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.

项目概要 恐惧调节，最初中性的警告刺激与天生的厌恶联系在一起 伤害性电击等刺激已被证明是研究学习和行为的有效模型。 一般的记忆过程以及习得的经历如何特别导致焦虑症。我们 报道称，一次强烈压力源的经历会导致恐惧学习的长期增强， 我们将这种效应称为“压力增强恐惧学习”（SEFL）。之前我们已经论证了 SEFL 中的基底外侧杏仁核 (BLA) 且 SEFL 伴随着 GluA1 的长期上调 AMPA 受体的亚基，特别是在 BLA 中。 AMPA 受体介导正常的兴奋性神经 传播。这表明 SEFL 以及压力的其他负面后果可能是可以调节的 通过兴奋性突触传递的改变。然而，压力改变的精确机制 恐惧条件反射尚不清楚。这些知识对于理解状态变量如何影响非常重要 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 压力相关疾病的转化目标。因此，我们提出了一系列利用杏仁核的研究 切片电生理学以解决文献中的这一空白，并为未来的研究打开大门，以确定 SEFL 的必要且充分的机制。我们使用全细胞记录的初步数据表明 SEFL 诱发的应激后，基底外侧杏仁核的兴奋性驱动增强。在这个 探索性应用我们建议使用 BLA 切片电生理学来实现两个目标。首先要识别 携带这种增强的兴奋驱动力的 BLA 的特定输入。第二是分子鉴定 负责兴奋性突触传递这种变化的机制，重点关注以下可能性： 神经可塑性的异常形式是这些适应不良变化的基础。