Progress in Neurobiology最新文献_第9页

Neuronal encoding of recognition memory for numerical quantities in macaque intraparietal and prefrontal cortices 猕猴顶内和前额叶皮质对数字数量识别记忆的神经元编码。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-13 DOI: 10.1016/j.pneurobio.2025.102794

Tobias Machts, Julia Grüb, Andreas Nieder

The parieto-frontal number network in primates is vital for extracting and memorizing numerical information. However, how neurons in these regions retain abstract numerical categories to recognize target numbers amidst ongoing numerical input is unclear. To explore this, single neurons were recorded from the ventral intraparietal cortex (VIP) and lateral prefrontal cortex (PFC) of two male macaques trained to memorize and recognize target numerosities while viewing sequences of irrelevant numerosities. In the VIP, neuronal selectivity for both target and irrelevant numerosities declined rapidly, making it unable to distinguish relevant from irrelevant quantities. Conversely, PFC neurons maintained selective tuning for target numerosities over time but not for irrelevant ones, enabling the distinction between sought and irrelevant quantities. Match enhancement effects, where firing increased for repeated target numerosities, were observed only in the PFC. In contrast, match suppression effects, involving reduced firing for repeated target numerosities, occurred in both the VIP and PFC. These findings suggest the VIP primarily encodes displayed numerosities, while the PFC is specialized for processing, storing, and recognizing numerical quantities by enhancing familiar numerosities. This highlights the PFC’s key role in recognition memory, contrasting with the transient coding observed in the VIP.

灵长类动物的顶叶-额叶数字网络对数字信息的提取和记忆至关重要。然而，这些区域的神经元如何在持续的数字输入中保持抽象的数字类别以识别目标数字尚不清楚。为了探索这一点，研究人员记录了两只雄性猕猴的单个神经元，这些猕猴被训练在观看无关数字序列的同时记忆和识别目标数字。在VIP中，神经元对目标数量和无关数量的选择性都迅速下降，使其无法区分相关数量和无关数量。相反，PFC神经元随着时间的推移对目标数量保持选择性调整，但对不相关的数量却没有，从而能够区分所寻找的数量和不相关的数量。匹配增强效应，即对重复的目标数字的激发增加，仅在PFC中观察到。相反，匹配抑制效应，即对重复的目标数字的激发减少，在VIP和PFC中都存在。这些发现表明，VIP主要对显示的数字进行编码，而PFC则专门通过增强熟悉的数字来处理、存储和识别数字数量。这突出了PFC在识别记忆中的关键作用，与在VIP中观察到的瞬态编码形成对比。

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引用次数: 0

The social salience network hypothesis of autism: Disrupted network activity, oxytocin signaling, and implications for social symptoms 自闭症的社会显著性网络假说：网络活动中断、催产素信号和对社会症状的影响。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-06 DOI: 10.1016/j.pneurobio.2025.102787

Aishwarya Patwardhan, Katrina Y. Choe

Autism Spectrum Disorder (ASD) is a complex condition characterized by its heterogeneity, with significant variability in symptoms across subtypes and associated comorbidities. Despite the urgent need to develop mechanism-based therapies for the core social symptoms of ASD, progress has been hindered by the heterogeneous etiology of this neurodevelopmental disorder and our still limited understanding of the neural mechanisms underlying social behavior. The evaluation of sociosensory cues and the modulation of motivation to engage socially are fundamental components of social interaction, thought to be coordinated by a network of interconnected brain regions called the social salience network (SSN). This network is strongly modulated by the neurohormone oxytocin (OXT) to facilitate appropriate social responses. It is increasingly recognized that disruptions within the SSN contribute to the atypical social perception and engagement observed in autistic individuals. This review will summarize evidence from current clinical and preclinical literature that provides compelling evidence for SSN disruptions as a possible mechanism that underlies the social symptoms of ASD. Furthermore, we discuss OXT-mediated correction of SSN disruptions at the regional and circuit levels that rescues social phenotypes in preclinical models of ASD-risk factors. These molecular, cellular, and circuit mechanisms within the SSN could serve as promising treatment targets which may propel the development of novel and effective options for alleviating the social difficulties of autistic individuals.

自闭症谱系障碍（ASD）是一种复杂的疾病，其特点是其异质性，在不同亚型和相关合并症的症状上存在显著差异。尽管迫切需要开发基于机制的治疗方法来治疗ASD的核心社交症状，但这种神经发育障碍的异质性病因以及我们对社交行为背后的神经机制的了解仍然有限，阻碍了进展。对社会感觉线索的评估和参与社会活动动机的调节是社会互动的基本组成部分，被认为是由一个被称为社会突出网络（SSN）的相互连接的大脑区域网络协调的。这个网络受到神经激素催产素（OXT）的强烈调节，以促进适当的社会反应。越来越多的人认识到，社会安全号内部的中断有助于在自闭症个体中观察到的非典型社会感知和参与。本综述将总结来自当前临床和临床前文献的证据，这些证据提供了令人信服的证据，证明SSN中断可能是ASD社交症状的潜在机制。此外，我们讨论了oxt在区域和回路水平上介导的SSN中断纠正，从而挽救了asd危险因素临床前模型中的社会表型。这些在SSN中的分子、细胞和电路机制可以作为有希望的治疗靶点，可能推动开发新的和有效的选择来减轻自闭症个体的社会困难。

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引用次数: 0

Changes in astrocyte function induced by stress-induced glucocorticoid exacerbate major depressive disorder 应激性糖皮质激素诱导的星形胶质细胞功能改变加重重度抑郁症。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-06-06 DOI: 10.1016/j.pneurobio.2025.102786

Beomjo Park , Gee Euhn Choi

Major depressive disorder (MDD) is a prevalent psychiatric condition that affects millions of people worldwide and is a leading cause of disability. Chronic stress is a key factor in the development of MDD, leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and elevated glucocorticoid levels, which in turn affect brain function and structure. Astrocytes, crucial for maintaining central nervous system (CNS) homeostasis, play a significant role in the pathophysiology of MDD. Dysregulation of glucocorticoid signaling in astrocytes contributes to changes in astrocyte survival, reactivity, metabolism, neurotrophic support, gliotransmitter release, and neuroinflammation, exacerbating depressive symptoms. This review explains the necessity for exploring the effects of glucocorticoid on astrocytes and subsequent MDD progression. Firstly, we briefly explore the glucocorticoid signaling and the multifaceted function of astrocytes. Then, this study discusses the mechanisms by which chronic stress and glucocorticoid exposure induce astrocyte-mediated neurodegenerative changes, highlighting the importance of targeting glucocorticoid-related signaling of astrocytes in developing therapeutic interventions for MDD. Understanding these mechanisms could lead to the development of more effective treatments aimed at restoring astrocyte function and alleviating MDD.

重度抑郁症（MDD）是一种流行的精神疾病，影响着全世界数百万人，是导致残疾的主要原因。慢性应激是MDD发展的关键因素，导致下丘脑-垂体-肾上腺（HPA）轴过度激活和糖皮质激素水平升高，进而影响大脑功能和结构。星形胶质细胞对维持中枢神经系统（CNS）稳态至关重要，在重度抑郁症的病理生理中起着重要作用。星形胶质细胞中糖皮质激素信号的失调有助于星形胶质细胞存活、反应性、代谢、神经营养支持、胶质递质释放和神经炎症的改变，加剧抑郁症状。这篇综述解释了探讨糖皮质激素在星形胶质细胞和随后的MDD进展中的作用的必要性。首先，我们简要探讨糖皮质激素信号通路和星形胶质细胞的多方面功能。然后，本研究讨论了慢性应激和糖皮质激素暴露诱导星形胶质细胞介导的神经退行性改变的机制，强调了靶向星形胶质细胞糖皮质激素相关信号在开发MDD治疗干预措施中的重要性。了解这些机制可能会导致开发更有效的治疗方法，旨在恢复星形胶质细胞功能和减轻MDD。

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引用次数: 0

Glutamine transport via amino acid transporter NTT4 (SLC6A17) maintains presynaptic glutamate supply at excitatory synapses in the CNS 通过氨基酸转运体NTT4 （SLC6A17）运输谷氨酰胺维持中枢神经系统兴奋性突触的突触前谷氨酸供应。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-26 DOI: 10.1016/j.pneurobio.2025.102785

Angela L. Nicoli , A. Shaam Al Abed , Sarah R. Hulme , Abhijit Das , Gregory Gauthier-Coles , Angelika Bröer , Sarojini Balkrishna , Gaetan Burgio , Nathalie Dehorter , Caroline D. Rae , Stefan Bröer , Brian Billups

The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and forms glutamine, before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle are established, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of ¹³C metabolites in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is eliminated when NTT4 is removed or inhibited. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning, and alterations in anxiety behaviour and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter, which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are important regulators of memory retention and normal behaviour.

谷氨酸-谷氨酰胺循环被认为是突触中谷氨酸循环的主要代谢途径。在这个循环中，突触释放的谷氨酸被星形胶质细胞隔离并形成谷氨酰胺，然后返回突触前末端转化为谷氨酸，以补充神经递质池。虽然这个循环的许多方面已经确定，但一个关键的组成部分仍然未知：负责突触前谷氨酰胺摄取的转运体的性质。我们假设神经递质转运蛋白4 （NTT4/SLC6A17）发挥了这一作用。因此，我们产生了NTT4敲除小鼠，以评估其对突触前谷氨酰胺运输和突触谷氨酸供应的贡献。通过对清醒小鼠13C代谢物的生化示踪，我们观察到NTT4缺失时神经元谷氨酸供应减少。此外，海马苔藓纤维钮扣的直接电记录显示，当NTT4被移除或抑制时，突触前谷氨酰胺运输电流被消除。海马电生理记录证实了NTT4在神经传递中的作用，这表明NTT4是维持水泡谷氨酸含量和在高频神经元活动期间维持足够水平的谷氨酸供应所必需的。最后，对老鼠的行为研究表明，老鼠在恐惧条件反射方面存在缺陷，焦虑行为和社会偏好也会发生改变。这些结果表明，NTT4是突触前谷氨酰胺转运蛋白，是谷氨酸-谷氨酰胺循环的核心组成部分。NTT4和谷氨酸-谷氨酰胺循环在高频突触活动中维持神经兴奋性神经传递的谷氨酸供应，并且是记忆保留和正常行为的重要调节因子。

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引用次数: 0

Switching state to engage and sustain attention: Dynamic synchronization of the frontoparietal network 转换状态以吸引和维持注意力：额顶叶网络的动态同步。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-17 DOI: 10.1016/j.pneurobio.2025.102777

Grace Ross , Wei A. Huang , Jared Reiling , Mengsen Zhang , Jimin Park , Susanne Radtke-Schuller , Joseph Hopfinger , Agnieszka Zuberer , Flavio Frohlich

Sustained attention (SA) is essential for maintaining focus over time, with disruptions linked to various neurological and psychiatric disorders. The oscillatory dynamics and functional connectivity in the dorsal frontoparietal network (dFPN) are crucial in SA. However, the neuronal mechanisms that control the level of SA, especially in response to heightened attentional demands, remain poorly understood. To examine the role of rhythmic synchronization in the dFPN in SA, we recorded local field potential and single unit activity in ferrets that performed the 5-Choice Serial Reaction Time Task (5-CSRTT) under both low and high attentional load. Under high attentional load, dFPN exhibited a pronounced state shift that corresponded with behavioral changes in the animal. Prior to the onset of the target stimulus, animals transitioned from a stationary state, characterized by frontal theta oscillations and dFPN theta connectivity, to an active exploration state associated with sensory processing. This shift was indexed by a suppression of inhibitory alpha oscillations and an increase in excitatory theta and gamma oscillations in parietal cortex. We further show that dFPN theta connectivity predicts performance fluctuations under high attentional load. Together, these results suggest that behavioral strategies for maintaining SA are tightly linked to neuronal state dynamics in the dFPN. Importantly, these findings identify rhythmic synchronization within the FPN as a potential neural target for novel therapeutic strategies for disrupted attention.

持续注意力（SA）对于长期保持注意力至关重要，其中断与各种神经和精神疾病有关。背侧额顶叶网络（dFPN）的振荡动力学和功能连通性在SA中至关重要。然而，控制SA水平的神经元机制，特别是对高度注意需求的反应，仍然知之甚少。为了研究节奏同步在SA dFPN中的作用，我们记录了在低注意负荷和高注意负荷下执行5-Choice系列反应时间任务（5-CSRTT）的雪貂的局部场电位和单单元活动。在高注意力负荷下，dFPN表现出明显的状态转移，这与动物的行为变化相对应。在目标刺激开始之前，动物从以额叶θ波振荡和dFPN θ波连接为特征的静止状态过渡到与感觉加工相关的主动探索状态。这种转变是通过抑制抑制性α振荡和增加顶叶皮层的兴奋性θ和γ振荡来指示的。我们进一步表明，dFPN theta连接可以预测高注意力负荷下的性能波动。总之，这些结果表明维持SA的行为策略与dFPN中的神经元状态动力学密切相关。重要的是，这些发现确定了FPN内的节律同步是注意力中断的新治疗策略的潜在神经靶点。

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引用次数: 0

Awake reactivation of cortical memory traces predicts subsequent memory retrieval 清醒时皮层记忆痕迹的再激活预示着随后的记忆提取。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-15 DOI: 10.1016/j.pneurobio.2025.102778

Wei Duan , Pingping Lu , Zhansheng Xu , Jing Wang , Yue Lu , Mengyang Wang , Ken A. Paller , Nikolai Axmacher , Liang Wang

Brief periods of rest after learning facilitate consolidation of new memories. Memory reactivation and hippocampal-cortical dialogue have been proposed as candidate mechanisms supporting consolidation. However, the study of these mechanisms has mostly concerned sleep-based consolidation. Whether and how awake reactivation can selectively consolidate cortical memory traces to guide subsequent behavior requires more human electrophysiological evidence. This study addressed these issues by utilizing intracranial electroencephalography (iEEG) recordings from 11 patients with drug-resistant epilepsy, who learned a set of object-location associations. Using representational similarity analysis, we found that, among the multiple cortical memory traces of object-location associations for the same object generated through several rounds of learning, the association corresponding to memory traces with stronger cortical activation during wakeful rest was more likely to be retrieved later. Awake reactivation of cortical memory trace was accompanied by increased hippocampal ripple rates and enhanced theta-band hippocampal-cortical communication, with hippocampal interactions with cortical regions within the default mode network preceding cortical reactivation. Together, these results suggest that awake reactivation of cortical memory trace during post-learning rest supports memory consolidation, predicting subsequent recall.

学习后短暂的休息有助于巩固新记忆。记忆再激活和海马体-皮层对话被认为是支持巩固的候选机制。然而，对这些机制的研究主要涉及基于睡眠的巩固。清醒再激活是否以及如何选择性地巩固皮层记忆痕迹以指导后续行为需要更多的人类电生理证据。本研究通过利用11例耐药癫痫患者的颅内脑电图（iEEG）记录来解决这些问题，这些患者学习了一组物体定位关联。通过表征相似性分析，我们发现，在通过多轮学习产生的对同一物体的物体定位关联的多个皮层记忆痕迹中，在清醒休息时皮层激活较强的记忆痕迹对应的关联更有可能在随后被检索。皮层记忆痕迹的清醒再激活伴随着海马纹波率的增加和海马-皮层通讯的增强，在皮层再激活之前，海马与默认模式网络内的皮层区域相互作用。总之，这些结果表明，在学习后休息期间皮层记忆痕迹的清醒再激活支持记忆巩固，预测随后的回忆。

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引用次数: 0

Neural dynamics encoding risky choices during deliberation reveal separate choice subspaces 在审议过程中编码风险选择的神经动力学揭示了单独的选择子空间。

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-07 DOI: 10.1016/j.pneurobio.2025.102776

Logan M. Peters , Alec Roadarmel , Jacqueline A. Overton , Matthew P. Stickle , Zhaodon Kong , Ignacio Saez , Karen Anne Moxon

Human decision-making involves the coordinated activity of multiple brain areas, acting in concert, to enable humans to make choices. Most decisions are carried out under conditions of uncertainty, where the desired outcome may not be achieved if the wrong decision is made. In these cases, humans deliberate before making a choice. The neural dynamics underlying deliberation are unknown and intracranial recordings in clinical settings present a unique opportunity to record high temporal resolution electrophysiological data from many (hundreds) brain locations during behavior. Combined with dynamic systems modeling, these allow identification of latent brain states that describe the neural dynamics during decision-making, providing insight into these neural dynamics and computations. Results show that the neural dynamics underlying risky decisions, but not decisions without risk, converge to separate subspaces depending on the subject’s preferred choice and that the degree of overlap between these subspaces declines as choice approaches, suggesting a network level representation of evidence accumulation. These results bridge the gap between regression analyses and data driven models of latent states and suggest that during risky decisions, deliberation and evidence accumulation toward a final decision are represented by the same neural dynamics, providing novel insights into the neural computations underlying human choice.

人类的决策涉及多个大脑区域的协调活动，协同行动，使人类能够做出选择。大多数决策都是在不确定的情况下进行的，如果做出错误的决策，预期的结果可能无法实现。在这些情况下，人类在做出选择之前会深思熟虑。思考背后的神经动力学是未知的，在临床环境下的颅内记录提供了一个独特的机会，可以记录行为过程中来自许多（数百个）大脑位置的高时间分辨率电生理数据。与动态系统建模相结合，可以识别决策过程中描述神经动力学的潜在大脑状态，从而深入了解这些神经动力学和计算。结果表明，基于风险决策（而非无风险决策）的神经动力学根据受试者的偏好收敛到独立的子空间，并且这些子空间之间的重叠程度随着选择的接近而下降，表明证据积累的网络级表示。这些结果弥合了回归分析和潜在状态数据驱动模型之间的差距，并表明在风险决策过程中，深思熟虑和最终决策的证据积累由相同的神经动力学表示，为人类选择背后的神经计算提供了新的见解。

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引用次数: 0

Bidirectional control of generalized absence epilepsy networks via real-time direct depolarization of thalamocortical neurons 通过丘脑皮质神经元实时直接去极化双向控制广泛性缺失癫痫网络。

IF 6.1 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-06 DOI: 10.1016/j.pneurobio.2025.102774

Tatiana P. Morais , Hannah L. Taylor , Olivér Nagy , Ferenc Mátyás , Francois David , Vincenzo Crunelli , Magor L. Lőrincz

Absence seizures (ASs), characterized by bilateral spike-and-wave discharges (SWDs), are a hallmark of idiopathic generalized epilepsies. We investigated the role of thalamocortical (TC) neurons in the generation and termination of ASs using optogenetic techniques in freely behaving GAERS rats, a well-established AS model. We demonstrate that direct depolarization of ChR2-transfected TC neurons in the ventrobasal thalamic nuclei during quiet wakefulness (QW) reliably elicits ethosuximide-sensitive ASs that have similar duration and frequency to those of spontaneous ASs, while showing little and no effect during active wakefulness (AW) and slow wave sleep (SWS), respectively. Light-stimulation of TC neurons fails to elicit ASs during AW, QW and SWS in non-epileptic control (NEC) rats, whereas it could evoke short ASs in Wistar rats, prevalently during QW. Notably, brief light stimulation effectively halted ongoing spontaneous ASs in GAERS rats (i.e. both SWDs and immobility), immediately altering thalamic multi-unit activity from rhythmic to irregular firing, irrespective of the SWD phase at which it was delivered. These findings support the view that the excitability of cortico-thalamic-cortical network is highly behavioural state-dependent, with increased susceptibility to the induction of ASs during QW, thus questioning the necessity of low-threshold burst firing of TC neurons in the generation of these seizures. Moreover, they highlight the dual control of ASs by TC neurons, underscoring their potential as therapeutic targets for AS modulation.

以双侧峰波放电（SWDs）为特征的失神性癫痫（ASs）是特发性全身性癫痫的一个标志。我们利用光遗传学技术在自由行为的GAERS大鼠（一种成熟的AS模型）中研究了丘脑皮质（TC）神经元在AS的产生和终止中的作用。我们证明，在安静清醒（QW）期间，腹基底丘脑核中chr2转染的TC神经元的直接去极化可靠地引发了与自发asa相似的持续时间和频率的乙氧亚胺敏感asa，而在活跃清醒（AW）和慢波睡眠（SWS）期间分别显示很少或没有影响。在非癫痫对照（NEC）大鼠中，光刺激TC神经元在AW、QW和SWS期间不能诱发ASs，而在Wistar大鼠中，光刺激可以诱发短ASs，主要在QW期间。值得注意的是，短暂的光刺激有效地阻止了GAERS大鼠（即SWD和静止）正在进行的自发性ASs，立即改变丘脑多单位活动，从有节奏的到不规则的放电，而不管它是在哪个SWD阶段传递的。这些发现支持了以下观点，即皮质-丘脑-皮质网络的兴奋性是高度依赖行为状态的，在QW期间对诱导ASs的易感性增加，因此质疑TC神经元在这些癫痫发作的产生中是否需要低阈值爆发放电。此外，他们强调了TC神经元对as的双重控制，强调了它们作为as调节的治疗靶点的潜力。

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引用次数: 0

Temporal impact of sepsis on Alzheimer's disease pathology and neuroinflammation 脓毒症对阿尔茨海默病病理和神经炎症的时间影响

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-03 DOI: 10.1016/j.pneurobio.2025.102775

Quan Vo , Dina C. Nacionales , Karen N. McFarland , Carmelina Gorski , Evan L. Barrios , Gwoncheol Park , Lyle L. Moldawer , Gemma Casadesus , Ravinder Nagpal , Philip A. Efron , Paramita Chakrabarty

Epidemiological evidence has revealed an associative link between sepsis survivorship and increased risk of dementia, particularly Alzheimer's disease (AD). Paradoxically, population studies show females are less susceptible to sepsis but more vulnerable to post-sepsis dementia. Here, we examined the temporal impacts of sepsis in the context of AD by using an AD-amyloidosis model (TgCRND8) and their wild-type littermates and assessing outcomes at 7 days and 3 months post-sepsis in male and female mice. Following 7-days recovery, the microglia and astrocytes in AD-model mice were largely refractile to the systemic immune stimuli. Notably, the female AD-model mice accumulated higher hippocampal amyloid-beta (Aβ) burden and upregulated AD-type transcriptomic signature at this time. On the other hand, male AD-model mice showed no Aβ changes. At this time, the wild-type post-septic males, but not females, displayed robust astrocytosis, with nominal microgliosis. By 3 months post-sepsis, microgliosis was specifically elevated in wild-type females, indicating a prolonged central immune response. At this time, both male and female AD-model mice showed exacerbated Aβ and anxiety indices. Gene network analysis revealed a stronger immune response in females, while the male response was linked to estrogen receptor (ESR) signaling, with ERα protein upregulated in the brains of post-septic AD-model males. Together, our data highlights a sex-dimorphic temporal response in post-sepsis neuroinflammation, with ESR signaling playing a key role in males, while Aβ burden is affected similarly in both males and females.

流行病学证据显示败血症存活与痴呆风险增加之间存在关联，尤其是阿尔茨海默病（AD）。矛盾的是，人口研究表明，女性不太容易患败血症，但更容易患败血症后痴呆。在这里，我们通过使用AD-淀粉样变模型（TgCRND8）和它们的野生型窝代，研究了败血症在AD背景下的时间影响，并评估了雄性和雌性小鼠败血症后7天和3个月的结果。恢复7天后，ad模型小鼠的小胶质细胞和星形胶质细胞对全身免疫刺激有很大的折射性。值得注意的是，雌性ad模型小鼠此时积累了更高的海马淀粉样蛋白- β (Aβ)负担和上调的ad型转录组特征。另一方面，雄性ad模型小鼠未见Aβ变化。此时，野生型感染后的雄性，而不是雌性，表现出强大的星形细胞增生，并伴有名义上的小胶质细胞增生。脓毒症后3个月，野生型女性的小胶质瘤特异性升高，表明中枢免疫反应延长。此时，雄性和雌性ad模型小鼠的Aβ和焦虑指数均升高。基因网络分析显示，雌性的免疫反应更强，而雄性的反应与雌激素受体（ESR）信号有关，在败血性ad模型雄性的大脑中，ERα蛋白上调。总之，我们的数据强调了脓毒症后神经炎症中的性别二态时间反应，ESR信号在男性中起关键作用，而a β负荷在男性和女性中都受到相似的影响。

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引用次数: 0

EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2 MDGA2负向调节EphB2受体酪氨酸激酶介导的兴奋性突触功能

IF 6.7 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology

Pub Date : 2025-05-01 DOI: 10.1016/j.pneurobio.2025.102772

Hyeonho Kim , Younghyeon Jeon , Seunghye Kim , Yuxuan Guo , Dongwook Kim , Gyubin Jang , Julia Brasch , Ji Won Um , Jaewon Ko

MDGA2 is an excitatory synapse-specific suppressor that uses distinct extracellular mechanisms to negatively regulate various postsynaptic properties. Here, we identify EphB2, an excitatory synapse-specific receptor tyrosine kinase, as a new binding partner for MDGA2. The first three immunoglobulin domains of MDGA2 undergo cis-binding to the ligand-binding domain of EphB2, enabling MDGA2 to compete with Ephrin-B1 for binding to EphB2. Moreover, EphB2 forms complexes with MDGA2 and GluN2B-containing NMDA receptors (NMDARs) in mouse brains. MDGA2 deletion promotes formation of the EphB2/Ephrin-B1 complex but does not alter the surface expression levels and Ephrin-stimulated activation of EphB2 receptors and downstream GluN2B-containing NMDARs in cultured neurons. AlphaFold-based molecular replacement experiments reveal that MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated, but not AMPAR-mediated, postsynaptic responses at excitatory synapses in cultured neurons. These results collectively suggest that MDGA2 is a versatile factor that suppresses distinct excitatory postsynaptic properties via different transsynaptic pathways.

MDGA2是一种兴奋性突触特异性抑制因子，使用不同的细胞外机制负性调节各种突触后特性。在这里，我们发现EphB2，一种兴奋性突触特异性受体酪氨酸激酶，作为MDGA2的新结合伙伴。MDGA2的前三个免疫球蛋白域与EphB2的配体结合域进行顺式结合，使MDGA2与Ephrin-B1竞争EphB2的结合。此外，EphB2在小鼠脑内与含有MDGA2和glun2b的NMDA受体（NMDARs）形成复合物。MDGA2缺失促进EphB2/Ephrin-B1复合物的形成，但不改变培养神经元中EphB2受体的表面表达水平和ephrin刺激的EphB2受体和下游含glun2b的NMDARs的激活。基于alphafold的分子替代实验表明，MDGA2必须结合EphB2才能抑制神经元兴奋性突触的自发突触传递和nmdar介导的突触后反应，而不是ampar介导的突触后反应。这些结果共同表明MDGA2是一个多用途因子，通过不同的跨突触途径抑制不同的兴奋性突触后特性。

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