Are microglia in charge of controlling stress-response behavior?
Are microglia in charge of controlling stress-response behavior?
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DOI：
10.1038/s41380-024-02511-x
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发表时间：
2024-03
影响因子：
11
通讯作者：
Rafaela C Cordeiro;G. Scaini;João Quevedo
中科院分区：
文献类型：
--
作者：
Rafaela C Cordeiro;G. Scaini;João Quevedo
慢性焦虑是一种普遍的心理健康挑战，影响着全球相当多的人口[1]。从2008年到2018年，美国的焦虑情绪显著上升，特别是在18-25岁的年轻人中。这一特定年龄组经历了最显著的增长，比其他年龄组更快[1]。焦虑显著影响患者的日常功能、心理发病率和生活质量[2]。这种情况通常存在于神经精神疾病中，并与压力相关行为有关[3]。与此相关的是，慢性压力暴露与各种神经精神疾病有关，压力与杏仁核中的树突肥大和突触重塑有关。这些变化是回路特异性的，有助于理解抑郁症、焦虑症和其他压力相关疾病的病理生理学基础[4]。然而，我们对慢性焦虑背后的分子遗传学及其与压力的关系的理解仍然有限。我们还没有在解释最初的保护性反应机制如何随着时间的推移而变得有害方面取得重大进展。越来越多的研究表明，Hoxb 8基因的靶向破坏/突变或小胶质细胞亚群的消融诱导慢性焦虑和强迫症样行为，强迫性病理性拔毛，以至于在过度修饰的部位显示病变[5，6]。Hoxb 8是一种转录因子，作为同源异型盒基因家族的一部分控制发育[7]。此外，Hoxb 8负责髓样祖细胞的维持和分化，这是小胶质细胞的两个来源之一。Chen等人[8]发现大脑中唯一可检测到的Hoxb 8标记的细胞谱系（复杂的先天行为梳理语法的来源）是小胶质细胞，支持Hoxb 8突变小鼠中观察到的过度病理梳理行为起源于缺陷小胶质细胞的假设，从而将造血功能与小鼠行为直接联系起来。在表征病理性和慢性焦虑、梳理行为以及Hoxb 8小胶质细胞在这种病理表现中所起的作用的过程中，Nagarajan和Capecchi使用一种使Capecchi在2007年获得诺贝尔奖的方法开发了一种小鼠模型[9]。在《分子精神病学》的这期专题中，Nagarajan和Capecchi转向了光遗传学刺激--一种结合激光和基因工程的技术--对小鼠Hoxb 8小胶质细胞的刺激。通过移植纯化的、细胞分选的Hoxb 8小胶质细胞，
Chronic anxiety is a widespread mental health challenge that affects a considerable population worldwide [1]. From 2008 to 2018, anxiety significantly risen in the United States, especially in young adults aged 18-25. This particular age group has experienced the most significant increase, which was faster than other age groups [1]. Anxiety significantly impacts patientsL daily functioning, psychological morbidity, and quality of life [2]. This condition is often present in neuropsychiatric disorders and is linked to stress-related behaviors [3]. Related to that, chronic stress exposure is linked to various neuropsychiatric illnesses, with stress correlating with dendritic hypertrophy and synaptic remodeling in the amygdala. These changes are circuit-specific and contribute to understanding the pathophysiological basis of depression, anxiety disorders, and other stress-related conditions [4]. However, our understanding of the molecular genetics behind chronic anxiety and its relation to stress is still limited. We have not yet made significant progress in explaining how an initial protective response mechanism can become detrimental over time.A growing body of research indicates that a targeted disruption/mutation of the Hoxb8 gene or ablation of a microglial subpopulation induced chronic anxiety and OCSD-like behavior, compulsive pathological hair pulling, to the point of showing lesions at the sites of overgrooming [5, 6]. Hoxb8 is a transcription factor that controls development as part of the Homeobox gene family [7]. Moreover, Hoxb8 is responsible for the maintenance and differentiation of myeloid progenitor cells, which are one of the two sources of microglia. Chen et al.[8] found that the only detectable Hoxb8 labeled cell lineage in the brain (the source of the complex, innate behavioral grooming syntax) is microglia, supporting the hypothesis that the excessive pathological grooming behavior observed in Hoxb8 mutant mice originates from defective microglia, thus directly connecting hematopoietic function to mouse behavior. In the course of characterizing pathological and chronic anxiety, grooming behavior, and the role played by Hoxb8 microglia in this pathological manifestation, Nagarajan and Capecchi developed a mouse model using a method that earned Capecchi a Nobel Prize in 2007 [9]. In this featured issue of Molecular Psychiatry [9], Nagarajan and Capecchi turned to optogenetics stimulation-a technique that combines laser light and genetic engineering-of Hoxb8 microglia in mice. By transplanting purified, cell-sorted Hoxb8 microglia