Pub Date : 2025-11-16DOI: 10.1016/j.pneurobio.2025.102855
Vittoria Spero , Sabrina D’Amelio , Sonia Eligini , Raffaella Molteni , Cristina Banfi , Maria Grazia Cattaneo
Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called "residual symptoms", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (e.g., cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.
{"title":"The neurobiology of major depressive disorder: Updates and perspectives from proteomics","authors":"Vittoria Spero , Sabrina D’Amelio , Sonia Eligini , Raffaella Molteni , Cristina Banfi , Maria Grazia Cattaneo","doi":"10.1016/j.pneurobio.2025.102855","DOIUrl":"10.1016/j.pneurobio.2025.102855","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a widespread and disabling condition whose etiology and pathophysiology are not fully understood. Furthermore, pharmacological treatment of MDD poses challenging aspects, including delayed therapeutic effects, ineffectiveness against the so-called \"residual symptoms\", and a high proportion of non-responder patients. On these bases, it is crucial to recognize the key molecular systems and mechanisms involved in the pathophysiology of MDD in order to improve diagnostic tools and develop more effective pharmacological strategies. In this context, proteomics is a highly effective tool for simultaneously identifying and quantifying a large number of proteins within biological samples. This review will describe and discuss proteomic data from stress-based experimental models of MDD as well as from human brains and bodily fluids (<em>e.g.,</em> cerebrospinal fluid and plasma), with the aim of elucidating the neurobiological counterparts of this psychiatric disorder. These findings will be summarized in an attempt to provide comprehensive maps of the biological systems involved in MDD, offering new insights into the molecular basis of different disease subtypes and paving the way to personalized diagnostic and treatment strategies.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102855"},"PeriodicalIF":6.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550279","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 : 2025-11-12DOI: 10.1016/j.pneurobio.2025.102853
Lucas Canto-de-Souza , Daniela Baptista-de-Souza , Cristiane Busnardo , Carlos C. Crestani
We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.
{"title":"Effects of oxytocin receptor ligands on anxiogenic-like effect, social avoidance and changes on medial prefrontal cortex oxytocin receptor expression evoked by chronic social defeat stress in rats","authors":"Lucas Canto-de-Souza , Daniela Baptista-de-Souza , Cristiane Busnardo , Carlos C. Crestani","doi":"10.1016/j.pneurobio.2025.102853","DOIUrl":"10.1016/j.pneurobio.2025.102853","url":null,"abstract":"<div><div>We investigated the effect of systemic administration of the synthetic oxytocin (OXT) analog carbetocin and/or OXT receptor antagonists (atosiban and L-368,899) on social avoidance and anxiogenic-like effect in male rats subjected to chronic social defeat stress (cSDS). Effect of cSDS and pharmacological manipulation of OXT system on expression of OXT receptor within the medial prefrontal cortex (mPFC) subregions [anterior cingulate (Cg), prelimbic (PL) and infralimbic (IL) cortices] was also evaluated. Our behavioral results indicated that cSDS, while not inducing social avoidance in the social interaction test, reliably induced anxiogenic-like effect as measured by the elevated plus maze test. Chronic systemic treatment with either carbetocin or atosiban, but not L-368,899, during cSDS protocol dose-dependently prevented the anxiogenic-like effect. Both atosiban and L-368,899 inhibited the anxiolytic effect of carbetocin in defeated animals, confirming OXT receptor-mediated effect. Also, cSDS increased OXT receptor levels within the Cg, which was inhibited by both atosiban and L-368,899 treatments. Conversely, cSDS did not affect OXT receptor within the PL and IL. However, carbetocin treatment increased OXT receptor expression within the PL and IL of defeated animals, an effect that was blocked by either atosiban or L-368,899. Taken together, our study provides evidence for the critical role of the OXT system and its pharmacological manipulation in modulating anxiogenic-like effects evoked by social stress. Furthermore, the region-specific modulation of OXT receptor expression within the mPFC by stress and OXT system pharmacological manipulation emphasize the complex and dynamic nature of OXT receptor regulation in brain regions crucial for emotional processing.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102853"},"PeriodicalIF":6.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524211","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}
Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored.
Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration.
We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior.
Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.
{"title":"Inhibiting the JAK-STAT3 pathway in nucleus accumbens astrocytes alleviates cocaine-induced motor hyperactivity","authors":"Isabelle Arnoux , Anna Capano , Rachida Yakoubi , Claire Boulogne , Pascal Ezan , Carole Escartin , Nathalie Rouach","doi":"10.1016/j.pneurobio.2025.102852","DOIUrl":"10.1016/j.pneurobio.2025.102852","url":null,"abstract":"<div><div>Cocaine use disorder is a significant global health issue, and despite its widespread impact, effective treatments are lacking. While research has largely focused on the underlying neuronal mechanisms, the role of astrocytes, key regulators of synaptic transmission and plasticity, remains underexplored.</div><div>Using a multidisciplinary approach that combines immunohistochemistry, electron microscopy, 3D cell reconstruction, viral gene transfer, and behavioral assays, we investigated the early adaptive responses of astrocytes to repeated cocaine administration.</div><div>We report that cocaine administration induces astrocyte reactivity in the nucleus accumbens, characterized by structural remodeling, reduced synaptic coverage, and upregulation of reactivity-associated markers, including STAT3. Furthermore, we demonstrated that the JAK/STAT3 signaling pathway plays a critical role in the pathological structural astrocytic responses and in the cocaine-induced motor behavior.</div><div>Our findings highlight astrocytes as pivotal players in the initial neural adaptations underlying cocaine-induced behavior. These data may provide a basis for the development of novel therapeutic strategies targeting astrocytes to address the structural and functional disruptions associated with cocaine exposure.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102852"},"PeriodicalIF":6.1,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506557","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 : 2025-11-07DOI: 10.1016/j.pneurobio.2025.102845
Patrycja Brzdąk , Katarzyna Lebida , Patrycja Droździel , Emilia Stefańczyk , Aleksandra Leszczyńska , Jerzy W. Mozrzymas
Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.
{"title":"D1-type dopamine receptors are critical for GABAergic synaptic plasticity in CA1 mouse hippocampal SST interneurons and pyramidal cells","authors":"Patrycja Brzdąk , Katarzyna Lebida , Patrycja Droździel , Emilia Stefańczyk , Aleksandra Leszczyńska , Jerzy W. Mozrzymas","doi":"10.1016/j.pneurobio.2025.102845","DOIUrl":"10.1016/j.pneurobio.2025.102845","url":null,"abstract":"<div><div>Dopamine modulates brain functions such as memory and learning, and studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Much less is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons targeting different cells. Herein, we addressed the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synapses between interneurons (INs) and pyramidal cells (PCs), as well as between INs in the CA1 region. Activation and blockade of D1Rs increased and reduced the mIPSCs amplitude (measured from PCs), respectively, while the decay kinetics was prolonged, indicating a complex postsynaptic mechanism. We also checked the D1Rs effect on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs and found that blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), whereas D1Rs activation slightly diminished iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, NMDA-induced iLTP in the somatostatin- (SST) positive INs was reversed to iLTD by both SKF and SCH, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102845"},"PeriodicalIF":6.1,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482798","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 : 2025-11-03DOI: 10.1016/j.pneurobio.2025.102844
Christos Panagiotis Lisgaras , Helen E. Scharfman
Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer’s disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250–500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1–500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2-/-, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.
{"title":"Opposing interictal dynamics in Alzheimer’s disease and epilepsy","authors":"Christos Panagiotis Lisgaras , Helen E. Scharfman","doi":"10.1016/j.pneurobio.2025.102844","DOIUrl":"10.1016/j.pneurobio.2025.102844","url":null,"abstract":"<div><div>Advanced EEG technology has revealed that epileptiform activity occurs more frequently in Alzheimer’s disease (AD) than previously recognized, prompting debate over the utility of EEG in AD diagnostics. Yet, unlike epilepsy, epileptiform activity is not always observed in AD, leading to skepticism. Historically, this absence has been attributed to limited recording depth or insufficient recording duration. We tested an alternative hypothesis that certain types of epileptiform activity, specifically high frequency oscillations (HFOs, defined as 250–500 Hz fast ripples), inhibit interictal spikes (IIS), which are currently used to assess hyperexcitability clinically. We recorded wideband (0.1–500 Hz) hippocampal local field potentials in three AD (Tg2576, Presenilin 2<sup>-/-</sup>, Ts65Dn Down syndrome model) and two epilepsy (intrahippocampal kainic acid, pilocarpine) mouse models during wakefulness and sleep. In both AD and epilepsy, HFOs consistently outnumbered IIS across behavioral states, age and recording contact. However, IIS and HFOs showed divergent relationships: a negative correlation between their rates was observed only in AD, in contrast to a positive correlation in epilepsy. HFOs preceded IIS at much shorter intervals in epilepsy than in AD. Co-occurrence of IIS with ripples did not differ between AD and epilepsy. These findings reveal a novel dissociation between clinically-relevant EEG biomarkers in AD and epilepsy. In AD, HFOs may inhibit IIS, which could lead to underestimation of hyperexcitability and hinder patient stratification for anti-seizure therapies. While non-invasive HFO detection remains challenging, we stress the need for wideband EEG/MEG, particularly in AD, to assess the full extent of hyperexcitability and biomarker interactions that would otherwise remain undetected.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102844"},"PeriodicalIF":6.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452771","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 : 2025-10-25DOI: 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}
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