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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要恐惧是生存所必需的。因此，大脑已经发展为强大而高效的能够快速灵活地组织恐惧行为以应对恐惧的神经回路威胁。因此，当恐惧不恰当地形成或过度表达时，后果可能是非常有害的。焦虑症就是一个例子，例如后遗症。创伤性应激障碍（PTSD），其中在经历极度创伤事件后，动物变得高度敏感并容易受到一些因素的发展和表达的影响适应不良行为。与适应性联想恐惧记忆甚至特定恐惧记忆相反恐惧症中，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引起的恐惧学习增强、攻击性增强和扰乱了性行为。目标 1 将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) 创伤。基因定义和解剖学限制的 dBNST 访问将使用 Tac2-Cre 小鼠和编码光遗传学的 Cre 依赖性病毒获得化学遗传学效应子。目标 2 将进一步剖析控制每个器件的独特微电路通过选择性地操纵和记录创伤诱发的行为表型使用光遗传学、CLARITY 和光纤接收 Tac2+ dBNST 输入的下游结构光度测定。基于从目标 1 和 2 获得的工具和信息，目标 3 将转变为上游，研究内侧前额叶皮层输入对 dBNST Tac2+ 细胞的作用，以及这些输入对创伤和相关行为进行自上而下的控制的能力。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脑。