Determining the role of noradrenergic heterogeneity in innate threat response

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。通过使用这些方法，我们可以共同确定 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， 作为巡回精神科医生的独立研究生涯。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

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.