Mechanisms of enhanced synaptic drive in basolateral amygdala following stress

应激后基底外侧杏仁核突触驱动增强的机制

• 批准号: 10723781
• 负责人: Michael S Fanselow
• 金额: $ 43.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2025-09-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723781
• 关键词: AMPA Receptors; Accounting; Address; Amygdaloid structure; Anxiety Disorders; Area; Auditory; Aversive Stimulus; Behavioral; Brain region; Calcium; Data; Electrophysiology (science); Fright; Future; Goals; Hippocampus; Hyperactivity; Knowledge; Lead; Learning; Literature; Long-Term Potentiation; Loudness; Medial; Mediating; Mental disorders; Modality; Molecular; Mus; N-Methylaspartate; Neuronal Plasticity; Neurons; Nociception; Noise; Pain; Pathway interactions; Permeability; Post-Traumatic Stress Disorders; Prefrontal Cortex; Reporting; Sensory; Series; Shock; Signal Transduction; Slice; Source; Stimulus; Stress; Stressful Event; Study models; Synapses; Synaptic Transmission; Thalamic structure; Time; Up-Regulation; Whole-Cell Recordings; conditioned fear; experience; learned behavior; memory process; midbrain central gray substance; optogenetics; response; stress reactivity; stress related disorder; stressor; transmission process

Project Summary Fear conditioning, where an initially neutral warning stimulus becomes associated with an innately aversive stimulus such as nociceptive electric shock, has proven to be an effective model for the study of learning and memory processes generally and how learned experiences contribute to anxiety disorders particularly. We reported that a single experience with a strong stressor leads to a long-term enhancement of fear learning, an effect we termed Stress-Enhanced Fear Learning (SEFL). Previously, we demonstrated the importance of the basolateral amygdala (BLA) in SEFL and that SEFL is accompanied by a long-term upregulation of the GluA1 subunit of the AMPA receptor, specifically in the BLA. AMPA receptors mediate normal excitatory neural transmission. This suggests that SEFL, and perhaps other negative consequences of stress, may be mediated by alterations in excitatory synaptic transmission. However, the precise mechanisms by which stress alters fear conditioning are not known. Such knowledge is important to understand how state variables impact learning and memory processes. Additionally, understanding how stress alters fear learning may point to translational targets for stress-related disorders. Therefore, we propose a series of studies using amygdala slice electrophysiology to address this gap in the literature and open the door to future studies determining the necessary and sufficient mechanisms for SEFL. Our preliminary data using whole-cell recordings indicates that there is enhanced excitatory drive in the basolateral amygdala following SEFL-inducing stress. In this exploratory application we propose to use BLA slice electrophysiology to achieve two aims. First to identify the specific inputs to the BLA that carries this enhanced excitatory drive. The second is to identify the molecular mechanisms responsible for this change in excitatory synaptic transmission focusing on the possibility that an abnormal form of neural plasticity underlies these maladaptive changes.

项目摘要 恐惧条件反射，最初中性的警告刺激与天生的厌恶相关联。 刺激，如伤害性电击，已被证明是一种有效的模型，用于研究学习和 一般的记忆过程以及学习经验如何导致焦虑症。我们 报告说，一个单一的经验，一个强大的压力源导致长期的增强恐惧学习， 压力增强恐惧学习（Stress-Enhanced Fear Learning，SEFL）在此之前，我们展示了 基底外侧杏仁核（BLA）在SEFL和SEFL是伴随着长期上调的GluA 1 AMPA受体的亚基，特别是在BLA中。AMPA受体介导正常兴奋性神经元 传输这表明自我外语，以及压力的其他负面后果，可能是由 兴奋性突触传递的改变。然而，压力改变的确切机制 恐惧条件反射是未知的。这些知识对于理解状态变量如何影响 学习和记忆过程。此外，了解压力如何改变恐惧学习可能会指出， 应激相关疾病的翻译靶点。因此，我们提出了一系列的研究，利用杏仁核 切片电生理学来解决文献中的这一空白，并为未来的研究打开大门， 有必要和充分的机制，以自我解放。我们使用全细胞记录的初步数据表明， 在SEFL诱导的应激之后，基底外侧杏仁核中存在增强的兴奋性驱动。在这 探索性应用我们建议使用BLA切片电生理学来实现两个目的。首先要确定 BLA的特定输入，携带这种增强的兴奋性驱动。第二是鉴定分子 负责兴奋性突触传递的这种变化的机制集中在一种可能性上， 神经可塑性的异常形式是这些适应不良变化的基础。