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: 9927083
• 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/9927083
• 关键词: Adaptive Behaviors; Aggressive behavior; American; Amygdaloid structure; Anatomy; Animals; 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; 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; cell cortex; cell type; effective therapy; fear memory; flexibility; intersectionality; 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.

项目摘要/摘要 恐惧是生存的必由之路。因此，大脑已经发展出强大而高效的 能够快速灵活地组织恐惧行为的神经回路 威胁。出于这个原因，当恐惧形成不当或过度表达时， 后果可能是非常有害的。这一点以焦虑障碍为例，如后焦虑 创伤应激障碍(PTSD)，在极端创伤事件后，动物 变得高度敏感，并对许多 适应不良的行为。与自适应联想恐惧记忆甚至是特定的 恐惧症，非联想恐惧敏感化的神经机制很差 明白了。在这里提出的研究中，我们的目标是研究潜在的神经回路 创伤以及创伤诱导的恐惧学习的增强，提高攻击性，以及 扰乱了性行为。目标1将结合细胞类型的特定功能操作与In 终纹背侧床核作用的深层次行为学分析 (DBNST)在创伤中。从基因上定义的和解剖上受限的dBNST访问将 使用Tac2-Cre小鼠和Cre依赖病毒编码光遗传和 化学发生效应器。目标2将进一步剖析控制每个目标的独特微电路 选择性操作和记录创伤后的行为表型 利用光遗传学、清晰度和光纤接收Tac2+dBNST输入的下游结构 测光学。基于从目标1和目标2获得的工具和信息，目标3将转向 上游，研究内侧前额叶皮质对dBNST Tac2+细胞和 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者的神经回路。 大脑。