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：
9319813
负责人：
Moriel Zelikowsky
金额：
$ 9.07万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319813
关键词：
Adaptive Behaviors Aggressive behavior American Amygdaloid structure Anatomy Animals Anxiety Disorders Behavior Behavior Control 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 Injectable 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

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.

项目摘要/摘要恐惧对于生存至关重要。因此，大脑发展了强大而高效能够快速，灵活地组织恐惧行为的神经回应威胁。因此，当恐惧形成不当或过度表达时后果可能是有害的。这是通过焦虑症（例如创伤性应激障碍（PTSD），其中极端创伤事件，动物变得高度敏感并容易受到许多的发展和表达适应不良的行为。与自适应的联想恐惧记忆甚至具体形成鲜明对比恐惧症，非缔合性恐惧敏感性的神经机制很差理解。在此处提出的研究中，我们旨在调查基础神经回路创伤以及创伤引起的恐惧学习，侵略性升高和破坏了性行为。 AIM 1将结合细胞类型的特定功能操纵与IN 深度行为分析以检查质末端的背床核的作用（DBNST）创伤。遗传定义和解剖学上限制对DBNST的访问将使用TAC2-CRE小鼠和CRE依赖性病毒来获得光学遗理和化学发生效应子。 AIM 2将进一步剖析控制每个的独特微电路创伤引起的行为表型通过选择性操纵和记录使用光遗传学，清晰度和纤维接收TAC2+ DBNST输入的下游结构光度法。在AIMS 1和2获得的工具和信息的基础上，AIM 3将转弯上游，研究内侧前额叶皮层输入到DBNST TAC2+细胞和这些输入能够对创伤和相关行为的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电路脑。