Determining the role of noradrenergic heterogeneity in innate threat response

项目摘要/摘要 研究精神障碍中恐惧的电路基础依赖于已有的联想 在刺激和威胁体验之间。天生具有威胁性的刺激代表着 一种解决这个问题的替代方法，并可能引发不同的神经电路机制 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，最近的研究证明存在多个亚型的 蓝斑(LC)内的去甲肾上腺素细胞。这个项目的科学目标是 确定LC中去甲肾上腺素神经元的亚型如何参与威胁的编码， 因此，在未来，我们可以基于以下方面开发出更好的创伤相关疾病治疗方法 这种知识。 我们的特定目标是使用微型头盔去甲肾上腺素的荧光生物传感器 记录LC去甲肾上腺素细胞、光遗传学和单细胞的显微镜 转录学。在我们的初步数据中，我们确定了一个计算框架，在其中 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 接近了。通过使用这些方法，我们可以共同识别 去甲肾上腺素细胞类型和分子、细胞和电路尺度上的威胁编码。 这将生成一个部件列表，以供将来研究威胁处理的性质。 除了拟议的研究外，这项建议还制定了一项计划，培训凯博士进行 作为巡回精神病学家的独立研究生涯。这个计划是由关颖珊博士指导的， 神经回路解剖的光学方法和计算方法方面的专家 行为，在克里·雷斯勒博士的共同指导下，他是一位神经生物学专家 创伤后应激障碍和罗纳德·杜曼博士，他是压力的神经生物学专家。 这项提议依赖于Nenad Sestan博士在转录学方面的额外培训 来自拉尔夫·迪里昂博士的光遗传学，以及来自 加里·阿斯顿·琼斯博士。

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.