Synaptic and circuit mechanisms of fear suppression

恐惧抑制的突触和回路机制

• 批准号: 9380135
• 负责人: Leon Reijmers
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380135
• 关键词: Agreement; Amygdaloid structure; Animals; Anxiety Disorders; Behavior; Behavior Therapy; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Data; Development; Ensure; Environment; Equilibrium; Extinction (Psychology); Freezing; Frequencies; Fright; Human; Inhibitory Synapse; Interneurons; Learning; Mammals; Measures; Medial; Mediating; Memory; Modeling; Monitor; Mus; Neurons; Parvalbumins; Pathway interactions; Patients; Phobias; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Reporting; Retrieval; Role; Safety; Signal Transduction; Synapses; Testing; Time; Work; base; brain cell; conditioned fear; design; effective therapy; fear memory; improved; learning extinction; neural circuit; neurobiological mechanism; neuronal circuitry; novel; optogenetics; response; traumatic event; treatment of anxiety disorders

PROJECT SUMMARY Exposure therapy is the most widely used treatment for excessive fear caused by post-traumatic stress disorder and phobias. During exposure therapy the patient repeatedly confronts the fear-inducing situation or the memory of a traumatic event in a safe environment, which over time results in decreased fear in most patients. However, exposure therapy in its current form rarely leads to a permanent suppression of fear. A better understanding of how exposure therapy, also known as fear extinction, works is therefore needed. A brain region called the basolateral amygdala (BLA) can cause increased fear in both humans and other mammals. We found that the BLA of mice undergoes changes during fear extinction that might help to suppress fear. Specifically, fear extinction silenced BLA fear neurons, while changing the inhibitory synapses that are located around these fear neurons. To test if these changes in perisomatic inhibitory synapses contribute to fear suppression, we silenced the parvalbumin-positive (PV+) interneurons that make these perisomatic inhibitory synapses. This increased the activation of BLA fear neurons and the expression of fear. Furthermore, it changed the activation of neurons in a brain region outside of the BLA called the medial prefrontal cortex (mPFC). Finally, silencing PV+ interneurons in the BLA altered the frequency distribution of local field potential (LFP) oscillations in both the BLA and mPFC, indicating broad changes in the activation of neuronal circuits that connect these two brain regions. Based on these results, we formulated a model in which extinction decreases fear by increasing the ability of PV+ perisomatic synapses to inhibit BLA fear neurons, thereby giving fear-suppressing circuits a competitive advantage over fear-promoting circuits. The three aims of this proposal will test if this model is correct. Aim 1 is to determine the contribution of PV+ perisomatic synapse remodeling in the BLA to extinction-induced fear suppression. To achieve this, we will monitor the strength of PV+ perisomatic synapses under conditions when fear suppression stops working, and by manipulating brain-derived neurotrophic factor signaling during fear extinction, which is predicted to interfere with extinction-induced perisomatic synapse remodeling. Aim 2 is to localize and manipulate functionally opposed LFP oscillations in the BLA during extinction-induced fear suppression. To achieve this, we will manipulate the activation state of three types of BLA neurons (PV+ interneurons, fear neurons, extinction neurons), while measuring both LFP oscillations and fear behavior. Aim 3 is to identify downstream neural circuits that mediate the contribution of BLA PV+ interneurons to extinction-induced fear suppression. This will be achieved by analyzing and manipulating BLA projection pathways to two subdivisions of the mPFC. Completion of this proposal can identify a critical role for BLA PV+ interneurons in tuning the balance between a fear-promoting circuit and a fear-suppressing circuit following fear extinction, which would aid the rationale design of new and more effective treatments for patients suffering from excessive fear.

项目总结