Understanding the nose–brain axis and its role in related diseases: A conceptual review

了解鼻脑轴及其在相关疾病中的作用: 概念综述

The nose-brain axis (NBA), a critical component of the body-brain axis, not only serves as a drug transport route for the treatment of brain diseases but also mediates changes such as neuroimmune disorders, which may be an important mechanism in the occurrence and development of some nasal or brain diseases. Despite its importance, there are substantial gaps that remain in our understanding of the characteristics of NBA-mediated diseases and of the cellular and molecular mechanisms underlying the bidirectional NBA crosstalk. These gaps have limited the translational application of NBA-related research findings to some extent. Therefore, this review aims to address the conceptual framework of NBA and highlight its values in representative diseases by combining existing literature with new research results from our group. We hope that this paper will provide a basis for further in-depth research in this field, and facilitate the clinical translation of NBA.

鼻-脑轴 (NBA) 是身体-脑轴的重要组成部分，不仅可以作为治疗脑部疾病的药物转运途径，还可以介导神经免疫紊乱等变化，这可能是某些鼻或脑部疾病发生和发展的重要机制。尽管它很重要，但我们对NBA介导的疾病的特征以及双向NBA串扰背后的细胞和分子机制的理解仍然存在很大的差距。这些差距在一定程度上限制了NBA相关研究成果的转化应用。因此，本综述旨在解决NBA的概念框架，并通过将现有文献与我们小组的新研究结果相结合，突出其在代表性疾病中的价值。希望本文能为该领域的进一步深入研究提供依据，为NBA的临床翻译提供帮助。

REF: Mou YK, Song XY, Wang HR, et al. Understanding the nose-brain axis and its role in related diseases: A conceptual review. Neurobiol Dis. 2024;202:106690. doi:10.1016/j.nbd.2024.106690 PMID: 39389156

Endoplasmic reticulum stress: The underlying mechanism of chronic pain

内质网应激: 慢性疼痛的潜在机制

Chronic pain (CP) affects over 30 % of the global population, imposing significant financial burdens on individuals and society. However, existing treatments for CP offer limited efficacy and troublesome side effects, primarily owing to a lack of knowledge of its precise underlying mechanism. Pathological stimuli disrupt the intricate process of protein folding and endoplasmic reticulum (ER) homeostasis. This disruption leads to the accumulation of misfolded or unfolded proteins in the ER, generating a condition termed ER stress. Emerging data have indicated that ER stress, occurring in the peripheral and central nervous systems, contributes to the development and maintenance of CP. This review aimed to comprehensively explore the intersection of ER stress and CP within the lower and upper nervous systems and highlight the cell-specific contributions of the unfolded protein response in different CP types. We provide a comprehensive synthesis of evidence from animal models, examining neuronal and non-neuronal mechanisms and discuss the damaging ER stress-linked inflammation, autophagy, oxidative stress, and apoptosis, which collectively drive disease progression and contribute to a neurotoxic environment. However, the mechanisms through which ER stress influences the most advanced centre-of-pain projections in the brain remain unclear. Further investigation in this area is crucial to elucidate the relationship between ER stress and CP and facilitate the development of novel therapeutic drugs for this intractable dilemma.

慢性疼痛 (CP) 影响了全球30% 以上的人口，给个人和社会带来了巨大的经济负担。然而，现有的CP治疗提供有限的功效和麻烦的副作用，主要是由于缺乏对其精确的潜在机制的了解。病理刺激破坏蛋白质折叠和内质网 (ER) 稳态的复杂过程。这种破坏导致错误折叠或未折叠的蛋白质在ER中积累，产生称为ER应激的条件。新出现的数据表明，在外周和中枢神经系统中发生的ER应激有助于CP的发展和维持。这篇综述旨在全面探讨ER应力和CP在上下神经系统中的交集，并强调不同CP类型中未折叠蛋白反应的细胞特异性贡献。我们提供了来自动物模型的全面综合证据，检查了神经元和非神经元机制，并讨论了损伤性ER应激相关的炎症，自噬，氧化应激和细胞凋亡，它们共同驱动疾病进展并导致神经毒性环境。然而，ER应激影响大脑中最先进的疼痛中心投射的机制仍不清楚。该领域的进一步研究对于阐明ER应激与CP之间的关系以及促进针对这一棘手难题的新型治疗药物的开发至关重要。

REF: Liu T, Ji X, Zang H, et al. Endoplasmic reticulum stress: The underlying mechanism of chronic pain. Neurobiol Dis. 2024;202:106697. doi:10.1016/j.nbd.2024.106697 PMID: 39389155

The role of microglia in neurological diseases with involvement of extracellular vesicles

小胶质细胞参与细胞外囊泡在神经系统疾病中的作用

As a subset of mononuclear phagocytes in the central nervous system, microglia play a crucial role in immune defense and homeostasis maintenance. Microglia can regulate their states in response to specific signals of health and pathology. Microglia-mediated neuroinflammation is a pathological hallmark of neurodegenerative diseases, neurological damage and neurological tumors, underscoring its key immunoregulatory role in these conditions. Intriguingly, a substantial body of research has indicated that extracellular vesicles can mediate intercellular communication by transporting cargoes from parental cells, a property that is also reflected in microenvironmental signaling networks involving microglia. Based on the microglial characteristics, we briefly outline the biological features of extracellular vesicles and focus on summarizing the integrative role played by microglia in the maintenance of nervous system homeostasis and progression of different neurological diseases. Extracellular vesicles may engage in the homeostasis maintenance and pathological process as a medium of intercellular communication. Here, we aim to provide new insights for further exploration of neurological disease pathogenesis, which may provide theoretical foundations for cell-free therapies.

小胶质细胞作为中枢神经系统单核吞噬细胞的一个亚群，在免疫防御和稳态维持中起着至关重要的作用。小胶质细胞可以调节其状态以响应特定的健康和病理信号。小胶质细胞介导的神经炎症是神经退行性疾病，神经系统损伤和神经系统肿瘤的病理标志，强调了其在这些疾病中的关键免疫调节作用。有趣的是，大量研究表明，细胞外囊泡可以通过从亲本细胞运输货物来介导细胞间通讯，这一特性也反映在涉及小胶质细胞的微环境信号网络中。基于小胶质细胞的特性，我们简要概述了细胞外囊泡的生物学特征，并着重总结了小胶质细胞在维持神经系统稳态和不同神经系统疾病进展中所发挥的整合作用。细胞外囊泡可能作为细胞间通讯的媒介参与体内平衡的维持和病理过程。在这里，我们旨在为进一步探索神经系统疾病的发病机制提供新的见解，这可能为无细胞疗法提供理论基础。

REF: Xie H, Wu F, Mao J, et al. The role of microglia in neurological diseases with involvement of extracellular vesicles. Neurobiol Dis. 2024;202:106700. doi:10.1016/j.nbd.2024.106700 PMID: 39401551

Diagnostic and mechanistic roles of MicroRNAs in neurodevelopmental & neurodegenerative disorders

MicroRNAs在神经发育和神经退行性疾病中的诊断和机制作用

MicroRNAs (miRNAs) are emerging as crucial elements in the regulation of gene expression, playing a significant role in the underlying neurobiology of a wide range of neuropsychiatric disorders. This review examines the intricate involvement of miRNAs in neuropsychiatric disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Fragile X syndrome (FXS), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), schizophrenia (SCZ), and mood disorders. This review highlights how miRNA dysregulation can illuminate the molecular pathways of these diseases and potentially serve as biomarkers for early diagnosis and prognosis. Specifically, miRNAs' ability to target genes critical to the pathology of neurodegenerative diseases, their role in the development of trinucleotide repeat and neurodevelopmental disorders, and their distinctive patterns in SCZ and mood disorders are discussed. The review also stresses the value of miRNAs in precision neuropsychiatry, where they could predict treatment outcomes and aid in disease management. Furthermore, the study of conserved miRNAs in model organisms like Drosophila underscores their broad utility and provides deeper mechanistic insights into their biological functions. This comprehensive examination of miRNAs across various conditions advocates for their integration into clinical practice, promising advancements in personalized healthcare for neurological and psychiatric conditions.

MicroRNAs (miRNAs) 正在成为基因表达调控中的关键元件，在广泛的神经精神疾病的潜在神经生物学中起着重要作用。这篇综述探讨了miRNAs在神经精神疾病中的复杂参与，如阿尔茨海默病 (AD)，帕金森病 (PD)，亨廷顿病 (HD)，脆性X综合征 (FXS)，自闭症谱系障碍 (ASD)，注意缺陷多动障碍 (ADHD)，抽动秽语综合征 (TS)，精神分裂症 (SCZ) 和情绪障碍。这篇综述强调了miRNA失调如何阐明这些疾病的分子途径，并可能作为早期诊断和预后的生物标志物。具体来说，讨论了mirna靶向对神经退行性疾病的病理学至关重要的基因的能力，它们在三核苷酸重复和神经发育障碍的发展中的作用，以及它们在SCZ和情绪障碍中的独特模式。该评论还强调了mirna在精确神经精神病学中的价值，它们可以预测治疗结果并有助于疾病管理。此外，对果蝇等模式生物中保守的mirna的研究强调了它们的广泛实用性，并为它们的生物学功能提供了更深入的机制见解。这种对各种条件下的mirna的全面检查提倡将其整合到临床实践中，有望在神经和精神疾病的个性化医疗保健方面取得进展。

REF: Khoodoruth MAS, Khoodoruth WNC, Uroos M, Al-Abdulla M, Khan YS, Mohammad F. Diagnostic and mechanistic roles of MicroRNAs in neurodevelopmental & neurodegenerative disorders. Neurobiol Dis. 2024;202:106717. doi:10.1016/j.nbd.2024.106717 PMID: 39461569

The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases

cGAS-STING通路通过细胞和分子机制在神经退行性疾病中驱动神经炎症和神经变性

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies.

神经退行性疾病 (NDs) 是一种常见的慢性进行性疾病，其特征是对神经系统中特定细胞群的进行性损害，最终导致残疾或死亡。由于对涉及多种细胞和分子途径的发病机制的了解有限，仍然缺乏对这些疾病的有效治疗。免疫应答的触发是神经退行性疾病的常见特征。一个关键的挑战是神经炎症，神经变性和免疫反应之间复杂的相互作用，这些尚未完全表征。近年来，干扰素基因 (STING) 途径的环gmp-amp合酶 (cGAS)-刺激物 (细胞内DNA感应的关键免疫反应) 逐渐受到关注。然而，该途径在免疫细胞，神经胶质细胞和神经元细胞等细胞类型中的特定作用及其对ND发病机理的贡献仍未完全阐明。在这篇综述中，我们系统地探讨了cGAS-STING信号如何在NDs的背景下将各种细胞类型与相关的细胞效应通路联系起来，以实现多方面的治疗方向。我们强调cgas-sting途径中条件依赖性细胞异质性的发现，这对于理解不同的细胞反应和潜在的治疗靶标是不可或缺的。此外，我们回顾了cgas-sting激活在帕金森氏病，共济失调-毛细血管扩张症和肌萎缩性侧索硬化症中的致病作用。我们专注于cgas-sting途径在阿尔茨海默氏病，亨廷顿氏病和多发性硬化症中的复杂双向作用，揭示了它们在疾病进展中的双刃性质。这篇综述的目的是阐明cgas-sting途径在ND发病机理中的关键作用，并为促进新治疗策略的发展提供新的见解。

REF: Zhang Y, Zou M, Wu H, Zhu J, Jin T. The cGAS-STING pathway drives neuroinflammation and neurodegeneration via cellular and molecular mechanisms in neurodegenerative diseases. Neurobiol Dis. 2024;202:106710. doi:10.1016/j.nbd.2024.106710 PMID: 39490400

A neural circuit from thalamic paraventricular nucleus via zona incerta to periaqueductal gray for the facilitation of neuropathic pain

从丘脑室旁核经不透明带到导水管周围灰质的神经回路，以促进神经性疼痛

Top-down projections transmit a series of signals encoding pain sensation to the ventrolateral periaqueductal gray (vlPAG), where they converge with various incoming projections to regulate pain. Clarifying the upstream regulatory hierarchy of vlPAG can enhance our understanding of the neural circuitry involved in pain modulation. Here, we show that a in a mouse model of spared nerve injury (SNI), activation of a circuit arising from posterior paraventricular thalamic nucleus CaMKIIα-positive neurons (PVPCaMKIIα) projects to gamma-aminobutyric acid neurons in the rostral zona incerta (ZIrGABA) to facilitate the development of pain hypersensitivity behaviors. In turn, these ZIrGABA neurons project to CaMKIIα-positive neurons in the vlPAG (vlPAGCaMKIIα), a well-known neuronal population involved in pain descending modulation. In vivo calcium signal recording and whole-cell electrophysiological recordings reveal that the PVPCaMKIIα→ZIrGABA→vlPAGCaMKIIα circuit is activated in SNI models of persistent pain. Inhibition of this circuit using chemogenetics or optogenetics can alleviate the mechanical pain behaviors. Our study indicates that the PVPCaMKIIα→ZIrGABA→vlPAGCaMKIIα circuit is involved in the facilitation of neuropathic pain. This previously unrecognized circuit could be explored as a potential target for neuropathic pain treatment.

自上而下的投射将一系列编码疼痛感觉的信号传递到腹外侧导水管周围灰色 (vlPAG)，在那里它们与各种传入的投射会聚以调节疼痛。阐明vlPAG的上游调节层次结构可以增强我们对疼痛调节中涉及的神经回路的理解。在这里，我们显示了在幸免神经损伤 (SNI) 的小鼠模型中，由后脑室丘脑旁核camkii α 阳性神经元 (pvpcamkii α) 引起的回路激活投射到延髓带中的 γ-氨基丁酸神经元 (ZIrGABA) 以促进疼痛超敏行为的发展。反过来，这些ZIrGABA神经元投射到vlPAG (vlpagcamkiia) 中的camkiia阳性神经元，vlPAG是一种众所周知的参与疼痛下降调节的神经元群体。体内钙信号记录和全细胞电生理记录显示，在持续疼痛的SNI模型中，PVPCaMKIIα→ZIrGABA→vlPAGCaMKIIα 电路被激活。使用化学遗传学或光遗传学抑制该回路可以减轻机械疼痛行为。我们的研究表明，PVPCaMKIIα→ZIrGABA→vlPAGCaMKIIα 回路参与了神经性疼痛的促进。这种以前未被认识的回路可以作为神经性疼痛治疗的潜在靶标进行探索。

REF: Li D, Mai JW, Deng J, et al. A neural circuit from thalamic paraventricular nucleus via zona incerta to periaqueductal gray for the facilitation of neuropathic pain. Neurobiol Dis. 2024;202:106699. doi:10.1016/j.nbd.2024.106699 PMID: 39393611

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein

Α-突触核蛋白预先形成的原纤维小鼠模型中的神经病理学独立于帕金森氏病相关的溶酶体ATP13A2蛋白而发生

Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinson's disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra pars compacta (SNc). Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate α-synuclein (α-syn) secretion via exosomes. However, the relationship between ATP13A2 and α-syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating α-syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of α-syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of α-syn pathology. In this study we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse α-syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, spread and extent of α-syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by α-syn PFFs in WT and KO mice but was already significantly higher in ATP13A2 KO mice due to pre-existing reactive gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by α-syn PFFs in WT or KO mice. Although α-syn PFFs induce an increase in lysosomal number in the SNc in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of genotype. Our study evaluating the spread of α-syn pathology reveals no exacerbation of α-syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in α-syn clearance or propagation in vivo.

ATP13A2 (PARK9) 基因的功能缺失突变与早发性常染色体隐性遗传帕金森病 (PD) 和其他神经退行性疾病有关。ATP13A2编码溶酶体跨膜P5B-type atp酶，该酶在脑中高度表达，特别是在黑质致密部 (SNc) 中。尽管其对PD相关病理学的贡献尚不清楚，但最近的研究表明其作为溶酶体多胺转运蛋白的正常作用。细胞研究报告ATP13A2可以通过外来体调节 α-突触核蛋白 (α-syn) 分泌。然而，动物模型中ATP13A2和 α-syn之间的关系仍然不确定。ATP13A2敲除 (KO) 小鼠表现出溶酶体异常和反应性星形胶质细胞增生，但不发展PD相关的神经病理学。在缺乏ATP13A2的小鼠中操纵 α-syn水平的研究表明对病理学的影响最小。将 α-syn预制原纤维 (pff) 递送到小鼠纹状体中是研究 α-syn病理学的发展和传播的明确定义的模型。在这项研究中，我们在纹状体中向野生型 (WT) 和纯合atp13a2ko小鼠单侧注射小鼠 α-synpffs，并在6个月后评估小鼠的神经病理学。小鼠大脑多个区域中 α-syn聚集的分布，扩散和程度在很大程度上与ATP13A2表达无关。在WT和ATP13A2 KO小鼠中，PFFs诱导的黑质纹状体途径多巴胺能神经元及其神经末梢的损失是相等的。在WT和KO小鼠中，α-syn PFFs等效地诱导了反应性星形胶质细胞增生，但由于预先存在反应性胶质细胞增生，在ATP13A2 KO小鼠中已经明显更高。我们没有在WT或KO小鼠中发现 α-syn PFFs诱导的不对称运动障碍，小胶质细胞激活或轴突损伤。尽管 α-syn PFFs通常会诱导SNc中溶酶体数量的增加，但无论基因型如何，TH阳性的多巴胺能神经元均未表现出溶酶体面积或强度的增加。我们的评估 α-syn病理学传播的研究表明，ATP13A2 KO小鼠中 α-syn病理学，神经元丢失，星形胶质细胞增生或运动缺陷没有恶化，这表明由ATP13A2丢失引起的选择性溶酶体异常在体内 α-syn清除或传播中没有主要作用。

REF: Massari CM, Dues DJ, Bergsma A, et al. Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein. Neurobiol Dis. 2024;202:106701. doi:10.1016/j.nbd.2024.106701 PMID: 39406291

α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice

Α-突触核蛋白聚集降低皮质-杏仁核连通性并损害小鼠的社交行为

Abnormal accumulation of insoluble α-synuclein (α-Syn) inclusions in neurons, neurites, and glial cells is the defining neuropathology of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Accumulation of α-Syn inclusions in the amygdala has been well-documented in post-mortem studies of PD and DLB brains, as well as preclinical animal models of these conditions. Though α-Syn pathology is closely associated with neurodegeneration, there is a poor correlation between neuronal loss in the amygdala and the clinical features of PD and DLB. Moreover, functional interaction between the cerebral cortex and the amygdala is critical to regulating emotion, motivation, and social behaviors. The cortico-amygdala functional interaction is likely to be disrupted by the development of α-Syn pathology in the brain. Thus, we hypothesize that neuronal α-Syn inclusions disrupt cortical modulation of the amygdala circuits and are sufficient to drive social behavioral deficits. In the present work, we designed a series of longitudinal studies to rigorously measure the time courses of neurodegeneration, functional impairment of cortico-amygdala connectivity, and development of amygdala-dependent social behavioral deficits to test this hypothesis. We injected α-Syn preformed fibrils (PFFs) into the dorsal striatum to induce α-Syn aggregation in the amygdala and the medial prefrontal cortex (mPFC) of C57BL6 mice of both sexes, followed by a detailed analysis of temporal development of α-Syn pathology, synaptic deficits, and neuronal loss in the amygdala, as well as behavioral deficits at 3-12 months post injections. Development of α-Syn inclusions caused losses of cortical axon terminals and cell death in the basolateral amygdala (BLA) at 6- and 12-months post injections, respectively. At a relatively early stage of 3 months post injections, the connection strength of the mPFC-BLA synapse was decreased in PFFs-injection mice compared to controls. Meanwhile, the PFFs-injected mice showed impaired social interaction behavior, which was rescued by chemogenetic stimulation of mPFC-BLA connections. Altogether, we presented a series of evidence to delineate circuit events in the amygdala associated with the accumulation of α-Syn inclusions in the mouse brain, highlighting that functional impairment of the amygdala is sufficient to cause social behavior deficits. The present work further suggests that early circuit modulation could be an effective approach to alleviate symptoms associated with α-Syn pathology, necessitating studies of functional consequences of α-Syn aggregation.

神经元，神经突和神经胶质细胞中不溶性 α-突触核蛋白 (α-syn) 包涵体的异常积累是突触核蛋白病的定义神经病理学，包括帕金森氏病 (PD)，路易体痴呆 (DLB) 和多系统萎缩。在PD和DLB大脑的验尸研究以及这些病症的临床前动物模型中，已经充分证明了杏仁核中 α-syn内含物的积累。尽管 α-syn病理学与神经变性密切相关，但杏仁核中的神经元丢失与PD和DLB的临床特征之间的相关性较差。此外，大脑皮层和杏仁核之间的功能性相互作用对于调节情绪，动机和社交行为至关重要。皮质-杏仁核功能相互作用可能会被大脑中 α-syn病理学的发展所破坏。因此，我们假设神经元 α-syn内含物会破坏杏仁核回路的皮质调节，并足以驱动社交行为缺陷。在目前的工作中，我们设计了一系列纵向研究，以严格测量神经变性的时间过程，皮质-杏仁核连接的功能障碍以及依赖杏仁核的社会行为缺陷的发展，以检验这一假设。我们将 α-syn预制原纤维 (PFFs) 注射到背侧纹状体中，以诱导两性C57BL6小鼠的杏仁核和内侧前额叶皮层 (mPFC) 中的 α-syn聚集，然后详细分析 α-syn病理学的时间发展，突触缺陷，杏仁核的神经元丢失，以及注射后3-12个月的行为缺陷。注射后6个月和12个月，α-syn内含物的发展分别导致皮质轴突末端的丢失和基底外侧杏仁核 (BLA) 的细胞死亡。在注射后3个月的相对早期，与对照相比，PFFs注射小鼠中mpfc-bla突触的连接强度降低。同时，注射PFFs的小鼠显示出受损的社交互动行为，这是通过mpfc-bla连接的化学遗传刺激而挽救的。总而言之，我们提供了一系列证据来描述杏仁核中与小鼠大脑中 α-syn内含物积累相关的电路事件，强调杏仁核的功能障碍足以引起社会行为缺陷。目前的工作进一步表明，早期电路调节可能是缓解与 α-syn病理相关的症状的有效方法，因此有必要研究 α-syn聚集的功能后果。

REF: Zhou W, Daniels S, Singh V, Menard M, Escobar Galvis ML, Chu HY. α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice. Neurobiol Dis. 2024;202:106702. doi:10.1016/j.nbd.2024.106702 PMID: 39406290

Altered cortical functional networks in Wilson's Disease: A resting-state electroencephalogram study

威尔逊氏病的皮质功能网络改变: 静息态脑电图研究

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD.

神经精神症状在Wilson病 (WD) 患者中很常见。然而，相关的功能性脑网络仍不清楚。在这项研究中，实施了基于源定位的闭眼静息态脑电图 (EEG) 的功能连接分析，以评估17名患有神经系统疾病的WD患者和17名健康对照 (HCs) 的功能网络特征。随后在五个不同频带的源空间中计算加权相位滞后指数 (wPLI)，并将得到的连通性矩阵转化为加权图，其结构由五个图形分析指标测量，最终与临床评分相关。与HCs相比，WD患者在 δ，θ 和 α 带中显示出断开的子网络。此外，WD患者在所有五个频带中均表现出显着降低的全局聚类系数和小世界性。在WD组中，神经系统症状和脑结构异常的严重程度与功能网络的破坏显着相关。总之，我们的研究表明，WD的功能网络缺陷可以反映其神经系统症状和结构性脑异常的严重程度。静息态脑电图可作为WD脑损伤的标志物。

REF: Chen RK, Zhang C, Lin JW, et al. Altered cortical functional networks in Wilson's Disease: A resting-state electroencephalogram study. Neurobiol Dis. 2024;202:106692. doi:10.1016/j.nbd.2024.106692 PMID: 39370050