Progress in Neurobiology最新文献

NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes NCAM2促进APP从细胞表面靶向到含有bace1的回收内体。

IF 6.1 2区医学

Progress in Neurobiology Pub Date : 2025-08-01 DOI: 10.1016/j.pneurobio.2025.102807

Grant Pfundstein , Ryan Keable , Shangfeng Hu , Muayad Al-Hadi , Maximilian Baker , Melitta Schachner , Iryna Leshchyns’ka , Vladimir Sytnyk

{"title":"NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes","authors":"Grant Pfundstein , Ryan Keable , Shangfeng Hu , Muayad Al-Hadi , Maximilian Baker , Melitta Schachner , Iryna Leshchyns’ka , Vladimir Sytnyk","doi":"10.1016/j.pneurobio.2025.102807","DOIUrl":"10.1016/j.pneurobio.2025.102807","url":null,"abstract":"<div><div>Convergence of amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) in endosomes initiates the production of amyloid-β (Aβ) peptides that accumulate in brains of Alzheimer’s disease patients. APP and BACE1 are segregated in neurons, and mechanisms triggering their convergence have remained poorly understood, limiting therapeutic attempts to reduce Aβ production. Neural cell adhesion molecule 2 (NCAM2) is a cell surface localized protein, which increases Aβ levels via mechanisms that are not known. We show that APP binds to the extracellular domain of NCAM2. The intracellular domain of NCAM2 binds to the Rab11 adaptor protein Rab11-FIP5. The NCAM2/APP complex is endocytosed from the cell surface and targeted to BACE1-containing Rab11-positive recycling endosomes where it is processed. Convergence of APP with BACE1 is increased in transfected CHO cells and neurons expressing NCAM2. Consequently, the levels of amyloidogenic APP cleavage products are increased in cells expressing NCAM2. In NCAM2-deficient neurons, APP accumulates at the cell surface and in early endosomes, and APP levels in recycling endosomes are reduced. Aβ production is increased by Aβ oligomers and neuronal activity, and we show that the binding of NCAM2 to APP is increased in neurons treated with Aβ oligomers or after activation of synaptic NMDA receptors. Together, our data indicate that NCAM2 binds to APP and promotes APP targeting from the neuronal cell surface to recycling endosomes where APP is cleaved by BACE1. This novel mechanism regulating the convergence of APP and BACE1 in neurons can contribute to Aβ accumulation in Alzheimer’s disease.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102807"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732944","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}

引用次数: 0

Astrocyte-interneuron interplay tunes neuronal excitability by enhancing the slow Ca2 + -activated K+ current 星形胶质细胞-神经元间相互作用通过增强缓慢的Ca2 +激活的K+电流来调节神经元的兴奋性

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-16 DOI: 10.1016/j.pneurobio.2025.102806

Sara Expósito , Samuel Alberquilla , Eduardo D. Martín

{"title":"Astrocyte-interneuron interplay tunes neuronal excitability by enhancing the slow Ca2 + -activated K+ current","authors":"Sara Expósito , Samuel Alberquilla , Eduardo D. Martín","doi":"10.1016/j.pneurobio.2025.102806","DOIUrl":"10.1016/j.pneurobio.2025.102806","url":null,"abstract":"<div><div>Neurons have the unique ability to integrate synaptic information by modulating the function of the voltage-gated membrane ion channels, which govern their excitability. Astrocytes play active roles in synaptic function, from synapse formation and maturation to plasticity processes. However, it remains elusive whether astrocytes can impact the neuronal activity by regulating membrane ionic conductances that control the intrinsic firing properties. Here, we found that astrocytes enhance the slow Ca<sup>2+</sup>-activated K<sup>+</sup> current (sIAHP) in CA1 hippocampal pyramidal neurons through the release of adenosine. Remarkably, our results indicate that interneuron activity plays a crucial role in this astrocyte-mediated modulation of sIAHP. Specifically, optogenetically stimulated hippocampal interneurons were found to evoke coordinated signaling between astrocytes and pyramidal neurons, relying on the activation of GABA<sub>B</sub> and adenosine A1 receptors. In addition, the selective genetic ablation of GABA<sub>B</sub> receptors in CA1 astrocytes prevented the potentiation of sIAHP and spike frequency adaptation in pyramidal cells following interneuron activation. Therefore, our data reveal the capability of astrocytes to modulate the intrinsic membrane properties that dictate neuronal firing rate, which in turn governs hippocampal network activity.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102806"},"PeriodicalIF":6.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653443","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}

引用次数: 0

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states 颗粒状脾后皮层细胞类型特异性胆碱能控制与大脑状态角速度编码的含义。

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-08 DOI: 10.1016/j.pneurobio.2025.102804

Izabela Jedrasiak-Cape , Chloe Rybicki-Kler , Isla Brooks , Megha Ghosh , Ellen K.W. Brennan , Sameer Kailasa , Tyler G. Ekins , Alan Rupp , Omar J. Ahmed

{"title":"Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states","authors":"Izabela Jedrasiak-Cape , Chloe Rybicki-Kler , Isla Brooks , Megha Ghosh , Ellen K.W. Brennan , Sameer Kailasa , Tyler G. Ekins , Alan Rupp , Omar J. Ahmed","doi":"10.1016/j.pneurobio.2025.102804","DOIUrl":"10.1016/j.pneurobio.2025.102804","url":null,"abstract":"<div><div>Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type – the low-rheobase (LR) neuron – has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102804"},"PeriodicalIF":6.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609241","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}

引用次数: 0

Tcf4 Deficiency causes recurrent seizures in mice Tcf4缺乏导致小鼠复发性癫痫发作

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-04 DOI: 10.1016/j.pneurobio.2025.102805

Laura Craciun , Vivianna R. DeNittis , Matthew T. Davis , Jeanne T. Paz , Kaoru Saijo

{"title":"Tcf4 Deficiency causes recurrent seizures in mice","authors":"Laura Craciun , Vivianna R. DeNittis , Matthew T. Davis , Jeanne T. Paz , Kaoru Saijo","doi":"10.1016/j.pneurobio.2025.102805","DOIUrl":"10.1016/j.pneurobio.2025.102805","url":null,"abstract":"<div><div>Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of <em>TCF4</em> due to deletions or mutations causes Pitt-Hopkins Syndrome (PTHS), a lifelong neurodevelopmental disorder characterized by seizures, autism, and intellectual disability. Previous studies have shown that various mutations, including deletion of exon 4 in the mouse <em>Tcf4</em> gene in neural progenitors, neurons, or oligodendrocytes, did not reproduce the seizure phenotype. Here, we report that mice with a heterozygous deletion of <em>Tcf4</em> in Aldehyde Dehydrogenase 1 Family Member L1 (<em>Aldh1l1</em>)-expressing cells—which resulted in approximately 60 % reduced <em>Tcf4</em> expression in astrocytes and a 35 % reduction in other cell types, including neurons and oligodendrocytes—developed astrogliosis as early as postnatal day 4, followed by severe recurrent seizures beginning at three months of age or later, and exhibited shortened lifespans. Additionally, these mice showed increased neuronal activity in the cortex, hippocampus, amygdala, and hypothalamus in adulthood. Furthermore, single-nucleus RNA sequencing revealed widespread gene expression changes, including genes associated with epilepsy, in excitatory neurons, inhibitory neurons, astrocytes, and oligodendrocytes in our PTHS mouse model compared to wild-type controls. Overall, this is the first report of a PTHS mouse model exhibiting seizures, providing a valuable tool to investigate the mechanisms underlying PTHS pathogenesis and to develop therapies for PTHS and its associated epilepsy.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102805"},"PeriodicalIF":6.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576150","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}

引用次数: 0

Cell types implement multiple coding schemes in distinct prefrontal cortex areas during goal-directed behavior 在目标导向行为中，不同类型的细胞在不同的前额皮质区域实现多种编码方案。

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-07-01 DOI: 10.1016/j.pneurobio.2025.102803

Francesco Ceccarelli , Lorenzo Ferrucci , Fabrizio Londei , Giulia Arena , Francesco Siano , Fabio Di Bello , Surabhi Ramawat , Satoshi Tsujimoto , Emiliano Brunamonti , Aldo Genovesio

{"title":"Cell types implement multiple coding schemes in distinct prefrontal cortex areas during goal-directed behavior","authors":"Francesco Ceccarelli , Lorenzo Ferrucci , Fabrizio Londei , Giulia Arena , Francesco Siano , Fabio Di Bello , Surabhi Ramawat , Satoshi Tsujimoto , Emiliano Brunamonti , Aldo Genovesio","doi":"10.1016/j.pneurobio.2025.102803","DOIUrl":"10.1016/j.pneurobio.2025.102803","url":null,"abstract":"<div><div>Goal-directed behavior in complex environments relies on prefrontal (PF) microcircuits to generate, maintain in working memory (WM) and monitor choices. However, the cellular mechanisms underlying WM and choice monitoring remain conflictual and poorly understood. We investigated how distinct cell types represent choice, examining both coding magnitude and temporal coding schemes to distinguish between static and dynamic schemes across dorsolateral (PFdl), orbital (PFo), and frontopolar (PFp) prefrontal cortex in two macaques performing a Cued Strategy task. We consistently observed in putative interneurons both a higher coding magnitude than putative pyramidal neurons and a dynamic coding scheme across the PF areas. However, putative pyramidal neurons showed heterogeneous coding schemes, which in PFdl shifted from static to dynamic from WM to monitoring. PFo showed a similar dynamic scheme, and PFp was the only area with a static scheme during monitoring. Our results reveal rich population dynamics in PF microcircuits governed by pyramidal neurons.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102803"},"PeriodicalIF":6.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560958","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}

引用次数: 0

FKBP5 deficiency selectively impairs NMDAR-dependent long-term depression via enhanced calcineurin activity: Implications for stress resilience FKBP5缺乏通过增强钙调磷酸酶活性选择性地损害nmda依赖的长期抑郁：对应激恢复能力的影响

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-06-25 DOI: 10.1016/j.pneurobio.2025.102801

Seungjae Zhang, Yong-Jae Jeon, Jung-Soo Han, Hoyong Park, ChiHye Chung

{"title":"FKBP5 deficiency selectively impairs NMDAR-dependent long-term depression via enhanced calcineurin activity: Implications for stress resilience","authors":"Seungjae Zhang, Yong-Jae Jeon, Jung-Soo Han, Hoyong Park, ChiHye Chung","doi":"10.1016/j.pneurobio.2025.102801","DOIUrl":"10.1016/j.pneurobio.2025.102801","url":null,"abstract":"<div><div>The co-chaperone FK506 binding protein 51 (FKBP5) is known to negatively regulate glucocorticoid receptors (GRs), and its genetic polymorphisms have been implicated in stress resilience in clinical studies. FKBP5-deficient animals are known to exhibit stress resilience, but minimal alterations in synaptic transmission were observed in the hippocampus. Given the crucial role of the hippocampus in GR regulation, we investigated the function of FKBP5 in the bidirectional synaptic plasticity in the hippocampus of male mice and found intact long-term potentiation (LTP) induction even in the absence of FKBP5. Furthermore, GR activation by corticosterone incubation blocked the LTP induction in controls but not in FKBP5 knockout (KO) mice. Interestingly, low-frequency stimulation (LFS) -induced long-term depression (LTD) was selectively impaired in male KO mice. Importantly, impaired LTD in KO mice was mediated by increased calcineurin expression, highlighting the importance of FKBP5 in regulating synaptic plasticity through its interaction with GR and calcineurin. Further research on the FKBP5-related signaling pathways may provide insights into the molecular mechanisms underlying stress resilience and potential therapeutic targets for psychiatric disorders associated with stress dysregulation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102801"},"PeriodicalIF":6.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501258","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}

引用次数: 0

CMTR1-catalyzed 2′-O-methylation promotes NMDA receptor signaling, long-term potentiation and memory cmtr1催化的2'- o -甲基化促进NMDA受体信号传导、长期增强和记忆。

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-06-25 DOI: 10.1016/j.pneurobio.2025.102802

Sayma Azeem , Tzu-Tung Chang , Chi Peng , Yen-Lurk Lee , Nai-Hsing Yeh , Yi-Shuian Huang

{"title":"CMTR1-catalyzed 2′-O-methylation promotes NMDA receptor signaling, long-term potentiation and memory","authors":"Sayma Azeem , Tzu-Tung Chang , Chi Peng , Yen-Lurk Lee , Nai-Hsing Yeh , Yi-Shuian Huang","doi":"10.1016/j.pneurobio.2025.102802","DOIUrl":"10.1016/j.pneurobio.2025.102802","url":null,"abstract":"<div><div>Eukaryotic mRNA includes a 5′-end m7G cap to prevent degradation and enable cap-dependent translation. The first transcribed ribonucleotide undergoes additional 2′-O-ribose methylation by Cap Methyltransferase 1 (CMTR1). Although this modification impacts gene expression, its physiological role remains largely unclear. High CMTR1 expression in the adult hippocampus prompted us to examine its role in learning and memory. In CMTR1-deficient hippocampi, numerous downregulated genes from transcriptome and proteome analyses were linked to glutamatergic synapses, including N-methyl-D-aspartate receptor (NMDAR) subunits. We generated CMTR1 conditional knockout mice targeting forebrain excitatory neurons and observed deficits in long-term potentiation (LTP) and spatial memory consolidation. D-cycloserine, an NMDAR allosteric agonist, restored memory consolidation and NMDAR hypofunction in these mice. Additionally, re-expression of wild-type, but not catalytically inactive, CMTR1 in hippocampal CA1 neurons rescued LTP and memory deficits. Our findings highlight the role of CMTR1 in regulating NMDAR signaling, which is critical for synaptic plasticity and memory consolidation.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102802"},"PeriodicalIF":6.7,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507991","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}

引用次数: 0

Regulation of sociability by the cortico-habenula pathway in an animal model of depression 抑郁症动物模型中皮质-缰核通路对社交能力的调节

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-06-24 DOI: 10.1016/j.pneurobio.2025.102799

Hoyong Park, ChiHye Chung

{"title":"Regulation of sociability by the cortico-habenula pathway in an animal model of depression","authors":"Hoyong Park, ChiHye Chung","doi":"10.1016/j.pneurobio.2025.102799","DOIUrl":"10.1016/j.pneurobio.2025.102799","url":null,"abstract":"<div><div>Impaired sociability is a hallmark behavioral symptom frequently associated with depression. The medial prefrontal cortex (mPFC) is known to regulate both social behaviors and stress responses. Given the mPFC's projections to the lateral habenula (LHb) and the abnormal hyperactivity of the LHb observed in depression, the mPFC-LHb pathway may play a pivotal role in mediating impaired social behaviors in depressive disorders. Recent studies have reported increased activity of the mPFC-LHb pathway in depressive animal models. However, how this pathway responds to social stimuli and the synaptic dynamics underlying this process remain unexamined. Utilizing an acute learned helplessness (aLH) mouse model, we demonstrated that exposure to non-social stress resulted in heightened excitability and enhanced excitatory synaptic transmission at mPFC-LHb synapses. Furthermore, during social interactions, aLH mice exhibited significantly elevated Ca<sup>2 +</sup> transient signals in mPFC neurons projecting to the LHb. This synaptic enhancement was specifically observed in LHb neurons projecting to the ventral tegmental area (VTA). Importantly, optogenetic suppression of the mPFC-LHb pathway effectively restored sociability, underscoring its crucial role in the social deficits associated with depression. These findings highlight the mPFC-LHb pathway as a promising target for investigating the neural mechanisms underlying sociability deficits in depressive disorders.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102799"},"PeriodicalIF":6.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492171","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}

引用次数: 0

Stress-induced heme metabolic disorder in peripheral B cells contributes to depressive-like behaviors in male mice 应激诱导的外周血B细胞血红素代谢紊乱与雄性小鼠抑郁样行为有关

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-06-21 DOI: 10.1016/j.pneurobio.2025.102800

Yuye Yin , Bin Li , Longfei Du , Shusheng Wu

{"title":"Stress-induced heme metabolic disorder in peripheral B cells contributes to depressive-like behaviors in male mice","authors":"Yuye Yin , Bin Li , Longfei Du , Shusheng Wu","doi":"10.1016/j.pneurobio.2025.102800","DOIUrl":"10.1016/j.pneurobio.2025.102800","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a common and burdensome psychiatric illness with high rates of recurrence. Most of the current therapeutic drugs for depression mainly achieve their antidepressant effect by tuning the landscape of neurotransmitters in the central nervous system (CNS). However, almost half of patients with MDD cannot fully benefit from these available treatments. Consequently, it is urgent to find novel therapeutic targets for the treatment of MDD. Peripheral B lymphocytes have been reported as a major contributor to the occurrence of stress-induced depression. However, the pathological role and underlying regulatory mechanism of peripheral B cells in MDD have not been well established. Here, we show that peripheral B cells are significantly infiltrated into the CNS of male mice after exposure to chronic unpredictable mild stress (CUMS). Adoptive transfer of B cells from CUMS mice into B-cell-deficient male mice could significantly induce higher severity depressive symptoms than adoptive transfer of B cells from control mice. The lack of B cells protects male mice from CUMS-induced neuroinflammation and depressive-like behaviors. Interestingly, the pathological B cells in CUMS mice are characterized by increased heme biosynthesis, whereas its inhibition can ameliorate depressive-like behaviors in B-cell-deficient mice that received pathological B cells from CUMS mice. Our findings suggest a critical role of the heme biosynthesis in B cells for contributing to the pathogenesis of depression and indicate that these pathological B cells featuring high heme may be a promising immune target for the development of precision medicine approaches in MDD.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102800"},"PeriodicalIF":6.7,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335892","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}

引用次数: 0

Differential susceptibility to repeated social stress induces synaptic plasticity impairment and cognitive deficit in the 5xFAD mouse model 在5xFAD小鼠模型中，对重复社会应激的不同易感性导致突触可塑性损伤和认知缺陷。

IF 6.7 2区医学

Progress in Neurobiology Pub Date : 2025-06-19 DOI: 10.1016/j.pneurobio.2025.102797

Eun-Jeong Yang , Md Al Rahim , Sibilla Masieri , Giulio Maria Pasinetti

{"title":"Differential susceptibility to repeated social stress induces synaptic plasticity impairment and cognitive deficit in the 5xFAD mouse model","authors":"Eun-Jeong Yang , Md Al Rahim , Sibilla Masieri , Giulio Maria Pasinetti","doi":"10.1016/j.pneurobio.2025.102797","DOIUrl":"10.1016/j.pneurobio.2025.102797","url":null,"abstract":"<div><div>Stress-related disorders including depression are common comorbidities in Alzheimer's Disease (AD). In AD, heightened stress reactivity may contribute to an increased risk of cognitive dysfunction. This study aimed to investigate the differential responses of wild-type (WT) and 5xFAD mice, a model of AD, to repeated social defeat stress (RSDS) and explore the molecular mechanisms associated with stress susceptibility. Both WT and 5xFAD mice exhibited susceptibility to initial exposure to RSDS, with a greater proportion of stress-susceptible (Sus) individuals observed in 5xFAD mice compared to WT mice. In presymptomatic 5xFAD mice repeatedly exposed to RSDS, cognitive impairment was evident through a lower discrimination index in the NOR test compared to controls. To investigate the effects of RSDS on peripheral immune responses, we performed CyTOF analysis, revealing a significant increase in CD8 + and CD4 + memory T cells exclusively in the peripheral blood of 5xFAD-Sus mice. To further explore the molecular mechanisms underlying RSDS in the brain, RNA sequencing revealed distinct patterns of differentially expressed genes associated with inflammatory pathways in stress-Sus mice. Specifically, 5xFAD-Sus mice exhibited dysregulation in immune-related pathways, while WT-Sus mice displayed alterations in pathways related to cell adhesion and cytoskeletal organization. In addition, when comparing 5xFAD-Sus to 5xFAD-resilience mice, significant disruptions in synaptic plasticity pathways were observed in 5xFAD-Sus mice, and these changes were accompanied by cognitive impairment. These findings suggest that increased stress susceptibility in 5xFAD is linked to distinct peripheral immune dysregulation, potentially contributing to synaptic plasticity impairments and cognitive dysfunction in the early stages of AD.</div></div>","PeriodicalId":20851,"journal":{"name":"Progress in Neurobiology","volume":"251 ","pages":"Article 102797"},"PeriodicalIF":6.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340371","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}

引用次数: 0