Astrocyte regulation of amygdala circuit function

总结 星形胶质细胞是脑中最丰富的胶质细胞类型，在脑生理的各个方面发挥着重要作用。 由于星形胶质细胞在大脑功能中的核心作用，它们与各种精神疾病有关 包括孤独症、焦虑症、精神分裂症、抑郁症和自杀。尽管在理解上取得了进展， 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，星形胶质细胞发挥作用， 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有助于人类抑郁症和相关的自杀。为此，我们进行了 对自杀死亡者（N=20）和年龄匹配的对照组进行免疫染色，发现典型星形胶质细胞 标记物GFAP和关键的星形胶质细胞转录因子NFIA都在杏仁核中急剧增加， 自杀死者。最近，我们报道了NFIA在细胞的生理活动中起重要作用， 星形胶质细胞、神经元回路活动和成年海马的脑功能。这些证据让我们 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 功能为了确定星形胶质细胞NFIA是否影响杏仁核回路功能和相关的抑郁症， 行为，我们利用NFIA功能获得（GOF）和功能丧失（LOF）小鼠模型。初步 研究表明，NFIA GOF诱导抑郁/焦虑行为，而NFIA LOF抑制这些行为， 行为。在这两种情况下，杏仁核回路活动的直接生理分析显示， 互补的变化。 因此，根据这些初步数据的强度，我们提出了以下具体目标。在 具体目标1，我们将确定星形胶质细胞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 GABA/MAOB。在本研究中，我们将利用RNA测序技术鉴定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，我们将描述星形胶质细胞 杏仁核中的NFIA转录网络。在本研究中，我们将解剖杏仁核特异性NFIA， 并在人类样本中证实了这一点。

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.