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Determining the role of noradrenergic heterogeneity in innate threat response

确定去甲肾上腺素能异质性在先天威胁反应中的作用

基本信息

批准号：
10651704
负责人：
Alfred P Kaye
金额：
$ 19.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651704
关键词：
Anatomy Arousal Autopsy Behavior Behavioral Behavioral Paradigm Biosensor Brain Calcium Cells Complement Complex Computer Analysis Computer Models Cues Data Disease Dissection Electrophysiology (science)Emotional Exploratory Behavior Exposure to Foundations Fright Funding Future Gene Expression Profile Genes Goals Head Heterogeneity Human Image Individual K-Series Research Career Programs Knowledge Learning Literature Mental disorders Mentors Mentorship Methods Microscope Modeling Molecular Mus Nature Neurobiology Neuromodulator Neurons Neurotransmitters Norepinephrine Optics Pattern Physicians Physiology Population Post-Traumatic Stress Disorders Predatory Behavior Prefrontal Cortex Psychiatrist Psychological reinforcement Reporting Research Role Scientist Shelter facility Source Stimulus Stress Structure Symptoms System Techniques Training Trauma Visit Visual Work career cell type computer framework differential expression experience experimental study improved in vivo innovation locus ceruleus structure microendoscope mind control neural circuit neurochemistry noradrenergic norepinephrine system novel optical imaging optogenetics programs response single cell sequencing single nucleus RNA-sequencing single-cell RNA sequencing transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY / ABSTRACT Studying the circuit basis of fear in psychiatric disorders has relied on learned associations between stimuli and threatening experiences. Stimuli which are innately threatening represent an alternative approach to this problem, and may elicit different neural circuit mechanisms to promote survival. The neurotransmitter norepinephrine serves an important role in threat response, and recent studies have demonstrated the existence of multiple subtypes of norepinephrine cells within the locus coeruleus (LC). The scientific objective of this project is to determine how subtypes of norepinephrine neurons in LC contribute to the encoding of threat, so that in the future we can develop improved therapies for trauma-related disorders based on that knowledge. Our specific aims employ fluorescent biosensors of norepinephrine, miniature head-mounted microscopes for recording LC norepinephrine cells, optogenetics, and single cell transcriptomics. In our preliminary data, we identify a computational framework in which to consider the problem of learning from innate threat, then show the feasibility of these approaches. By employing these methods, we can collectively identify the relationship between norepinephrine cell-types and the encoding of threat at molecular, cellular, and circuit scales. This will generate a parts list for future studies into the nature of threat processing. In addition to the proposed studies, this proposal develops a plan to train Dr. Kaye for an independent research career as a circuit psychiatrist. This plan is mentored by Dr. Alex Kwan, an expert in optical approaches to neural circuit dissection and computational approaches to behavior, with the co-mentorship of Dr. Kerry Ressler, an expert in the neurobiology of posttraumatic stress disorder and Dr. Ronald Duman, an expert in the neurobiology of stress. This proposal relies on additional training in transcriptomics from Dr. Nenad Sestan, in optogenetics from Dr. Ralph DiLeone, and in the physiology of the norepinephrine system from Dr. Gary Aston-Jones.

项目总结/摘要研究精神疾病中恐惧的电路基础依赖于习得性联想刺激和威胁之间的关系天生具有威胁性的刺激代表着这是解决这个问题的另一种方法，可能会引出不同的神经回路机制，促进生存。神经递质去甲肾上腺素在威胁中起着重要作用反应，最近的研究表明，存在多种亚型的蓝斑内的去甲肾上腺素细胞。该项目的科学目标是确定LC中去甲肾上腺素神经元的亚型如何有助于威胁的编码，这样在未来我们就可以开发出更好的治疗创伤相关疾病的方法，这种知识。我们的具体目标是使用去甲肾上腺素的荧光生物传感器，微型头戴式用于记录LC去甲肾上腺素细胞、光遗传学和单细胞的显微镜转录组学在我们的初步数据中，我们确定了一个计算框架，考虑从先天威胁中学习的问题，然后展示这些方法的可行性。接近。通过采用这些方法，我们可以共同识别去甲肾上腺素细胞类型和在分子、细胞和电路尺度上的威胁编码。这将生成一个部件列表，用于将来研究威胁处理的性质。除了拟议的研究，本提案还制定了一项计划，培训Kaye博士，作为巡回精神病学家的独立研究生涯该计划由Alex Kwan博士指导，神经回路解剖的光学方法和计算方法的专家， Kerry Ressler博士是神经生物学专家，创伤后应激障碍和罗纳德杜曼博士，在压力的神经生物学专家。该提案依赖于Nenad Sestan博士在转录组学方面的额外培训，光遗传学博士拉尔夫DiLeone，并在去甲肾上腺素系统的生理学，博士加里·阿斯顿·琼斯