Observational fear enhanced plasticity in dmPFC-BLA circuit as a modulator of affective behaviors

观察性恐惧增强了 dmPFC-BLA 回路作为情感行为调节器的可塑性

• 批准号: 9973171
• 负责人: Alexei Morozov
• 金额: $ 40万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973171
• 关键词: AMPA Receptors; Adverse event; Affect; Affective; Amygdaloid structure; Animals; Attention; Attenuated; Avoidance Learning; Behavior; Behavioral; Bilateral; Brain; Characteristics; Chronic; Data; Disease; Disinhibition; Distress; Early Intervention; Emotional disorder; Equilibrium; Etiology; Exposure to; Fright; Future; Glutamates; Goals; Hour; Knowledge; Light; Mediating; Memory; Mental Depression; Methods; Mus; Neuronal Plasticity; Neurons; Outcome; Output; Pathologic; Pathway interactions; Pharmacogenetics; Phase; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Process; Property; Psyche structure; Risk Factors; Rodent; Role; Signal Transduction; Social Concepts; Structure; Synapses; Synaptic Transmission; Testing; Training; Trauma; cell type; classical conditioning; designer receptors exclusively activated by designer drugs; emotional behavior; experimental study; fear memory; in vivo; pre-clinical; prevent; psychological trauma; social; social stress; trait; transmission process

Project summary Forming stronger aversive memories is a characteristic of PTSD. Meanwhile, psychological trauma is a risk factor for developing PTSD in the future, upon exposure to another adverse event. This project will use mice to investigate how observing fear in others, as a form of social distress, enhances the retention of new inhibitory avoidance (IA) memories. It serves our long- term goal to understand how neuronal plasticity contributes to emotional behaviors and to identify the means for reversing PTSD-relevant behavioral traits by artificial circuit manipulations. We have recently found that a brief exposure to a conspecific receiving electrical footshocks, the observational fear paradigm (OF), enables a stronger inhibitory avoidance (IA) learning in mice. Our preliminary data strongly implicate the pathways between the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) pathway in the enhancement. First, a pharmacogenetic disconnection of these structures during OF prevented the enhancement. Second, OF enabled facilitation of this pathway by IA training, which lasted for several hours. Third, OF generated NMDAR-only (silent) synapses, which we unsilenced by IA training. In addition, OF attenuated GABAbR-mediated depression of the feedforward GABAergic currents, evoked in BLA neurons by a 5 Hz repeated stimulation of the dmPFC inputs. We will test a hypothesis that OF enhances IA by generating silent synapses and by altering the GABAbR- dependent inhibitory balance between PV- and Sst-IN in the prefrontal-amygdala circuit, both of which enable a stronger synaptic facilitation during IA training. We will determine the necessity of dmPFC-BLA synapses at each phase of the OF-IA paradigm (Aim 1), test the causal role of the silent synapses and the transient synaptic facilitation (Aim 2), and identify the micro-circuit mechanism responsible for the abnormally high plasticity (Aim 3). The study may inform about potential targets and methods for early intervention to prevent PTSD in traumatized people.

项目总结