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 恐惧条件作用，一开始中性的警告刺激变得与天生的厌恶有关 伤害性电击等刺激已被证明是学习和学习研究的有效模型。 一般的记忆过程，以及学习到的经验如何特别有助于焦虑症。我们 报道称，单一的经历与强大的压力源会导致恐惧学习的长期增强，以及 我们称之为压力增强恐惧学习(SEFL)的效果。在此之前，我们演示了 SEFL的杏仁基底外侧核(BLA)和SEFL伴随着GluA1的长期上调 AMPA受体的亚基，特别是在血乳酸中。AMPA受体介导正常兴奋性神经 变速箱。这表明，SEFL，也许还有其他压力的负面后果，可能是通过调节的 通过兴奋性突触传递的改变。然而，压力改变的确切机制 恐惧的条件反射是未知的。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，了解压力如何改变对学习的恐惧可能会指向 应激相关障碍的翻译靶标。因此，我们提出了一系列关于杏仁核的研究。 切片电生理学来解决这一文献中的空白，并为未来确定 SEFL的必要和充分的机制。我们使用全细胞记录的初步数据表明 在SEFL诱导的应激后，杏仁基底外侧核的兴奋性驱动增强。在这 探索性应用我们提出利用BLA切片电生理学来实现两个目的。第一个确定 携带这种增强的兴奋性驱动的血乳酸的特定输入。二是鉴定分子 负责兴奋性突触传递这种变化的机制关注于一种可能性 神经可塑性的异常形式是这些不适应变化的基础。