Astrocyte activity in amygdala-related fear conditioned behaviors

杏仁核相关恐惧条件行为中的星形胶质细胞活性

基本信息

批准号：
10593940
负责人：
Alfonso Araque
金额：
$ 44.72万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593940
关键词：
Address Amygdaloid structure Animal Behavior Anxiety Anxiety Disorders Association Learning Astrocytes Behavior Behavioral Brain Brain Diseases CNR1 gene Calcium Communication Coupled Cues Disease Electrophysiology (science)Emotional Endocannabinoids Extinction Fiber Fright Genetic Goals ITPR1 gene Image Impairment Investigation Knowledge Learning Light Measurement Measures Medial Methods Monitor Mus Neurons Neurotransmitters Optics Output Pathway interactions Pattern Phase Photometry Physiological Play Post-Traumatic Stress Disorders Preparation Property Research Role Signal Transduction Slice Specificity Synapses Synaptic Transmission Syndrome Testing Transgenic Mice Work calcium indicator cell type cellular targeting conditioned fear designer receptors exclusively activated by designer drugs endocannabinoid signaling excessive anxiety gain of function in vivo information processing insight loss of function melanopsin memory process mouse model nervous system disorder neurochemistry neurotransmission novel optogenetics pharmacologic post-traumatic stress receptor receptor expression response selective expression synaptic function synaptic inhibition targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this research is to better understand how astrocytes in the medial subnucleus of the central amygdala (CeM) modulate conditioned fear behaviors. We recently found using brain slices that exogenous activation of astrocytes in the CeM powerfully regulates synaptic transmission and decreases CeM neuronal activity. However, critical gaps remain in identifying the role of CeM astrocytes in vivo, their contribution during fear conditioned behaviors, and the neurochemical pathways that couple the concerted activity of neuronal and astrocyte networks in the CeM. The goal of this proposal is therefore to address these gaps in knowledge by performing measurements of astrocytic and neuronal activity in the amygdala in freely, behaving mice using optical and genetic methods. In Aim1 we will record the activity of astrocytes in the CeM during the acquisition, expression and extinction of cued fear conditioned behaviors. They will provide the first physiological evidence that astrocytes are specifically and differentially activated during specific phases of conditioned fear responses. In Aim 2 we will determine whether CeM astrocytes have an endogenous role in modulating amygdala-driven responses. It will also further test the role of astrocytic endocannabinoid signaling in these behaviors. In Aim 3 we will determine the cellular and behavioral consequences upon exogenous activation of CeM astrocytes using chemogenetic and optogenetic methods. In summary, the proposed studies will provide a much more detailed picture on the role of astrocytes in the central amygdala and extend our recent ex vivo amygdala slice studies. This knowledge will pave the way for new pharmacological strategies to treat anxiety/fear disorders, by taking advantage of the uncommon profile of receptor expression of astrocytes to regulate their activity. Therefore, our studies will contribute to generate a new strategy to treat neurological diseases, such as anxiety, post-traumatic stress syndrome by targeting a relatively understudied cell type in the amygdala.

项目概要/摘要这项研究的总体目标是更好地了解内侧亚核中的星形胶质细胞如何中央杏仁核（CeM）调节条件性恐惧行为。我们最近发现使用大脑切片 CeM 中星形胶质细胞的外源性激活可强有力地调节突触传递并减少 CeM 神经元活动。然而，在确定 CeM 星形胶质细胞在体内的作用方面仍然存在关键差距，它们在恐惧条件行为期间的贡献，以及耦合恐惧条件行为的神经化学途径 CeM 中神经元和星形胶质细胞网络的协同活动。因此，该提案的目标是通过测量星形胶质细胞和神经元活动来解决这些知识差距使用光学和遗传方法研究自由行为小鼠的杏仁核。在 Aim1 中我们将记录在暗示恐惧的获得、表达和消除过程中，CeM 中星形胶质细胞的活动条件行为。他们将提供第一个生理学证据，证明星形胶质细胞是特异性的并在条件性恐惧反应的特定阶段有差异地激活。在目标 2 中，我们将确定 CeM 星形胶质细胞在调节杏仁核驱动的反应中是否具有内源性作用。它还将进一步测试星形细胞内源性大麻素信号在这些行为中的作用。在目标 3 中，我们将确定 CeM 星形胶质细胞外源激活后的细胞和行为后果使用化学遗传学和光遗传学方法。总之，拟议的研究将提供很多关于星形胶质细胞在中央杏仁核中的作用的更详细的图片，并扩展了我们最近的离体杏仁核切片研究。这些知识将为新的治疗药物策略铺平道路通过利用星形胶质细胞受体表达的不常见特征来治疗焦虑/恐惧症来规范他们的活动。因此，我们的研究将有助于制定一种新的治疗策略神经系统疾病，如焦虑症、创伤后应激综合症，通过针对相对杏仁核中正在研究的细胞类型。