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.

摘要 星形胶质细胞是大脑中含量最丰富的神经胶质细胞，在脑生理的各个方面发挥着重要作用。 鉴于星形胶质细胞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 脑回路和相关分子通路的异常，星形胶质细胞如何参与回路功能障碍 与精神障碍相关的疾病仍处于萌芽状态。最近的研究表明，星形胶质细胞扮演着一种 在杏仁核功能和相关的行为输出中的重要作用，这导致我们进一步研究 杏仁核星形胶质细胞导致人类抑郁和相关的自杀。为此，我们表演了 来自自杀死者(N=20)和年龄匹配的对照组的免疫染色发现，典型的星形胶质细胞 标记物GFAP和关键的星形胶质细胞转录因子NFIA在杏仁核中均显著增加 自杀死者。最近，我们报道了NFIA在心脏的生理活动中起着重要的作用。 成年海马区的星形胶质细胞、神经回路活动和脑功能。这一证据使我们得以 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的假说 功能。确定星形细胞NFIA是否影响杏仁核回路功能和相关的抑郁 行为方面，我们使用了NFIA功能增益(GOF)和功能丧失(LOF)小鼠模型。初步 研究表明，NFIA GOF会导致抑郁/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学分析都显示出显著的 互补性的改变。 因此，基于这些初步数据的实力，我们提出了以下具体目标。在……里面 具体目标1，我们将使用NFIA来确定星形细胞NFIA在杏仁核回路活动和功能中的作用 GOF和LOF小鼠模型。在特定目标2中，我们将破译星形细胞NFIA是如何调节杏仁核回路的 通过GABA/MAOB。在本研究中，我们将使用RNA测序和 用药理/遗传工具操控目标基因。在具体目标3中，我们将描绘星形细胞 杏仁核中的NFIA转录网络。在这项研究中，我们将剖析杏仁核特异的NFIA 转录网络，并在人类样本中证实这一点。