Genetic dissection of neural circuits underlying trauma, fear, and social behavior

对创伤、恐惧和社会行为背后的神经回路进行基因剖析

• 批准号: 9978917
• 负责人: Moriel Zelikowsky
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978917
• 关键词: Adaptive Behaviors; Aggressive behavior; American; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain; Brain imaging; Brain region; Cells; Data; Development; Disease; Dissection; Dorsal; Engineering; Enterobacteria phage P1 Cre recombinase; Environment; Extinction (Psychology); Failure; Fiber; Fright; Functional disorder; Genetic; Hand; Human; Hypothalamic structure; Label; Laboratory Study; Learning; Mammals; Maps; Medial; Memory; Mus; Neurons; Output; Pattern; Phenotype; Phobias; Photometry; Play; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Preoptic Areas; Process; Proteins; Public Health; Rattus; Research; Resistance; Rodent; Role; Sex Behavior; Social Behavior; Specific Phobia; Structure; Structure of terminal stria nuclei of preoptic region; Testing; Training; Transgenic Mice; Trauma; Viral Vector; Virus; behavioral phenotyping; cell cortex; cell type; effective therapy; fear memory; flexibility; neural circuit; neuromechanism; optogenetics; psychosocial; relating to nervous system; response; retrograde transport; sex; tool; traumatic event

Project Summary/Abstract Fear is imperative to survival. As such, the brain has developed powerful and highly effective neural circuits that are capable of rapidly and flexibly organizing fear behaviors in response to threat. For this reason, when fears are formed inappropriately or expressed excessively, the consequences can be highly detrimental. This is exemplified by anxiety disorders such as post- traumatic stress disorder (PTSD), wherein following an extremely traumatic event, animals become highly sensitized and susceptible to the development and expression of a number of maladaptive behaviors. In contrast to adaptive associative fear memories or even specific phobias, the neural mechanisms underlying non-associative fear sensitization are poorly understood. In the research proposed here, we aim to investigate the neural circuits underlying trauma as well as trauma-induced enhancements in fear learning, elevated aggression, and disrupted sexual behavior. Aim 1 will combine cell-type specific functional manipulations with in depth behavioral analyses to examine the role of the dorsal bed nucleus of the stria terminalis (dBNST) in trauma. Genetically defined and anatomically restricted access to the dBNST will be obtained using Tac2-Cre mice and Cre-dependent viruses encoding optogenetic and chemogenetic effectors. Aim 2 will further dissect the unique microcircuits that control each trauma-induced behavioral phenotype by selectively manipulating and recording from downstream structures receiving Tac2+ dBNST input using optogenetics, CLARITY and fiber photometry. Building upon the tools and information obtained from Aims 1 and 2, Aim 3 will turn upstream, investigating the role of medial prefrontal cortex inputs onto dBNST Tac2+ cells and the ability for these inputs to exert top-down control of trauma and associated behaviors. Collectively, these aims will help to elucidate the neural circuitry that controls the fear-sensitized brain.

项目总结/摘要 恐惧是生存的必要条件。因此，大脑已经发展出强大而高效的 神经回路能够快速灵活地组织恐惧行为， 威胁因此，当恐惧形成不当或表达过度时， 后果可能非常有害。这是典型的焦虑症，如后， 创伤性应激障碍（PTSD），其中在极度创伤性事件之后，动物 变得高度敏感，容易受到一些 适应不良的行为与适应性联想恐惧记忆或特定的 恐惧症，非联想恐惧敏感化的神经机制很差， 明白在这里提出的研究中，我们的目标是调查潜在的神经回路， 创伤以及创伤诱导的恐惧学习增强，攻击性升高， 扰乱性行为。目标1将联合收割机细胞类型特异性功能操作与 深度行为分析，以检查终纹背床核的作用 （dBNST）在创伤中的作用。基因定义和解剖学限制的dBNST访问将 使用Tac 2-Cre小鼠和编码光遗传学和 化学遗传效应子Aim 2将进一步剖析控制每一个的独特微电路 创伤诱导的行为表型，通过选择性地操纵和记录 下游结构使用光遗传学、微生物学和光纤接收Tac 2 + dBNST输入 测光法在目标1和2所提供的工具和信息的基础上，目标3将 上游，研究内侧前额叶皮层输入到dBNST Tac 2+细胞的作用， 这些输入对创伤和相关行为施加自上而下控制的能力。 总的来说，这些目标将有助于阐明控制恐惧敏感的神经回路。 个脑袋