Progress in Neurobiology最新文献_第8页

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 Q1 NEUROSCIENCES

Progress in Neurobiology

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

Sara Expósito , Samuel Alberquilla , Eduardo D. Martín

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 Ca²⁺-activated K⁺ 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_B and adenosine A1 receptors. In addition, the selective genetic ablation of GABA_B 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.

神经元具有独特的整合突触信息的能力，通过调节控制其兴奋性的电压门控膜离子通道的功能。星形胶质细胞在突触的形成、成熟和可塑性过程中发挥着积极的作用。然而，星形胶质细胞是否能通过调节膜离子电导率来影响神经元的活动，从而控制其固有的放电特性，目前尚不清楚。在这里，我们发现星形胶质细胞通过释放腺苷来增强CA1海马锥体神经元中缓慢的Ca2+激活K+电流（sIAHP）。值得注意的是，我们的研究结果表明，神经元间活动在星形胶质细胞介导的sIAHP调节中起着至关重要的作用。具体来说，光遗传刺激的海马中间神经元依赖GABAB和腺苷A1受体的激活，在星形细胞和锥体神经元之间唤起协调的信号传导。此外，CA1星形胶质细胞中GABAB受体的选择性基因消融阻止了中间神经元激活后锥体细胞中sIAHP和尖峰频率适应的增强。因此，我们的数据揭示了星形胶质细胞调节决定神经元放电率的内在膜特性的能力，而神经元放电率反过来又控制海马体网络的活动。

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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 Q1 NEUROSCIENCES

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

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.

胆碱能受体的激活使皮质锥体神经元持续放电，为包括工作记忆、路径整合和头部方向编码在内的空间导航理论提供了关键的细胞基础。颗粒状脾后皮层（RSG）对空间引导行为很重要，但乙酰胆碱如何影响RSG神经元尚不清楚。在这里，我们展示了一种转录组学、形态学和生物物理上不同的RSG细胞类型-低流变酶（LR）神经元-与所有其他邻近的兴奋性神经元亚型相比，具有非常独特的胆碱能毒蕈碱受体表达谱。LR神经元对胆碱能激动剂的反应不会持续放电，这与在RSG和中线皮层内检查的所有其他主要神经元亚型形成鲜明对比。这种持续性的缺乏使得LR神经元模型能够快速计算角头速度（AHV），而不依赖于导航过程中所见的胆碱能变化。因此，LR神经元可以在不同的大脑状态下一致地计算AHV，突出显示支持导航的特殊RSG神经代码。

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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 Q1 NEUROSCIENCES

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

Transcription factor 4 (TCF4) is essential for the normal development and function of the central nervous system. Haploinsufficiency of TCF4 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 Tcf4 gene in neural progenitors, neurons, or oligodendrocytes, did not reproduce the seizure phenotype. Here, we report that mice with a heterozygous deletion of Tcf4 in Aldehyde Dehydrogenase 1 Family Member L1 (Aldh1l1)-expressing cells—which resulted in approximately 60 % reduced Tcf4 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.

转录因子4 （TCF4）对中枢神经系统的正常发育和功能至关重要。由于TCF4缺失或突变导致的单倍性缺陷会导致皮特-霍普金斯综合征（PTHS），这是一种以癫痫发作、自闭症和智力残疾为特征的终身神经发育障碍。先前的研究表明，各种突变，包括神经祖细胞、神经元或少突胶质细胞中小鼠Tcf4基因外显子4的缺失，不会重现癫痫表型。在这里，我们报告了在醛脱氢酶1家族成员L1 （Aldh1l1）表达细胞中杂合缺失Tcf4的小鼠——导致星形胶质细胞中Tcf4表达减少约60%，其他细胞类型（包括神经元和少突胶质细胞）中Tcf4表达减少35%——早在出生后第4天就出现了星形胶质细胞增生，随后在3个月或更晚开始出现严重的复发性癫痫发作，并表现出寿命缩短。此外，这些小鼠在成年期表现出皮层、海马体、杏仁核和下丘脑的神经元活动增加。此外，单核RNA测序显示，与野生型对照相比，PTHS小鼠模型中兴奋性神经元、抑制性神经元、星形胶质细胞和少突胶质细胞中广泛存在的基因表达变化，包括与癫痫相关的基因。总的来说，这是首次报道PTHS小鼠模型出现癫痫发作，为研究PTHS发病机制和开发PTHS及其相关癫痫的治疗方法提供了有价值的工具。

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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 Q1 NEUROSCIENCES

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

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.

复杂环境下的目标导向行为依赖于前额叶（PF）微电路产生、维持工作记忆（WM）和监测选择。然而，WM和选择监测背后的细胞机制仍然存在冲突，而且人们对其知之甚少。我们研究了不同的细胞类型如何代表选择，研究了编码量和时间编码方案，以区分背侧（PFdl）、眶（PFo）和额极（PFp）前额叶皮层的静态和动态方案，在两只执行提示策略任务的猕猴中。我们一致地观察到，在假定的中间神经元中，编码幅度高于假定的锥体神经元，并且在PF区域中存在动态编码方案。然而，假设的锥体神经元表现出异构的编码方案，在PFdl中从静态到动态，从WM到监测。在监测过程中，PFp是唯一具有静态方案的区域，PFo表现出类似的动态方案。我们的研究结果揭示了由锥体神经元控制的PF微电路中丰富的种群动态。

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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 Q1 NEUROSCIENCES

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

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.

真核mRNA包括一个5'端m7G帽，以防止降解并实现帽依赖翻译。第一个转录的核糖核苷酸通过Cap甲基转移酶1 （CMTR1）进行额外的2'- o -核糖甲基化。虽然这种修饰影响基因表达，但其生理作用仍不清楚。CMTR1在成人海马中的高表达促使我们研究其在学习和记忆中的作用。在cmtr1缺失的海马中，转录组和蛋白质组分析显示，许多下调的基因与谷氨酸突触有关，包括n -甲基-d -天冬氨酸受体（NMDAR）亚基。我们制造了靶向前脑兴奋性神经元的CMTR1条件敲除小鼠，并观察到长期增强（LTP）和空间记忆巩固的缺陷。d -环丝氨酸，一种NMDAR变构激动剂，在这些小鼠中恢复记忆巩固和NMDAR功能减退。此外，在海马CA1神经元中重新表达野生型CMTR1，但没有催化失活，可以挽救LTP和记忆缺陷。我们的研究结果强调了CMTR1在调节NMDAR信号中的作用，这对突触可塑性和记忆巩固至关重要。

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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 Q1 NEUROSCIENCES

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

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.

已知共伴侣蛋白FK506结合蛋白51 （FKBP5）负调控糖皮质激素受体（gr），其遗传多态性在临床研究中与应激恢复有关。已知缺乏fkbp5的动物表现出应激恢复能力，但在海马中观察到突触传递的微小变化。考虑到海马在GR调节中的重要作用，我们研究了FKBP5在雄性小鼠海马双向突触可塑性中的功能，发现即使在没有FKBP5的情况下，长期增强（LTP）诱导也完好无损。此外，皮质酮培养的GR激活在对照组中阻断了LTP的诱导，但在FKBP5敲除（KO）小鼠中没有。有趣的是，低频刺激（LFS）诱导的长期抑郁（LTD）在雄性KO小鼠中选择性受损。重要的是，KO小鼠的LTD受损是由钙调神经磷酸酶表达增加介导的，这突出了FKBP5通过与GR和钙调神经磷酸酶的相互作用来调节突触可塑性的重要性。对fkbp5相关信号通路的进一步研究可能为应激恢复的分子机制和与应激失调相关的精神疾病的潜在治疗靶点提供新的见解。

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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 Q1 NEUROSCIENCES

Progress in Neurobiology

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

Hoyong Park, ChiHye Chung

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^2 + 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.

社交能力受损是一种典型的行为症状，通常与抑郁症有关。内侧前额叶皮层（mPFC）调节社会行为和压力反应。考虑到mPFC对侧链（LHb）的投射以及抑郁症中观察到的LHb异常亢进，mPFC-LHb通路可能在抑郁症社交行为受损的介导中起关键作用。最近的研究报道了抑郁症动物模型中mPFC-LHb通路的活性增加。然而，这条通路如何对社会刺激作出反应以及这一过程背后的突触动力学仍未得到研究。利用急性习得性无助（aLH）小鼠模型，我们证明了暴露于非社会压力导致mPFC-LHb突触的兴奋性增强和兴奋性突触传递增强。此外，在社交互动过程中，aLH小鼠在mPFC神经元中显示出明显升高的Ca2 +瞬时信号，这些信号投射到LHb。这种突触增强在LHb神经元投射到腹侧被盖区（VTA）中特别观察到。重要的是，光遗传学抑制mPFC-LHb通路有效地恢复了社交能力，强调了其在抑郁症相关的社交缺陷中的关键作用。这些发现强调mPFC-LHb通路是研究抑郁症社交能力缺陷的神经机制的一个有希望的靶点。

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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 Q1 NEUROSCIENCES

Progress in Neurobiology

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

Yuye Yin , Bin Li , Longfei Du , Shusheng Wu

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.

重度抑郁症（MDD）是一种常见的精神疾病，复发率高。目前大多数治疗抑郁症的药物主要通过调节中枢神经系统（CNS）中的神经递质来达到抗抑郁效果。然而，几乎一半的重度抑郁症患者不能从这些现有的治疗中充分受益。因此，迫切需要寻找新的治疗靶点来治疗重度抑郁症。据报道，外周B淋巴细胞是应激性抑郁症发生的主要因素。然而，外周B细胞在MDD中的病理作用和潜在的调节机制尚未很好地确定。在这里，我们发现外周B细胞在暴露于慢性不可预测的轻度应激（CUMS）后显著浸润到雄性小鼠的中枢神经系统。将来自CUMS小鼠的B细胞过继移植到B细胞缺陷的雄性小鼠中，可显著诱导比来自对照小鼠的B细胞过继移植更严重的抑郁症状。B细胞的缺乏保护雄性小鼠免受cums诱导的神经炎症和抑郁样行为。有趣的是，CUMS小鼠的病理性B细胞以血红素生物合成增加为特征，而其抑制可以改善接受CUMS小鼠病理性B细胞的B细胞缺陷小鼠的抑郁样行为。我们的研究结果表明，B细胞中的血红素生物合成在抑郁症的发病机制中起着关键作用，并表明这些具有高血红素特征的病理B细胞可能是MDD精准医学方法发展的一个有希望的免疫靶点。

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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 Q1 NEUROSCIENCES

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

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.

包括抑郁症在内的压力相关疾病是阿尔茨海默病（AD）的常见合并症。在阿尔茨海默病中，应激反应的增强可能会增加认知功能障碍的风险。本研究旨在研究野生型（WT）和AD模型5xFAD小鼠对重复社会失败应激（RSDS）的差异反应，并探讨应激易感性的分子机制。WT和5xFAD小鼠均表现出对初始暴露于RSDS的易感性，与WT小鼠相比，5xFAD小鼠中观察到的应激易感（Sus）个体比例更高。在反复暴露于rsd的症状前5xFAD小鼠中，与对照组相比，NOR测试中的识别指数较低，明显存在认知障碍。为了研究RSDS对外周免疫应答的影响，我们进行了CyTOF分析，发现5xFAD-Sus小鼠外周血中CD8+和CD4+记忆T细胞显著增加。为了进一步探索RSDS在大脑中的分子机制，RNA测序揭示了应激- sus小鼠中与炎症通路相关的差异表达基因的不同模式。具体来说，5xFAD-Sus小鼠在免疫相关通路中表现出失调，而WT-Sus小鼠在细胞粘附和细胞骨架组织相关通路中表现出改变。此外，将5xFAD-Sus与5xFAD-resilience小鼠进行比较，发现5xFAD-Sus小鼠突触可塑性通路明显中断，并且这些变化伴随着认知障碍。这些发现表明，5xFAD中应激易感性的增加与明显的外周免疫失调有关，可能导致AD早期的突触可塑性损伤和认知功能障碍。

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引用次数: 0

Beyond neurons: How does dopamine signaling impact astrocytic functions and pathophysiology? 超越神经元：多巴胺信号如何影响星形细胞功能和病理生理？

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-19 DOI: 10.1016/j.pneurobio.2025.102798

Giulia Favetta , Luigi Bubacco

Astrocytes, the most abundant glial cells in the central nervous system (CNS), are critical regulators of brain homeostasis and play an active role in synaptic signaling and plasticity. While dopamine, a key catecholamine neurotransmitter, has been traditionally associated with neuronal functions, emerging evidence highlights its significant impact on astrocytic physiology. This review explores how astrocytes contribute to dopaminergic signaling and the implications of this interaction in both physiological and pathological contexts. Specifically, we examined astrocytic dopamine receptor expression, signaling mechanisms, and region-specific effects on neuroinflammation, synaptic regulation, and neurotrophic factor secretion. Notably, astrocytic dopamine receptor activation plays dual inflammatory roles, modulating both anti- and pro- inflammatory responses depending on the receptor subtype and pathological environment. Furthermore, dopamine-evoked gliotransmitter release and neurotrophin secretion highlight the role of astrocytes in astrocyte-to-neuron communication, which impacts synaptic plasticity and neuronal survival. Dysfunction of astrocytic dopaminergic signaling has been implicated in neurodegenerative diseases such as Parkinson’s disease, where dopamine depletion drives reactive astrogliosis, altered glutamate homeostasis, and inflammatory responses. These findings underscore the complexity of astrocytic responses to dopamine and their potential as targets in conditions characterized by dysregulation of dopaminergic signaling. By highlighting recent advancements in understanding dopamine-astrocyte interactions, this review aims to provide insights into the broader roles of astrocytes in dopaminergic systems and their therapeutic potential in CNS disorders.

星形胶质细胞是中枢神经系统（CNS）中最丰富的胶质细胞，是大脑稳态的关键调节细胞，在突触信号传导和可塑性中发挥积极作用。虽然多巴胺是一种关键的儿茶酚胺神经递质，传统上一直与神经元功能有关，但新出现的证据强调了它对星形细胞生理学的重要影响。这篇综述探讨了星形胶质细胞如何参与多巴胺能信号传导，以及这种相互作用在生理和病理背景下的意义。具体来说，我们研究了星形细胞多巴胺受体的表达、信号机制以及区域特异性对神经炎症、突触调节和神经营养因子分泌的影响。值得注意的是，星形细胞多巴胺受体激活具有双重炎症作用，根据受体亚型和病理环境调节抗炎和促炎反应。此外，多巴胺诱发的胶质递质释放和神经营养因子分泌突出了星形胶质细胞在星形胶质细胞与神经元通讯中的作用，从而影响突触可塑性和神经元存活。星形胶质细胞多巴胺能信号的功能障碍与神经退行性疾病（如帕金森病）有关，其中多巴胺耗损驱动反应性星形胶质增生、谷氨酸稳态改变和炎症反应。这些发现强调了星形细胞对多巴胺反应的复杂性，以及它们在多巴胺能信号失调的条件下作为靶点的潜力。通过强调在多巴胺-星形胶质细胞相互作用方面的最新进展，本综述旨在深入了解星形胶质细胞在多巴胺能系统中的广泛作用及其在中枢神经系统疾病中的治疗潜力。

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