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，最初是中性警告刺激与天生厌恶相关的 事实证明，诸如伤害性电击之类的刺激是学习和学习的有效模型 通常，记忆过程以及学到的经历如何尤其会导致焦虑症。我们 报道说，具有强烈压力源的单一经验会导致恐惧学习的长期增强 效果我们称为压力增强的恐惧学习（SEFL）。以前，我们证明了 SEFL中的基底外侧杏仁核（BLA），SEFL伴有GLUA1的长期上调 AMPA受体的亚基，特别是在BLA中。 AMPA受体介导正常兴奋性神经 传播。这表明SEFL，也许是压力的其他负面后果，可能会介导 通过改变兴奋性突触传播。但是，压力改变的确切机制 恐惧条件尚不清楚。这样的知识对于了解状态变量如何影响很重要 学习和记忆过程。此外，了解压力如何改变恐惧学习可能指向 与压力有关的疾病的翻译目标。因此，我们提出了使用杏仁核的一系列研究 切片电生理学，以解决文献中的这一差距，并为未来的研究打开了决定 SEFL的必要和足够的机制。我们使用全细胞记录的初步数据表明 诱导SEFL的应力后，基底外侧杏仁核的兴奋性驱动力增强。在这个 我们建议使用BLA切片电生理学实现两个目标。首先确定 带有这种增强兴奋性驱动器的BLA的特定输入。第二个是识别分子 负责这种兴奋性突触传播变化的机制，重点是 神经可塑性的异常形式是这些不良适应性变化的基础。