selectively modulates CA1 pyramidal neuron and interneuron activity, reflecting diverse circuit dynamics. Finally, loud broadband noise stimulus increased theta coherence between the dHPC and the medial prefrontal cortex (mPFC), enhancing interregional synchronization. These results highlight the mechanisms in which the DCN filters behaviorally relevant sounds promoting acoustic motor integration in the hippocampus during locomotion, without direct influence of the auditory cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102811"},"PeriodicalIF":6.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842491","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 : 2025-08-13DOI: 10.1016/j.pneurobio.2025.102812
Marcin Leszczynski , Elizabeth Espinal , Elliot Smith , Catherine Schevon , Sameer Sheth , Charles E. Schroeder
Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.
Summary
Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.
{"title":"Eye movements organize excitability state, information coding and network connectivity in the human hippocampus","authors":"Marcin Leszczynski , Elizabeth Espinal , Elliot Smith , Catherine Schevon , Sameer Sheth , Charles E. Schroeder","doi":"10.1016/j.pneurobio.2025.102812","DOIUrl":"10.1016/j.pneurobio.2025.102812","url":null,"abstract":"<div><div>Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related phase reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.</div></div><div><h3>Summary</h3><div>Saccade-fixation cycle: a fundamental sampling unit, organizing input representation, information coding and network coordination.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102812"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859560","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 : 2025-08-13DOI: 10.1016/j.pneurobio.2025.102810
Keshav Jindal , Amanda Ringland , Sydney Fitzcharles , Chase Redd , Damian G. Wheeler , Laurence Coutellier
Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear. Here, we identified the neuronal-specific transcription factor Npas4 as a key player in this process. We first showed that social isolation results in aberrant adolescent developmental trajectories of Npas4 and PV expression in the prefrontal cortex (PFC) leading to prolonged downregulation of Npas4 and upregulation of PV, suggesting an Npas4-driven over-inhibition of prefrontal circuits following early social isolation. Using Npas4 knockout (KO) mice and iDISCO whole brain cFos mapping, we then further implicated Npas4-dependent reduction in prefrontal activity with appearance of sociability deficits in adulthood: Npas4 KO mice failed to show an age-increase in sociability and in activity of the anterior cingulate cortex (ACC) that we observed in wild-type mice during the transition from adolescence to adulthood. Finally, using a viral approach to restore prefrontal Npas4 expression during early adolescence, we were able to rescue the sociability deficits and aberrant expression of PV in the AAC induced by social isolation. Altogether, our findings identified Npas4 as a novel molecular mediator of early social isolation on social deficits, through the role it plays on the adolescent maturation of prefrontal PV neurons.
{"title":"Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons","authors":"Keshav Jindal , Amanda Ringland , Sydney Fitzcharles , Chase Redd , Damian G. Wheeler , Laurence Coutellier","doi":"10.1016/j.pneurobio.2025.102810","DOIUrl":"10.1016/j.pneurobio.2025.102810","url":null,"abstract":"<div><div>Social behaviors mature during the adolescent period. Prefrontal parvalbumin (PV) neurons have been shown to play a critical role in this process, and their deregulation by early social isolation leads to social deficits in adulthood. However, the molecular mechanisms by which early social isolation affects prefrontal PV neurons causing social impairments remain unclear. Here, we identified the neuronal-specific transcription factor Npas4 as a key player in this process. We first showed that social isolation results in aberrant adolescent developmental trajectories of Npas4 and PV expression in the prefrontal cortex (PFC) leading to prolonged downregulation of Npas4 and upregulation of PV, suggesting an Npas4-driven over-inhibition of prefrontal circuits following early social isolation. Using Npas4 knockout (KO) mice and iDISCO whole brain cFos mapping, we then further implicated Npas4-dependent reduction in prefrontal activity with appearance of sociability deficits in adulthood: Npas4 KO mice failed to show an age-increase in sociability and in activity of the anterior cingulate cortex (ACC) that we observed in wild-type mice during the transition from adolescence to adulthood. Finally, using a viral approach to restore prefrontal Npas4 expression during early adolescence, we were able to rescue the sociability deficits and aberrant expression of PV in the AAC induced by social isolation. Altogether, our findings identified Npas4 as a novel molecular mediator of early social isolation on social deficits, through the role it plays on the adolescent maturation of prefrontal PV neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102810"},"PeriodicalIF":6.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856204","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 : 2025-08-08DOI: 10.1016/j.pneurobio.2025.102809
Mouna Haidar , Aida Viden , Christin Daniel , Brittany Cuic , Taide Wang , Marius Rosier , Doris Tomas , Samuel A. Mills , Alistair Govier-Cole , Elvan Djouma , Nirma D. Perera , Sophia Luikinga , Valeria Rytova , Samantha K. Barton , David G. Gonsalvez , Lucy M. Palmer , Catriona McLean , Matthew C. Kiernan , Steve Vucic , Bradley J. Turner
Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.
{"title":"Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice","authors":"Mouna Haidar , Aida Viden , Christin Daniel , Brittany Cuic , Taide Wang , Marius Rosier , Doris Tomas , Samuel A. Mills , Alistair Govier-Cole , Elvan Djouma , Nirma D. Perera , Sophia Luikinga , Valeria Rytova , Samantha K. Barton , David G. Gonsalvez , Lucy M. Palmer , Catriona McLean , Matthew C. Kiernan , Steve Vucic , Bradley J. Turner","doi":"10.1016/j.pneurobio.2025.102809","DOIUrl":"10.1016/j.pneurobio.2025.102809","url":null,"abstract":"<div><div>Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"252 ","pages":"Article 102809"},"PeriodicalIF":6.1,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817410","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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