Silent synapses and plasticity of prefrontal-amygdala pathway after emotional distress

情绪困扰后的沉默突触和前额叶-杏仁核通路的可塑性

• 批准号: 8953261
• 负责人: Alexei Morozov
• 金额: $ 24.15万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953261
• 关键词: AMPA Receptors; Address; Adult; Amygdaloid structure; Anesthetics; Animals; Anxiety; Avoidance Learning; Behavioral; Brain; Brain Pathology; Cell membrane; Chemosensitization; Chronic stress; Decision Making; Development; Disease; Distress; Electrons; Elements; Emotional; Emotional disorder; Emotions; Environmental Risk Factor; Event; Excision; Exposure to; Fiber; Fright; Future; Generations; Glutamate Receptor; Goals; Immunoelectron Microscopy; Ketamine; Knowledge; Lead; Learning; Long-Term Potentiation; Medial; Mediating; Memory; Mental Depression; Mental disorders; Microscopic; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Outcome; Pain; Pathology; Pathway interactions; Physiological; Plastics; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Preparation; Procedures; Process; Psyche structure; Research; Risk; Rodent; Role; Schizophrenia; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Testing; Time; Training; Traumatic Brain Injury; addiction; analog; behavior test; classical conditioning; emotional distress; emotional trauma; fear memory; in vivo; neuronal patterning; novel; optogenetics; postnatal; postsynaptic; prevent; psychological trauma; public health relevance; research study; response; synaptogenesis; trait; traumatic event

 DESCRIPTION (provided by applicant): Abnormal function of the prefrontal cortex and the amygdala, which interact with each other to control emotions, memory, and decision making, have been implicated in behavioral traits of major mental disorders. Yet, very little is known about how synaptic transmission between the two structures is altered by environmental factors that lead to mental disease. Psychological trauma is one of such factors. It increases risk of developing stronger fear memories in the future, upon exposure to another traumatic event. Here, we will test a hypothesis that a purely psychological trauma makes synaptic connections between prefrontal cortex and amygdala more prone to facilitation during fear learning and that silent synapses, which are generated after psychological trauma, are responsible for the enhanced facilitation. Our preliminary experiments, in which mice are exposed to a conspecific under distress, revealed that such exposure enhances future formation of fear memory in the passive avoidance paradigm. We also found increased number of silent synapses in dmPFC-BLA pathway, which have NMDA receptor, but do not have functional AMPA receptor. Interestingly, the emergence of silence synapses and enhanced avoidance learning were abolished when mice were treated with sub-anesthetic doze of ketamine immediately after psychological trauma. The objectives of the proposal are to understand the process leading to formation of silent synapses, their removal by ketamine and the role silent synapses may play in plastic changes that occur in dmPFC-BLA connections during avoidance learning. The proposal employs optogenetic stimulation of specific axonal fibers and recording of synaptic responses in amygdala slices prepared from animals exposed to combinations of psychological trauma and avoidance learning paradigms. As a parallel approach, we will use immuno-electron microscopy quantification of glutamate receptors in dmPFC-BLA synapses, identified using anterograde tracing. The following questions will be addressed. Are silent synapses between dmPFC and BLA generated by insertion of NMDAR into cell membrane, or by removal of AMPAR? Do they enhance long-term potentiation in dmPFC-BLA pathway in slice? Are they used during passive avoidance learning? What is the mechanism of their elimination by ketamine? By focusing on dmPFC-BLA connection and BLA microcircuit, this study will help elucidate role of defined cellular and synaptic elements underlying emotional traumatization and validate them as a potential target for novel therapies PTSD, depression and related emotional disorders.

 描述（由申请人提供）：前额叶皮层和杏仁核的异常功能，它们相互作用以控制情绪、记忆和决策，与主要精神障碍的行为特征有关。然而，很少有人知道这两种结构之间的突触传递是如何被导致精神疾病的环境因素改变的。心理创伤就是其中一个因素。它增加了在未来暴露于另一个创伤事件时发展更强烈的恐惧记忆的风险。在这里，我们将测试一个假设，即一个纯粹的心理创伤使前额叶皮层和杏仁核之间的突触连接更容易促进恐惧学习和沉默的突触，这是心理创伤后产生的，负责增强促进。我们的初步实验中，小鼠暴露于同种下的痛苦，揭示了这种曝光增强未来的恐惧记忆的形成在被动回避范式。我们还发现在dmPFC-BLA通路中沉默突触的数量增加，这些突触具有NMDA受体，但不具有功能性AMPA受体。有趣的是，当小鼠在心理创伤后立即用亚麻醉剂量的氯胺酮治疗时，沉默突触的出现和增强的回避学习被取消。该提案的目的是了解导致沉默突触形成的过程，氯胺酮对其的去除以及沉默突触在回避学习期间dmPFC-BLA连接中发生的塑性变化中可能发挥的作用。该提案采用特定轴突纤维的光遗传学刺激和杏仁核切片中突触反应的记录，杏仁核切片是从暴露于心理创伤和回避学习范式组合的动物中制备的。作为一种平行的方法，我们将使用免疫电子显微镜定量的谷氨酸受体在dmPFC-BLA突触，确定使用顺行追踪。将讨论以下问题。dmPFC和BLA之间的沉默突触是通过NMDAR插入细胞膜还是通过去除AMPAR产生的？它们是否能增强脑片dmPFC-BLA通路的长时程增强作用？它们在被动回避学习中使用吗？氯胺酮消除它们的机制是什么？通过关注dmPFC-BLA连接和BLA微电路，这项研究将有助于阐明情绪创伤背后的细胞和突触元件的作用，并验证它们作为新型治疗PTSD，抑郁症和相关情绪障碍的潜在靶点。