Astrocyte regulation of amygdala circuit function

星形胶质细胞调节杏仁核回路功能

• 批准号: 10852065
• 负责人: Junsung Woo
• 金额: $ 62.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852065
• 关键词: Adult; Affect; Age; Amygdaloid structure; Anxiety; Astrocytes; Automobile Driving; Behavior; Behavioral; Blood flow; Brain; Brain region; Cell Nucleus; ChIP-seq; Data; Depressed mood; Depressive disorder; Emotions; Enzymes; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glial Fibrillary Acidic Protein; Goals; Hippocampus; Homeostasis; Human; Knock-out; Link; Measures; Mental Depression; Mental disorders; Metabolic; Modeling; Molecular; Monoamine Oxidase B; Morphology; Mus; NFIA gene; Neuroglia; Neurons; Output; Pathway interactions; Physiological; Physiology; Play; Psychiatric therapeutic procedure; Regulation; Reporting; Role; Sampling; Schizophrenia; Suicide; Synaptic Transmission; anxious behavior; autism spectrum disorder; depressive behavior; depressive symptoms; excitatory neuron; gain of function; gamma-Aminobutyric Acid; gene network; genetic approach; inhibitory neuron; loss of function; mouse model; neuronal circuitry; neuronal excitability; pharmacologic; promoter; prospective; tool; transcription factor; transcriptome sequencing

Summary Astrocytes are the most abundant type of glial cell in the brain, playing vital roles in all facets of brain physiology. Given their central role in brain function, astrocytes have been implicated in a variety of psychiatric disorders including autism, anxiety, schizophrenia, depression, and suicide. Despite the progress in understanding the abnormalities in brain circuits and related molecular pathways, how astrocytes contribute to circuit dysfunction associated with psychiatric disorders remains nascent. Recent studies have shown that astrocytes play an essential role in amygdala function and associated behavioral outputs, which led us to further examine how amygdala astrocytes contribute to human depression and associated suicide. Towards this, we performed immunostaining from suicide decedents (N=20) and age-matched control, finding that the canonical astrocyte marker GFAP and a key astrocyte transcription factor NFIA are both drastically increased in the amygdala of suicide decedents. Recently, we reported that NFIA plays an essential role in the physiological activities of astrocytes, neuronal circuit activity, and brain function in the adult hippocampus. This evidence led us to hypothesize that astrocytic NFIA contributes to depression and associated suicide by regulating amygdala circuit function. To determine whether astrocytic NFIA affects amygdala circuit function and associated depressive behaviors, we utilized NFIA gain-of-function (GOF) and loss-of-function (LOF) mouse models. Preliminary studies revealed that NFIA GOF induced depressive/anxiety behaviors, while NFIA LOF suppressed these behaviors. In both cases, direct physiological analysis of amygdala circuit activity revealed significant and complementary alterations. Therefore, based on the strength of these preliminary data, we propose the following specific aims. In specific aim 1, we will determine the role of astrocytic NFIA in amygdala circuit activity and function using NFIA GOF and LOF mice models. In specific aim 2, we will decipher how astrocytic NFIA regulates amygdala circuits through GABA/MAOB. In this study, we will identify the target gene of NFIA using RNA-sequencing and manipulate the target gene with pharmacological/genetic tools. In specific aim 3, we will delineate astrocytic NFIA transcriptional networks in the amygdala. In this study, we will dissect the amygdala-specific NFIA transcriptional networks and confirm this in human samples.

概括 星形胶质细胞是大脑中最丰富的神经胶质细胞类型，在大脑生理学的各个方面发挥着重要作用。 鉴于其在大脑功能中的核心作用，星形胶质细胞与多种精神疾病有关 包括自闭症、焦虑症、精神分裂症、抑郁症和自杀。尽管在理解方面取得了进展 脑回路和相关分子通路的异常，星形胶质细胞如何导致回路功能障碍 与精神疾病相关的疾病仍处于萌芽状态。最近的研究表明星形胶质细胞发挥着 杏仁核功能和相关行为输出中的重要作用，这使我们进一步研究如何 杏仁核星形胶质细胞导致人类抑郁症和相关自杀。为此，我们进行了 对自杀者（N = 20）和年龄匹配的对照进行免疫染色，发现典型的星形胶质细胞 标记物 GFAP 和关键星形胶质细胞转录因子 NFIA 在杏仁核中均急剧增加 自杀的死者。最近，我们报道了 NFIA 在人体生理活动中发挥着重要作用 星形胶质细胞、神经元回路活动和成年海马体的脑功能。这个证据引导我们 假设星形胶质细胞 NFIA 通过调节杏仁核回路导致抑郁症和相关自杀 功能。确定星形细胞 NFIA 是否影响杏仁核回路功能和相关抑郁症 为了观察行为，我们利用了 NFIA 功能获得（GOF）和功能丧失（LOF）小鼠模型。初步的 研究表明，NFIA GOF 会诱发抑郁/焦虑行为，而 NFIA LOF 会抑制这些行为 行为。在这两种情况下，对杏仁核回路活动的直接生理分析揭示了显着且 互补的改变。 因此，根据这些初步数据的强度，我们提出以下具体目标。在 具体目标1，我们将使用NFIA确定星形细胞NFIA在杏仁核回路活动和功能中的作用 GOF 和 LOF 小鼠模型。在具体目标 2 中，我们将破译星形胶质细胞 NFIA 如何调节杏仁核回路 通过 GABA/MAOB。在本研究中，我们将使用 RNA 测序和技术鉴定 NFIA 的靶基因 用药理学/遗传学工具操纵靶基因。在具体目标 3 中，我们将描绘星形胶质细胞 NFIA 杏仁核转录网络。在本研究中，我们将剖析杏仁核特异性 NFIA 转录网络并在人类样本中证实了这一点。