Role of cholecystokinin-expressing interneurons in the oscillatory control of experience-dependent fear behavior

表达胆囊收缩素的中间神经元在经验依赖性恐惧行为的振荡控制中的作用

• 批准号: 10629152
• 负责人: Leon Reijmers
• 金额: $ 20.63万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629152
• 关键词: Amygdaloid structure; Behavior; Behavioral; Bilateral; Brain; Cholecystokinin; Data; Dependovirus; Electrodes; Environment; Exploratory Behavior; Extinction; Fiber Optics; Freezing; Frequencies; Fright; Future; Goals; Hippocampus; Human; Individual; Inhibitory Synapse; Interneurons; Light; Measures; Mediating; Mus; Neurons; Output; Parvalbumins; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Phase; Play; Post-Traumatic Stress Disorders; Retrieval; Role; Safety; Testing; Therapeutic; brain cell; conditioned fear; experience; fear memory; improved; member; mental state; neural circuit; neuronal cell body; optical fiber; optogenetics; promoter; receptor; therapeutic target

PROJECT SUMMARY An important functional role for oscillatory brain activity is supported by the observation that brain oscillations at specific frequencies correlate with specific behavioral and mental states, including states of fear. The precise mechanistic basis for these correlations is unclear. Achieving a deeper mechanistic understanding requires the identification of specific types of neurons that mediate causal relationships between specific patterns of oscillatory activity and specific behavioral and mental states. Different patterns of oscillatory activity have been detected in the basolateral amygdala (BLA) during the expression versus the suppression of experience- dependent fear behavior. Oscillatory activity that causes the suppression of experience-dependent fear behavior is controlled by parvalbumin-expressing (PV+) interneurons located in the BLA. PV+ interneurons exert strong control over both oscillatory activity and functional output of BLA circuits through inhibitory synapses that they make onto the soma of BLA projection neurons. Perisomatic inhibitory synapses in the BLA are also made by interneurons that express cholecystokinin (CCK+ interneurons). Based on previous findings, CCK+ interneurons in the BLA could play a role that is opposite from the role played by PV+ interneurons in the BLA with regards to the oscillatory control of experience-dependent fear behavior. The goal of this study is to determine if CCK+ interneurons in BLA control oscillatory activity that causes increased behavioral expression of experience-dependent fear. To achieve this goal, mice will be subjected to contextual fear conditioning, contextual fear extinction, and contextual fear retrieval. CCK+ interneurons in the BLA of these mice will be silenced with an optogenetic approach. Silencing CCK+ interneurons is hypothesized to decrease the behavioral expression of the fear memory, as measured by observing freezing behavior, and to also decrease oscillatory activity that causes experience-dependent fear behavior, as measured by recording local-field potentials in the BLA. In addition, the spiking activity of single-units in the BLA will be recorded and analyzed in order to identify neuronal mechanisms that might underlie the relationship between oscillatory and behavioral changes. Completion of this study will increase the mechanistic understanding of how brain oscillations control experience-dependent fear behavior, and might lead to improved treatment options for patients suffering from excessive fear, for example as a result of post-traumatic stress disorder.

项目总结