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

• 批准号: 10176598
• 负责人: Alfonso Araque
• 金额: $ 44.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10176598
• 关键词: Address; Amygdaloid structure; Animal Behavior; Anxiety; Anxiety Disorders; Astrocytes; Behavior; Behavioral; Brain; Brain Diseases; CNR1 gene; Calcium; Communication; Coupled; Cues; Disease; Electrophysiology (science); Emotional; Endocannabinoids; Extinction (Psychology); Fiber; Fright; Genetic; Goals; Image; Impairment; Investigation; Knowledge; Lead; Learning; Light; Measurement; Measures; Medial; Methods; Monitor; Mus; Neurons; Optics; Output; Pathway interactions; Pattern; Pharmacology; 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; classical conditioning; 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; neurotransmitter release; novel; optogenetics; post-traumatic stress; receptor expression; response; selective expression; synaptic function; synaptic inhibition; targeted treatment

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.

项目总结/摘要 这项研究的总体目标是更好地了解星形胶质细胞在内侧亚核中的作用， 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有力地调节突触传递， 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， 他们的贡献在恐惧制约行为，和神经化学途径，耦合 在CeM中神经元和星形胶质细胞网络的协同活动。因此，本提案的目的是 为了解决这些知识的差距，通过测量星形胶质细胞和神经元的活动， 用光学和遗传学方法研究了行为自由的老鼠的杏仁核。在Aim 1中，我们将记录 脑内星形胶质细胞在恐惧线索获得、表达和消退过程中的活性 条件性行为他们将提供第一个生理学证据，表明星形胶质细胞是特异性的。 并且在条件性恐惧反应的特定阶段被不同地激活。在目标2中， 确定CeM星形胶质细胞是否在调节杏仁核驱动的反应中具有内源性作用。 它还将进一步测试星形胶质细胞内源性大麻素信号在这些行为中的作用。在目标3中， 将决定CeM星形胶质细胞外源性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。总而言之，拟议的研究将提供 星形胶质细胞在中央杏仁核中的作用的更详细的图片，并扩展我们最近的离体 杏仁核切片研究。这些知识将为新的药理学策略铺平道路， 焦虑/恐惧障碍，通过利用星形胶质细胞受体表达的不常见特征， 来调节它们的活动。因此，我们的研究将有助于产生一种新的治疗策略， 神经系统疾病，如焦虑，创伤后应激综合征，通过针对相对 杏仁核中未被充分研究的细胞类型。