Astrocytes play a significant role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE), contributing to neuroexcitotoxicity and inflammatory responses. However, the specific pathways through which astrocytes influence neurons remain incompletely understood. In this study, we found that Yes-associated protein (YAP) was down-regulated and inactivated in hippocampal astrocytes in a hypoxic-ischemic brain damage (HIBD) rat model, as well as in astrocytes subjected to oxygen-glucose deprivation (OGD). Overexpression of YAP in astrocytes reduced neuronal death and improved motor, learning and memory dysfunction deficits associated with HIE. Further investigation demonstrated that YAP exerts neuroprotective effects by modulating lipid metabolism through the SCAP/SREBP1 pathway. Ultimately, activating YAP signaling by XMU-MP-1, a Hippo kinase MST1/2 inhibitor, partially restored brain tissue integrity and function, as well as improved motor, learning and memory functions in HIBD rats. In conclusion, our study has identified a novel YAP/SCAP/SREBP1 pathway that plays neuroprotective roles in HIE.
{"title":"The YAP/SCAP/SREBP1 Pathway in Astrocytes: A Novel Target for Treating Neonatal Hypoxic-Ischemic Encephalopathy.","authors":"Jiaojiao Wang, Chunfang Dai, Hao Yuan, Qiuyun Tian, Qian Xiao, Xiaohuan Li, Xiuyu Shi, Zhifang Dong","doi":"10.1016/j.pneurobio.2025.102869","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2025.102869","url":null,"abstract":"<p><p>Astrocytes play a significant role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE), contributing to neuroexcitotoxicity and inflammatory responses. However, the specific pathways through which astrocytes influence neurons remain incompletely understood. In this study, we found that Yes-associated protein (YAP) was down-regulated and inactivated in hippocampal astrocytes in a hypoxic-ischemic brain damage (HIBD) rat model, as well as in astrocytes subjected to oxygen-glucose deprivation (OGD). Overexpression of YAP in astrocytes reduced neuronal death and improved motor, learning and memory dysfunction deficits associated with HIE. Further investigation demonstrated that YAP exerts neuroprotective effects by modulating lipid metabolism through the SCAP/SREBP1 pathway. Ultimately, activating YAP signaling by XMU-MP-1, a Hippo kinase MST1/2 inhibitor, partially restored brain tissue integrity and function, as well as improved motor, learning and memory functions in HIBD rats. In conclusion, our study has identified a novel YAP/SCAP/SREBP1 pathway that plays neuroprotective roles in HIE.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102869"},"PeriodicalIF":6.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752067","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}
Stroke is renowned for its high rates of disability and mortality. Ischemic stroke (IS), the most prevalent type, imposes a heavy burden on patients. In recent years, ferroptosis has garnered significant interest in the field of neurological disease research and has been implicated in the pathophysiology of IS. This article provides a comprehensive review of the core mechanisms of ferroptosis. From the perspective of glia-neuron interactions, it explores iron metabolism, lipid peroxidation, and oxidative damage during IS, elucidating how these processes ultimately lead to ferroptosis and significant neuronal damage. Additionally, the emerging findings concerning the targets associated with ferroptosis in IS and related pharmacological therapies are described, thereby offering insights into innovative treatments for IS that focus on ferroptosis.
{"title":"Ferroptosis in Ischemic Stroke: From a Glia-Neuron Crosstalk Perspective.","authors":"Chuxin Zhang, Jialin Cheng, Xin Yan, Yuxiao Zheng, Xin Lan, Yang Zhao, Ying Liu, Yiping Wu, Fafeng Cheng, Changxiang Li, Xueqian Wang","doi":"10.1016/j.pneurobio.2025.102868","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2025.102868","url":null,"abstract":"<p><p>Stroke is renowned for its high rates of disability and mortality. Ischemic stroke (IS), the most prevalent type, imposes a heavy burden on patients. In recent years, ferroptosis has garnered significant interest in the field of neurological disease research and has been implicated in the pathophysiology of IS. This article provides a comprehensive review of the core mechanisms of ferroptosis. From the perspective of glia-neuron interactions, it explores iron metabolism, lipid peroxidation, and oxidative damage during IS, elucidating how these processes ultimately lead to ferroptosis and significant neuronal damage. Additionally, the emerging findings concerning the targets associated with ferroptosis in IS and related pharmacological therapies are described, thereby offering insights into innovative treatments for IS that focus on ferroptosis.</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102868"},"PeriodicalIF":6.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752041","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 : 2025-12-10DOI: 10.1016/j.pneurobio.2025.102867
Zaneta Navratilova, Dhruba Banerjee, Fjolla Muqolli, Jordan Zhang, Sunil P Gandhi, Bruce L McNaughton
The encoding, storage, and updating of memories in cortical networks are poorly understood. In retrosplenial cortex (RSC), cells respond to the animal's position as it traverses a real or virtual (VR) linear track. Most position correlated cells (PCCs) in RSC require an intact hippocampus to form, but survive subsequent hippocampal damage. To examine whether RSC and hippocampal PCCs undergo remapping and spatial tuning development in parallel or sequentially, neuronal activity in RSC or CA1 was recorded using two-photon calcium imaging in mice running on VR tracks. RSC PCC activity underwent global remapping like CA1, with approximately the same dynamics of tuning development in the novel context. However, fields in RSC did not show place field expansion, in familiar or novel environments. Thus, while most properties of global remapping are shared between RSC and CA1, place field shift and expansion are notably restricted to hippocampus. Thus, our data suggests that RSC place specificity is either not 'inherited' directly from hippocampus or the hippocampal influence on RSC PCC formation may be restricted to hippocampal spikes occurring in the early phase of the theta rhythm (and thus late within the place field).
{"title":"Place Field Dynamics in Retrosplenial Cortex Compared to Hippocampus.","authors":"Zaneta Navratilova, Dhruba Banerjee, Fjolla Muqolli, Jordan Zhang, Sunil P Gandhi, Bruce L McNaughton","doi":"10.1016/j.pneurobio.2025.102867","DOIUrl":"https://doi.org/10.1016/j.pneurobio.2025.102867","url":null,"abstract":"<p><p>The encoding, storage, and updating of memories in cortical networks are poorly understood. In retrosplenial cortex (RSC), cells respond to the animal's position as it traverses a real or virtual (VR) linear track. Most position correlated cells (PCCs) in RSC require an intact hippocampus to form, but survive subsequent hippocampal damage. To examine whether RSC and hippocampal PCCs undergo remapping and spatial tuning development in parallel or sequentially, neuronal activity in RSC or CA1 was recorded using two-photon calcium imaging in mice running on VR tracks. RSC PCC activity underwent global remapping like CA1, with approximately the same dynamics of tuning development in the novel context. However, fields in RSC did not show place field expansion, in familiar or novel environments. Thus, while most properties of global remapping are shared between RSC and CA1, place field shift and expansion are notably restricted to hippocampus. Thus, our data suggests that RSC place specificity is either not 'inherited' directly from hippocampus or the hippocampal influence on RSC PCC formation may be restricted to hippocampal spikes occurring in the early phase of the theta rhythm (and thus late within the place field).</p>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":" ","pages":"102867"},"PeriodicalIF":6.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744018","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 : 2025-12-07DOI: 10.1016/j.pneurobio.2025.102866
Anton Offermanns, Jastyn A. Pöpplau , Ileana L. Hanganu-Opatz
Gamma oscillations are critical for cortical cognitive processing. The ability to generate gamma oscillations evolves with age and requires cellular adjustments of the underlying neural networks. In the prefrontal cortex, gamma oscillations emerge relatively late compared to other cortical areas and the developmental mechanisms underlying the generation of adult-like gamma oscillations are poorly understood. Here, we combine in vivo electrophysiology and selective optogenetic manipulations of parvalbumin- (PV+) and somatostatin-positive (SOM+) interneurons in the mouse medial prefrontal cortex of both hemispheres along development to investigate their role for the age-dependent maturation of gamma oscillations. We show that crosshemispheric gamma synchrony strengthens with age, in line with the previously reported increase in local gamma power. The inhibitory effect of PV+ interneurons follows a similar timeline, enabling them to functionally operate within the classical gamma frequency range from adolescence onwards. In contrast, SOM+ interneurons have an age-independent inhibitory function, modulating beta-band oscillatory activity along development. These data identify the SOM+ to PV+ interneuron shift as a mechanism of gamma ontogeny and emergence of crosshemispheric synchrony in the developing prefrontal cortex.
{"title":"Developmental embedding of parvalbumin-positive interneurons drives local and crosshemispheric prefrontal gamma synchrony","authors":"Anton Offermanns, Jastyn A. Pöpplau , Ileana L. Hanganu-Opatz","doi":"10.1016/j.pneurobio.2025.102866","DOIUrl":"10.1016/j.pneurobio.2025.102866","url":null,"abstract":"<div><div>Gamma oscillations are critical for cortical cognitive processing. The ability to generate gamma oscillations evolves with age and requires cellular adjustments of the underlying neural networks. In the prefrontal cortex, gamma oscillations emerge relatively late compared to other cortical areas and the developmental mechanisms underlying the generation of adult-like gamma oscillations are poorly understood. Here, we combine <em>in vivo</em> electrophysiology and selective optogenetic manipulations of parvalbumin- (PV<sup>+</sup>) and somatostatin-positive (SOM<sup>+</sup>) interneurons in the mouse medial prefrontal cortex of both hemispheres along development to investigate their role for the age-dependent maturation of gamma oscillations. We show that crosshemispheric gamma synchrony strengthens with age, in line with the previously reported increase in local gamma power. The inhibitory effect of PV<sup>+</sup> interneurons follows a similar timeline, enabling them to functionally operate within the classical gamma frequency range from adolescence onwards. In contrast, SOM<sup>+</sup> interneurons have an age-independent inhibitory function, modulating beta-band oscillatory activity along development. These data identify the SOM<sup>+</sup> to PV<sup>+</sup> interneuron shift as a mechanism of gamma ontogeny and emergence of crosshemispheric synchrony in the developing prefrontal cortex.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"257 ","pages":"Article 102866"},"PeriodicalIF":6.1,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705564","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 : 2025-12-04DOI: 10.1016/j.pneurobio.2025.102864
Mirte Scheper , Alessandro Gaeta , Gabriele Ruffolo , Lilian J. Lissner , Marie Le Bihan , Jasper J. Anink , Floor E. Jansen , Wim van Hecke , Angelika Mühlebner , Dirk Schubert , James D. Mills , Eleonora Palma , Eleonora Aronica
Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in Xenopus laevis oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.
{"title":"Altered somatostatin receptor 3 expression and functional dysregulation in tuberous sclerosis complex","authors":"Mirte Scheper , Alessandro Gaeta , Gabriele Ruffolo , Lilian J. Lissner , Marie Le Bihan , Jasper J. Anink , Floor E. Jansen , Wim van Hecke , Angelika Mühlebner , Dirk Schubert , James D. Mills , Eleonora Palma , Eleonora Aronica","doi":"10.1016/j.pneurobio.2025.102864","DOIUrl":"10.1016/j.pneurobio.2025.102864","url":null,"abstract":"<div><div>Somatostatin (SST), a neuropeptide primarily synthesized by GABAergic interneurons, modulates neuronal excitability and synaptic transmission through its interaction with somatostatin receptors (SSTRs). Dysregulation of SST signaling has been implicated in neurodevelopmental disorders, including tuberous sclerosis complex (TSC). However, its precise role in these pathologies remains incompletely understood. We investigated SST and SSTR expression across diverse brain cell types in control and TSC cortical samples using single-cell RNA sequencing (scRNA-seq). We conducted functional assessments of SST signaling using electrophysiological recordings in <em>Xenopus laevis</em> oocytes microtransplanted with human brain membranes. We pharmacologically modulated SST receptor activity to elucidate receptor-specific effects on GABAergic transmission. scRNA-seq analysis revealed that SST expression is predominantly confined to GABAergic interneurons, while SSTR1 and SSTR2 exhibit strong expression in both glutamatergic and GABAergic neuronal populations. In TSC samples, SSTR5 was upregulated in GABAergic neurons, SSTR2 in glutamatergic neurons, while SSTR3 was downregulated in both glutamatergic neurons and microglia. Functional experiments demonstrated that SST enhances GABAergic currents in control tissues through a receptor-mediated mechanism involving protein kinase C activation. In contrast, SST application in TSC samples resulted in a significant suppression of GABAergic currents. Pharmacological inhibition of SSTR3 further exacerbated this effect, suggesting a compensatory role for this receptor subtype. Our findings reveal a disruption of SST signaling in TSC, contributing to altered coordination of excitatory-inhibitory activity and epileptogenesis. Targeting SST signaling may represent a therapeutic strategy for restoring inhibitory network function in TSC and related disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102864"},"PeriodicalIF":6.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682970","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 : 2025-12-04DOI: 10.1016/j.pneurobio.2025.102865
Michael Trubshaw , Oliver Kohl , Chetan Gohil , Mats W.J. van Es , Andrew J. Quinn , Katie Yoganathan , Evan Edmond , Malcolm Proudfoot , Nahid Zokaei , Vanessa Raymont , Jemma Pitt , Tony Thayanandan , Alexander G. Thompson , Kevin Talbot , Michele T. Hu , Marlou Nadine Perquin , Ece Kocagoncu , James B. Rowe , Mark W. Woolrich , Anna C. Nobre , Martin R. Turner
Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and is the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders with a large healthy cohort to characterise patterns of activity deviating from healthy ageing.
Task-free MEG recordings were acquired from patients with Alzheimer’s disease (AD, n = 29), Parkinson’s disease (PD, n = 25), amyotrophic lateral sclerosis (ALS, n = 33) and healthy controls (HC, n = 191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (power spectrum slope, which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, controlling for age and sex.
The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared with younger patients. Compared with matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS.
MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.
{"title":"Divergence of cortical neurophysiology across different neurodegenerative disorders compared to healthy ageing","authors":"Michael Trubshaw , Oliver Kohl , Chetan Gohil , Mats W.J. van Es , Andrew J. Quinn , Katie Yoganathan , Evan Edmond , Malcolm Proudfoot , Nahid Zokaei , Vanessa Raymont , Jemma Pitt , Tony Thayanandan , Alexander G. Thompson , Kevin Talbot , Michele T. Hu , Marlou Nadine Perquin , Ece Kocagoncu , James B. Rowe , Mark W. Woolrich , Anna C. Nobre , Martin R. Turner","doi":"10.1016/j.pneurobio.2025.102865","DOIUrl":"10.1016/j.pneurobio.2025.102865","url":null,"abstract":"<div><div>Neurodegenerative diseases involve disruption of healthy brain network communication occurring before the emergence of symptoms. Magnetoencephalography (MEG) is sensitive to the magnetic fields generated by cortical neuronal activity, and is the most spatio-temporally accurate method of directly assessing neuronal activity non-invasively. We used MEG to directly compare three neurodegenerative disorders with a large healthy cohort to characterise patterns of activity deviating from healthy ageing.</div><div>Task-free MEG recordings were acquired from patients with Alzheimer’s disease (AD, n = 29), Parkinson’s disease (PD, n = 25), amyotrophic lateral sclerosis (ALS, n = 33) and healthy controls (HC, n = 191). Healthy ageing trajectories for metrics including spectral power (local neuronal recruitment), connectivity (long-range communication), 1/f exponent (power spectrum slope, which may reflect inhibition), and oscillatory speed were extracted. These metrics were compared pairwise between HC and patient groups, controlling for age and sex.</div><div>The modelled trajectories of healthy ageing included increasing beta power and oscillatory speed, with reduced power spectrum slope. PD, AD, and ALS groups all showed reductions in beta power and slowing of oscillatory activity compared to matched HC. In AD, older patients showed lower beta power compared with younger patients. Compared with matched HC, the power spectrum slope was uniquely reduced in ALS, in contrast to the increase seen in PD and AD. Gamma connectivity increased in AD and ALS.</div><div>MEG has unique potential as a source of biomarkers that might be used to detect deviation from healthy ageing if applied at an earlier presymptomatic stage of neurodegeneration than current tools permit. It might also provide outcome measures for prevention trials.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"257 ","pages":"Article 102865"},"PeriodicalIF":6.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687957","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 : 2025-12-03DOI: 10.1016/j.pneurobio.2025.102857
Andrea Sánchez Corzo , Esteban Bullón Tarrasó , Martina Saltafossi , Teresa Berther , Tobias Staudigl , Daniel S. Kluger , Thomas Schreiner
While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.
{"title":"Respiratory coordination of excitability states across the human wake-sleep cycle","authors":"Andrea Sánchez Corzo , Esteban Bullón Tarrasó , Martina Saltafossi , Teresa Berther , Tobias Staudigl , Daniel S. Kluger , Thomas Schreiner","doi":"10.1016/j.pneurobio.2025.102857","DOIUrl":"10.1016/j.pneurobio.2025.102857","url":null,"abstract":"<div><div>While the respiratory rhythm is increasingly recognized as a key modulator of oscillatory brain activity across the wake-sleep cycle in humans, very little is known about its influence on aperiodic brain activity during sleep. This broadband activity indicates spontaneous fluctuations in excitation-inhibition (E:I) balance across vigilance states and has recently been shown to systematically covary across the respiratory cycle during waking resting state. We used simultaneous EEG and respiratory recordings over a full night of sleep collected from N = 23 healthy participants to unravel the nested dynamics of respiration phase-locked excitability states across the wake-sleep cycle. We demonstrate a robust phase shift in the coupling of aperiodic brain activity to respiratory rhythms as participants were transitioning from wakefulness to sleep. Moreover, respiration-brain coupling became more consistent both across and within participants, as interindividual as well as intraindividual variability systematically lessened from wakefulness and the transition to sleep towards deeper sleep stages. Our results suggest that respiration phase-locked changes in E:I balance conceivably add to sleep stage-specific neural signatures of REM and NREM sleep, highlighting the complexity of brain-body coupling during sleep.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102857"},"PeriodicalIF":6.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682971","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 : 2025-11-24DOI: 10.1016/j.pneurobio.2025.102856
Kirsten Bohmbach , Vincent Bauer , Christian Henneberger
Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.
神经元树突整合兴奋性输入。它们可以通过放大同步的局部输入和树突尖峰来执行局部计算，例如巧合检测。细胞外甘氨酸可以作为n -甲基- d -天冬氨酸（NMDA）亚型谷氨酸受体的协同激动剂，也可以作为抑制性甘氨酸受体（GlyRs）的配体，从而成为这一过程的强大调节剂。类似地，甘氨酸转运蛋白（GlyTs）是一种新兴的精神疾病和其他疾病的药物靶点，它可以通过环境甘氨酸水平控制树突整合。通过药理学分析甘氨酸、GlyTs和GlyRs如何改变局部树突兴奋性输入的突触后反应，在急性海马切片CA1锥体细胞的树突上验证了这两种假设。使用谷氨酸微离子电泳应用，我们发现甘氨酸确实可以显著增加树突的兴奋性和树突尖峰。我们还发现GlyTs是树突尖峰的强大调节剂，可以限制甘氨酸来源对CA1锥体细胞的影响。我们的实验还表明，GlyRs对缓慢的树突突成分具有相反的抑制作用。这直接表明甘氨酸可以动态增强树突对局部输入的响应性，促进树突尖峰，而GlyTs和GlyRs则相反。总之，这使得甘氨酸能信号成为CA1径向斜树突突触输入非线性整合的强大调制器。
{"title":"Glycine and glycine transport control dendritic excitability and spiking","authors":"Kirsten Bohmbach , Vincent Bauer , Christian Henneberger","doi":"10.1016/j.pneurobio.2025.102856","DOIUrl":"10.1016/j.pneurobio.2025.102856","url":null,"abstract":"<div><div>Neuronal dendrites integrate excitatory input. They can perform local computations such as coincidence detection by amplifying synchronized local input and dendritic spiking. Extracellular glycine could be a powerful modulator of such processes through its action as a co-agonist at glutamate receptors of the N-methyl-<span>D</span>-aspartate (NMDA) subtype but also as a ligand of inhibitory glycine receptors (GlyRs). Similarly, glycine transporters (GlyTs), an emerging drug target for psychiatric and other diseases, could control dendritic integration through ambient glycine levels. Both hypotheses were tested at dendrites of CA1 pyramidal cells in acute hippocampal slices by pharmacologically analysing how glycine, GlyTs and GlyRs change the postsynaptic response to local dendritic excitatory input. Using microiontophoretic glutamate application, we found that glycine can indeed significantly increase dendritic excitability and dendritic spiking. We also uncovered that GlyTs are powerful modulators of dendritic spiking, which can limit the impact of glycine sources on CA1 pyramidal cells. Our experiments also revealed that GlyRs can have an opposite, inhibitory effect on the slow dendritic spike component. This directly demonstrates that glycine can dynamically enhance dendritic responsiveness to local input and promote dendritic spiking, while GlyTs and GlyRs have an opposing effect. Together, this makes glycinergic signalling a powerful modulator of the nonlinear integration of synaptic input in CA1 radial oblique dendrites.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"256 ","pages":"Article 102856"},"PeriodicalIF":6.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145638142","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 : 2025-11-16DOI: 10.1016/j.pneurobio.2025.102854
Courtney Lane-Donovan , Mercedes Paredes , Aimee W. Kao
In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs—development and aging—that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (GBA: Gaucher’s disease and Parkinson’s disease), progranulin (GRN: neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (TSC1: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as “Lysosomal Clearance Disorders.”
{"title":"The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases","authors":"Courtney Lane-Donovan , Mercedes Paredes , Aimee W. Kao","doi":"10.1016/j.pneurobio.2025.102854","DOIUrl":"10.1016/j.pneurobio.2025.102854","url":null,"abstract":"<div><div>In the last two decades, many gene mutations have been identified that when homozygous, lead to childhood neurological disorders, but when heterozygous, result in adult-onset neurodegenerative disease. A shared feature linking these genes? They encode proteins residing in or impacting the function of the lysosome, a key organelle in macromolecular degradation and recycling whose loss leads to the inability to manage proteostatic stress. Here, we propose that lysosomes connect a subset of genetic neurological and neurodegenerative disorders as they occur in two distinct life epochs—development and aging—that endure high levels of proteostatic and other physiological stresses. In this Perspective, we highlight the differing mechanisms of three genes that exemplify this link: glucocerebrosidase A (<em>GBA</em>: Gaucher’s disease and Parkinson’s disease), progranulin (<em>GRN:</em> neuronal ceroid lipofuscinosis and frontotemporal dementia), and tuberous sclerosis complex 1 (<em>TSC1</em>: tuberous sclerosis complex and frontotemporal dementia). We discuss why neurons seem particularly vulnerable to lysosomal dysfunction and ways in which lysosomes potentially contribute to selective neuronal vulnerability. Finally, as disrupted lysosomal catabolism of macromolecules connects these diseases of the nervous system, we propose that they be jointly conceptualized as “Lysosomal Clearance Disorders.”</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"255 ","pages":"Article 102854"},"PeriodicalIF":6.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550252","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 : 2025-11-16DOI: 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}
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