Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy

肠-脑轴在脓毒症相关性脑病发病机制中的作用

The gut-brain axis is a bidirectional communication network linking the gut and the brain, overseeing digestive functions, emotional responses, body immunity, brain development, and overall health. Substantial research highlights a connection between disruptions of the gut-brain axis and various psychiatric and neurological conditions, including depression and Alzheimer's disease. Given the impact of the gut-brain axis on behavior, cognition, and brain diseases, some studies have started to pay attention to the role of the axis in sepsis-associated encephalopathy (SAE), where cognitive impairment is the primary manifestation. SAE emerges as the primary and earliest form of organ dysfunction following sepsis, potentially leading to acute cognitive impairment and long-term cognitive decline in patients. Notably, the neuronal damage in SAE does not stem directly from the central nervous system (CNS) infection but rather from an infection occurring outside the brain. The gut-brain axis is posited as a pivotal factor in this process. This review will delve into the gut-brain axis, exploring four crucial pathways through which inflammatory signals are transmitted and elevate the incidence of SAE. These pathways encompass the vagus nerve pathway, the neuroendocrine pathway involving the hypothalamic-pituitary-adrenal (HPA) axis and serotonin (5-HT) regulation, the neuroimmune pathway, and the microbial regulation. These pathways can operate independently or collaboratively on the CNS to modulate brain activity. Understanding how the gut affects and regulates the CNS could offer the potential to identify novel targets for preventing and treating this condition, ultimately enhancing the prognosis for individuals with SAE.

肠-脑轴是连接肠和大脑的双向通信网络，监督消化功能、情绪反应、身体免疫力、大脑发育和整体健康。大量研究强调了肠脑轴的破坏与各种精神和神经疾病之间的联系，包括抑郁症和阿尔茨海默病。鉴于肠-脑轴对行为，认知和脑部疾病的影响，一些研究已经开始关注该轴在脓毒症相关性脑病 (SAE) 中的作用，其中认知障碍是主要表现。SAE是脓毒症后器官功能障碍的主要和最早形式，可能导致患者急性认知功能障碍和长期认知功能下降。值得注意的是，SAE中的神经元损伤不是直接源于中枢神经系统 (CNS) 感染，而是源于脑外发生的感染。肠-脑轴被认为是这一过程中的关键因素。这篇综述将深入研究肠-脑轴，探索炎症信号传递和提高SAE发生率的四个关键途径。这些途径包括迷走神经途径，涉及下丘脑-垂体-肾上腺 (HPA) 轴和5-羟色胺 (5-HT) 调节的神经内分泌途径，神经免疫途径和微生物调节。这些途径可以在CNS上独立地或协作地操作以调节大脑活动。了解肠道如何影响和调节中枢神经系统，可以为确定预防和治疗这种疾病的新目标提供潜力，最终改善SAE患者的预后。

REF: Wang X, Wen X, Yuan S, Zhang J. Gut-brain axis in the pathogenesis of sepsis-associated encephalopathy. Neurobiol Dis. 2024;195:106499. doi:10.1016/j.nbd.2024.106499 PMID: 38588753

Disrupted autonomic pathways in spinal cord injury: Implications for the immune regulation

脊髓损伤中自主神经通路的破坏: 对免疫调节的影响

Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.

脊髓损伤 (SCI) 破坏了负责调节免疫功能的关键自主神经通路。因此，患有SCI的个体通常表现出一系列免疫功能障碍，范围从破坏性促炎反应的发展到严重的免疫抑制。因此，必须更全面地了解SCI诱导的自主神经功能障碍影响免疫反应的程度和机制。在这篇综述中，我们概述了自主神经系统 (ANS) 的解剖组织和生理学，阐明了SCI如何影响其功能，特别关注淋巴器官和免疫活性。我们重点介绍了在理解SCI后的椎管内可塑性如何导致淋巴器官异常自主活动方面的最新进展。此外，我们讨论了这些神经元末端释放的交感介质如何影响免疫细胞功能。最后，我们讨论了针对ANS的新兴创新技术和潜在的临床干预措施，作为恢复SCI患者免疫反应正常调节的策略。

REF: Moura MM, Monteiro A, Salgado AJ, Silva NA, Monteiro S. Disrupted autonomic pathways in spinal cord injury: Implications for the immune regulation. Neurobiol Dis. 2024;195:106500. doi:10.1016/j.nbd.2024.106500 PMID: 38614275

Sex-specific vulnerabilities in human astrocytes underpin the differential impact of palmitic acid

人类星形胶质细胞中的性别特异性脆弱性是棕榈酸的不同影响的基础

Obesity and neurometabolic diseases have been linked to neurodegenerative diseases. Our hypothesis is that the endogenous estrogenic component of human astrocytes plays a critical role in cell response during lipotoxic damage, given that obesity can disrupt hormonal homeostasis and cause brain inflammation. Our findings showed that high concentrations of palmitic acid (PA) significantly reduced cell viability more in male astrocytes, indicating sex-specific vulnerabilities. PA induced a greater increase in cytosolic reactive oxygen species (ROS) production in males, while female astrocytes exhibited higher superoxide ion levels in mitochondria. In addition, female astrocytes treated with PA showed increased expression of antioxidant proteins, including catalase, Gpx-1 and Nrf2 suggesting a stronger cellular defence mechanism. Interestingly, there was a difference in the expression of estrogenic components, such as estrogen, androgens, and progesterone receptors, as well as aromatase and 5α-reductase enzymes, between males and females. PA induced their expression mainly in females, indicating a potential protective mechanism mediated by endogenous hormones. In summary, our findings highlight the impact of sex on the response of human astrocytes to lipotoxicity. Male astrocytes appear to be more susceptible to cellular damage when exposed to high concentrations of fatty acids.

肥胖和神经代谢疾病与神经退行性疾病有关。我们的假设是，人类星形胶质细胞的内源性雌激素成分在脂毒性损伤过程中的细胞反应中起着至关重要的作用，因为肥胖会破坏激素的稳态并引起脑部炎症。我们的发现表明，高浓度的棕榈酸 (PA) 显着降低了男性星形胶质细胞的细胞活力，表明性别特异性脆弱性。PA在雄性中诱导了胞质活性氧 (ROS) 产生的更大增加，而雌性星形胶质细胞在线粒体中表现出更高的超氧离子水平。此外，用PA处理的雌性星形胶质细胞显示抗氧化蛋白 (包括过氧化氢酶、Gpx-1和Nrf2) 的表达增加，表明更强的细胞防御机制。有趣的是，男性和女性之间的雌激素成分，例如雌激素，雄激素和孕激素受体，以及芳香酶和5 α-还原酶的表达存在差异。PA主要在雌性中诱导其表达，表明内源激素介导的潜在保护机制。总之，我们的发现强调了性别对人星形胶质细胞对脂毒性反应的影响。当暴露于高浓度的脂肪酸时，雄性星形胶质细胞似乎更容易受到细胞损伤。

REF: Hidalgo-Lanussa O, González Santos J, Barreto GE. Sex-specific vulnerabilities in human astrocytes underpin the differential impact of palmitic acid. Neurobiol Dis. 2024;195:106489. doi:10.1016/j.nbd.2024.106489 PMID: 38552721

Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease

帕金森病LRRK2 G2019S小鼠模型小胶质细胞多样性的研究

Microglia contribute to the outcomes of various pathological conditions including Parkinson's disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models. Here, we delved into the diversity of microglia in a preclinical PD model featuring the G2019S mutation in LRRK2, a known pathological mutation associated with PD. Specifically, we investigated the 'dark microglia' (DM) and the 'disease-associated microglia' (DAM) which present a selective enrichment of CLEC7A expression. In the dorsal striatum - a region affected by PD pathology - extensive ultrastructural features of cellular stress as well as reduced direct cellular contacts, were observed for microglia from old LRRK2 G2019S mice versus controls. In addition, DM were more prevalent while CLEC7A-positive microglia had extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Furthermore, our findings revealed a higher proportion of DM in LRRK2 G2019S mice, and an increased number of CLEC7A-positive cells with age, exacerbated by the pathological mutation. These CLEC7A-positive cells exhibited a selective enrichment of ameboid morphology and tended to cluster in the affected animals. In summary, we provide novel insights into the occurrence and features of recently defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.

小胶质细胞有助于各种病理状况的结果，包括帕金森病 (PD)。小胶质细胞是异质的，最近在衰老和神经退行性疾病模型中发现了多种状态。在这里，我们深入研究了临床前PD模型中小胶质细胞的多样性，该模型具有LRRK2中的G2019S突变，这是一种与PD相关的已知病理突变。具体来说，我们研究了 “暗小胶质细胞” (DM) 和 “疾病相关小胶质细胞” (DAM)，它们表现出CLEC7A表达的选择性富集。在背侧纹状体-受PD病理影响的区域-观察到老年LRRK2 G2019S小鼠与对照组的小胶质细胞具有广泛的细胞应激超微结构特征以及减少的直接细胞接触。此外，DM更为普遍，而CLEC7A-positive小胶质细胞在LRRK2 G2019S小鼠中具有广泛的吞噬超微结构特征。此外，我们的发现揭示了LRRK2 G2019S小鼠中DM的比例较高，并且随着年龄的增长，CLEC7A-positive细胞的数量增加，并因病理突变而加剧。这些CLEC7A-positive细胞表现出选择性富集的阿米虫形态，并倾向于在受影响的动物中聚集。总之，我们在LRRK2 G2019S PD病理学的背景下，对最近定义的小胶质细胞状态，CLEC7A-positive细胞和DM的发生和特征提供了新的见解。

REF: Iovino L, VanderZwaag J, Kaur G, et al. Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease. Neurobiol Dis. 2024;195:106481. doi:10.1016/j.nbd.2024.106481 PMID: 38527708

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata

人类丘脑底核和黑质网状物的听觉oddball反应

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

听觉古怪球是注意力、新颖性和感觉预测研究的中流砥柱。这项任务如何与丘脑底核和黑质网状皮层下结构结合尚不清楚。我们执行了听觉OB任务，同时记录了30例接受脑深部电刺激手术的帕金森氏病患者的丘脑底核和黑质网状组织的单个单位活动 (35个单位) 和局部场电位 (57个记录)。我们在两个区域都发现了音调调制和oddball调制单元。人口活动将两个地区的音调从200毫秒到1000毫秒的标准试验区分为oddball。在黑质中，随着古怪的音调，局部场电位中的 β 带活性降低。我们观察到的与怪异球相关的活动可能是注意力，感觉预测或意外引起的运动抑制的基础。

REF: Leavitt D, Alanazi FI, Al-Ozzi TM, et al. Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata. Neurobiol Dis. 2024;195:106490. doi:10.1016/j.nbd.2024.106490 PMID: 38561111

Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia

共济失调模型moonwalker小鼠的表型，基因型和病理学特征

We performed a comprehensive study of the morphological, functional, and genetic features of moonwalker (MWK) mice, a mouse model of spinocerebellar ataxia caused by a gain of function of the TRPC3 channel. These mice show numerous behavioral symptoms including tremor, altered gait, circling behavior, impaired motor coordination, impaired motor learning and decreased limb strength. Cerebellar pathology is characterized by early and almost complete loss of unipolar brush cells as well as slowly progressive, moderate loss of Purkinje cell (PCs). Structural damage also includes loss of synaptic contacts from parallel fibers, swollen ER structures, and degenerating axons. Interestingly, no obvious correlation was observed between PC loss and severity of the symptoms, as the phenotype stabilizes around 2 months of age, while the cerebellar pathology is progressive. This is probably due to the fact that PC function is severely impaired much earlier than the appearance of PC loss. Indeed, PC firing is already impaired in 3 weeks old mice. An interesting feature of the MWK pathology that still remains to be explained consists in a strong lobule selectivity of the PC loss, which is puzzling considering that TRPC is expressed in every PC. Intriguingly, genetic analysis of MWK cerebella shows, among other alterations, changes in the expression of both apoptosis inducing and resistance factors possibly suggesting that damaged PCs initiate specific cellular pathways that protect them from overt cell loss.

我们对moonwalker (MWK) 小鼠的形态，功能和遗传特征进行了全面研究，MWK小鼠是由TRPC3通道功能增强引起的脊髓小脑性共济失调的小鼠模型。这些小鼠表现出许多行为症状，包括震颤、步态改变、盘旋行为、运动协调受损、运动学习受损和肢体力量下降。小脑病理学的特征是单极刷细胞的早期和几乎完全丧失，以及浦肯野细胞 (PCs) 的缓慢进行性，中度丧失。结构损伤还包括来自平行纤维的突触接触的丧失、肿胀的ER结构和退化的轴突。有趣的是，在PC丧失和症状的严重程度之间没有观察到明显的相关性，因为表型在2个月左右稳定，而小脑病理是进行性的。这可能是由于PC功能比PC丢失的出现早得多而严重受损的事实。事实上，PC放电在3周龄的小鼠中已经受损。MWK病理学的一个有趣特征仍有待解释，这在于PC损失的强大的小叶选择性，考虑到TRPC在每个PC中都有表达，这令人困惑。有趣的是，MWK小脑的遗传分析显示，除其他改变外，凋亡诱导因子和抗性因子表达的变化可能表明受损的pc启动特定的细胞途径，保护它们免受明显的细胞损失。

REF: Sekerková G, Kilic S, Cheng YH, et al. Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia. Neurobiol Dis. 2024;195:106492. doi:10.1016/j.nbd.2024.106492 PMID: 38575093

Progressive alterations in polysomal architecture and activation of ribosome stalling relief factors in a mouse model of Huntington's disease

亨廷顿氏病小鼠模型中多体结构的进行性改变和核糖体停滞缓解因子的激活

Given their highly polarized morphology and functional singularity, neurons require precise spatial and temporal control of protein synthesis. Alterations in protein translation have been implicated in the development and progression of a wide range of neurological and neurodegenerative disorders, including Huntington's disease (HD). In this study we examined the architecture of polysomes in their native brain context in striatal tissue from the zQ175 knock-in mouse model of HD. We performed 3D electron tomography of high-pressure frozen and freeze-substituted striatal tissue from HD models and corresponding controls at different ages. Electron tomography results revealed progressive remodelling towards a more compacted polysomal architecture in the mouse model, an effect that coincided with the emergence and progression of HD related symptoms. The aberrant polysomal architecture is compatible with ribosome stalling phenomena. In fact, we also detected in the zQ175 model an increase in the striatal expression of the stalling relief factor EIF5A2 and an increase in the accumulation of eIF5A1, eIF5A2 and hypusinated eIF5A1, the active form of eIF5A1. Polysomal sedimentation gradients showed differences in the relative accumulation of 40S ribosomal subunits and in polysomal distribution in striatal samples of the zQ175 model. These findings indicate that changes in the architecture of the protein synthesis machinery may underlie translational alterations associated with HD, opening new avenues for understanding the progression of the disease.

鉴于其高度极化的形态和功能奇异性，神经元需要对蛋白质合成进行精确的空间和时间控制。蛋白质翻译的改变与包括亨廷顿氏病 (HD) 在内的多种神经和神经退行性疾病的发展和进展有关。在这项研究中，我们检查了来自HD的zQ175敲入小鼠模型的纹状体组织中天然脑环境中多核糖体的结构。我们对来自HD模型和不同年龄的相应对照的高压冷冻和冷冻替代纹状体组织进行了3D电子断层扫描。电子断层扫描结果显示，在小鼠模型中，逐渐重塑为更紧凑的多体结构，这种效果与HD相关症状的出现和进展相吻合。异常的多体结构与核糖体停滞现象兼容。实际上，我们还在zQ175模型中检测到停滞缓解因子EIF5A2的纹状体表达增加，eIF5A1，eIF5A2和hypusalized eIF5A1 (eIF5A1的活性形式) 的积累增加。多体沉降梯度显示了zQ175模型纹状体样品中40s核糖体亚基的相对积累和多体分布的差异。这些发现表明，蛋白质合成机制的结构变化可能是与HD相关的翻译改变的基础，为了解疾病的进展开辟了新的途径。

REF: Martin-Solana E, Diaz-Lopez I, Mohamedi Y, Ventoso I, Fernandez JJ, Fernandez-Fernandez MR. Progressive alterations in polysomal architecture and activation of ribosome stalling relief factors in a mouse model of Huntington's disease. Neurobiol Dis. 2024;195:106488. doi:10.1016/j.nbd.2024.106488 PMID: 38565397

Aberrant dynamic functional network connectivity in progressive supranuclear palsy

进行性核上性麻痹的异常动态功能网络连接

The clinical symptoms of progressive supranuclear palsy (PSP) may be mediated by aberrant dynamic functional network connectivity (dFNC). While earlier research has found altered functional network connections in PSP patients, the majority of those studies have concentrated on static functional connectivity. Nevertheless, in this study, we sought to evaluate the modifications in dynamic characteristics and establish the correlation between these disease-related changes and clinical variables. Our findings were that the altered connectivity was mostly concentrated in the CBN and MO. In addition, PSP patients had different temporal dynamics, which were associated with bulbar and oculomotor symptoms in PSPRS. It suggest that variations in dynamic functional network connectivity properties may represent an essential neurological mechanism in PSP.

进行性核上性麻痹 (PSP) 的临床症状可能是由异常的动态功能网络连接 (dFNC) 介导的。虽然早期的研究发现PSP患者的功能网络连接发生了改变，但大多数研究都集中在静态功能连接上。尽管如此，在这项研究中，我们试图评估动态特征的变化，并建立这些疾病相关变化与临床变量之间的相关性。我们的发现是，改变的连接性主要集中在CBN和MO中。此外，PSP患者具有不同的时间动力学，这与PSPRS的眼球和动眼症状有关。这表明动态功能网络连接特性的变化可能代表了PSP的基本神经机制。

REF: Qu J, Tian M, Zhu R, et al. Aberrant dynamic functional network connectivity in progressive supranuclear palsy. Neurobiol Dis. 2024;195:106493. doi:10.1016/j.nbd.2024.106493 PMID: 38579913

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy

增强肌肉中的BDNF可挽救di-cmtc周围神经病变小鼠模型中受损的轴突运输

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Charcot-marie-tooth病 (CMT) 是由许多功能不同的基因突变引起的遗传性周围神经病变。氨酰基-tRNA合成酶 (ARS) 酶将氨基酸转移到伴侣tRNA以进行蛋白质合成，代表了与CMT病因遗传相关的最大蛋白质家族，表明了病理机制的共性。显性中间CMT C型 (di-cmtc) 是由YARS1突变引起的，该突变驱动了编码的酪氨酰-tRNA合成酶 (TyrRS) 的毒性功能获得，这是通过突变蛋白的构象变化暴露共有新形态表面介导的。在这项研究中，我们首先显示了人类di-cmtc引起的TyrRSE196K与BDNF受体TrkB的细胞外结构域发生mis相互作用，这是一种异常关联，我们先前已表征了与CMT型2D (CMT2D) 相关的几种突变甘氨酰tRNA合成酶。然后，我们对模拟di-cmt的YarsE196K小鼠进行了颞神经肌肉评估。我们确定YarsE196K纯合子在含有神经营养蛋白的信号核内体的体内轴突运输中显示出选择性的，年龄依赖性的损害，从而使CMT2D小鼠表型化。通过将重组TyrRSE196K而不是TyrRSWT注射到野生型小鼠的肌肉中来复制这种损伤。通过注射重组蛋白或肌肉特异性基因疗法增强di-cmtc肌肉中的BDNF，导致完全的轴突运输校正。因此，这项工作确定了与ARS相关的神经病常见的非细胞自主病理机制，并强调了提高肌肉中BDNF水平作为治疗策略的潜力。

REF: Rhymes ER, Simkin RL, Qu J, et al. Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy. Neurobiol Dis. 2024;195:106501. doi:10.1016/j.nbd.2024.106501 PMID: 38583640