The role of cortical long-range GABAergic inhibition on emotional learning

皮质长程 GABA 能抑制对情绪学习的作用

• 批准号: 10551286
• 负责人: Alfonso J Apicella
• 金额: $ 59.04万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551286
• 关键词: Affective; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Association Learning; Attention; Auditory; Auditory area; Axon; Behavior; Behavioral; Belief; Brain; Calcium; Cells; Cerebellum; Characteristics; Communication; Corpus striatum structure; Dendrites; Discrimination; Distal; Electrophysiology (science); Elements; Emotional; Ensure; Extinction; Fright; Functional disorder; Gene Expression; Genetic; Glutamates; Goals; Head; Image; Individual; Interneurons; Knowledge; Label; Lateral; Learning; Mediating; Mus; Neurons; Output; Parvalbumins; Pathway interactions; Phobias; Physiological; Play; Population; Positioning Attribute; Property; Psychopathology; Research; Retrieval; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Social Interaction; Somatostatin; Stains; Synapses; Testing; Vasoactive Intestinal Peptide; Viral; Work; auditory pathway; awake; biocytin; cell type; extracellular; genetic approach; hippocampal pyramidal neuron; in vivo; insight; microendoscope; multisensory; neglect; neural circuit; neuropathology; new therapeutic target; novel; optogenetics; patch clamp; photoactivation; reconstruction; recruit; response; selective expression; sensory input; sound; success; tool; transcriptome sequencing; transmission process; treatment of anxiety disorders

PROJECT SUMMARY/ABSTRACT Proper emotional responses are characterized by the dynamic interplay of two major forces: excitation and inhibition. A current belief is that dysfunction of inhibition, mediated by local GABAergic interneurons, leads to a wide range of psychopathologies including phobias and anxiety disorders. A well-established principle of the circuit organization underlying emotional learning is that inhibition is local while excitation is both local and long- range. Specifically, a considerable amount of research on cortico-amygdala communication (coordination of sensory input between the auditory cortex and the lateral amygdala) relies on the reductionist view that the auditory cortex transmits only excitatory signals. However, it has long been known that long-range GABAergic neurons are important circuits element in many brain areas, such as the spiny projection neurons in the striatum and the Purkinje neurons in the cerebellum. Therefore, despite the fact that the existence of cortical long-range GABAergic neurons has been proven anatomically, previous studies have primarily focused on the local circuit organization of GABAergic interneurons, and inhibition is frequently described as being exclusively local. A growing body of evidence from our lab and others indicates that many of these long-range GABAergic projections arise from neurons expressing somatostatin, parvalbumin, and more recently from vasoactive intestinal peptide. Since somatostatin neurons form synapses primarily on the distal dendrites of target neurons, it has been suggested that this subpopulation of GABAergic cells plays a critical role modulating the plasticity of incoming sensory inputs. Importantly, strong preliminary evidence from our labs show that somatostatin- expressing neurons project to the lateral amygdala (CLA-Som). This proposal aims at determining the circuit organization and behavioral relevance of CLA-Som neurons in fear learning driven by auditory signals. Specifically, this proposal will dissect the CLA-Som microcircuits and behavior responsible for cortical amygdala communication answering the following questions: What are the anatomical, electrophysiological, and gene expression properties of CLA-Som neurons? What is the impact of CLA-Som neurons on the amygdala network and which are the circuit mechanisms through which they produce inhibition? Which are the behavioral conditions that recruit CLA-Som neurons and their role in fear learning? These questions will be investigated using retrograde and optogenetic labeling, specific neuronal-tagging-physiological recordings, in vivo patch clamping and linear probe recordings, calcium imaging in freely moving mice, and pathway selective chemogentic tools during actual learning. Discoveries from this work will be significant because they will provide foundational knowledge regarding cortical modulation of fear learning, describe a new GABAergic cortical-amygdala pathway, and provide new therapeutic targets for neuropathologies involving anxiety and phobias.

项目摘要/摘要 正确的情感反应的特征是两个主要力量的动态相互作用：激发和 抑制。当前的一种看法是，局部gabaergic interneurons介导的抑制功能障碍导致 多种心理病理学，包括恐惧症和焦虑症。公认的原则 情绪学习的基础电路组织是抑制是局部的，而激发既是局部又是长期的 范围。具体而言，关于Cortico-Amygdala沟通的大量研究（协调 听觉皮层和外侧杏仁核之间的感觉输入依赖于还原论的观点 听觉皮层仅传输兴奋性信号。但是，长期以来一直知道远距离Gabaergic 神经元是许多大脑区域的重要电路元素，例如在 小脑中的纹状体和浦肯野神经元。因此，尽管存在皮质的事实 长期GABA能神经元已被解剖学证明，以前的研究主要集中在 GABA能中间神经元的本地电路组织和抑制经常被描述为完全是 当地的。来自我们实验室和其他实验室的越来越多的证据表明，其中许多远程GABA能 预测来自表达生长抑素，白蛋白的神经元，而最近来自血管活性 肠肽。由于生长抑素神经元主要在靶神经元的远端树突上形成突触，因此 有人提出，这种GABA能细胞的亚群起着调节可塑性的关键作用 传入的感觉输入。重要的是，我们实验室的有力初步证据表明，生长抑素 - 表达神经元向外侧杏仁核（CLA-SOM）表达。该建议旨在确定电路 在听觉信号驱动的恐惧学习中，CLA-SOM神经元的组织和行为相关性。 具体而言，该建议将剖析CLA-SOM微电路和负责皮质杏仁核的行为 回答以下问题的沟通：解剖学，电生理和基因是什么 CLA-SOM神经元的表达特性？ CLA-SOM神经元对杏仁核网络和 它们产生的电路机制是什么？哪些行为条件 招募CLA-SOM神经元及其在恐惧学习中的作用？这些问题将使用逆行和 光遗传学标记，特定的神经元标记 - 生理记录，体内贴剂和线性探针 录音，自由移动的小鼠中的钙成像以及在实际的途径选择性化学工具 学习。这项工作的发现将是重要的，因为它们将提供基本知识 关于恐惧学习的皮质调节，描述一种新的GABA能皮质 - 杏仁核途径和 为涉及焦虑和恐惧症的神经病理学提供新的治疗靶标。