Multimodal and Supramodal processing of threatening emotional stimuli

威胁性情绪刺激的多模态和超模态处理

• 批准号: 10093134
• 负责人: David J Anderson
• 金额: $ 55.15万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-13 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093134
• 关键词: Acute; Address; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavior; Behavior Control; Behavioral; Brain; Cell Nucleus; Complex; Cues; Data; Dimensions; Disease; Elements; Emotional; Emotions; Exposure to; Fiber; Freezing; Fright; Functional disorder; Genetic; Head; Health; Human; Hypothalamic structure; Image; Interneurons; Learning; Maps; Measurement; Measures; Medial; Mediating; Mental Depression; Mental disorders; Mission; Modality; Neural Pathways; Neurobiology; Neurons; Neurosciences; Pattern; Photometry; Play; Post-Traumatic Stress Disorders; Process; Property; Public Health; Research; Resolution; Role; SF1; Sensory; Shock; Signal Transduction; Stimulus; Structure; System; Testing; Time; Ultrasonography; United States National Institutes of Health; Work; base; behavioral response; brain circuitry; conditioned fear; emotional stimulus; experience; innovation; midbrain central gray substance; multimodality; neural circuit; optogenetics; relating to nervous system; response; tool; ventromedial hypothalamic nucleus

Project Summary/Abstract Defining the brain mechanisms that mediate multidimensional representation of emotion states, such as fear, is an important problem in neuroscience with high relevance to human health, including psychiatric disorders such as anxiety and depression. The study of fear in animal models has been dominated by the Pavlovian fear conditioning paradigm, and a focus on the amygdala. However there is a need to extend the study of fear circuitry to extra-amygdala systems, as well as to paradigms for innate fear where emotion states can be studied without the additional complexities introduced by learning. There is also a need to expand the study of such circuits from a focus on single nuclei to meso-scale connectivity and function. The medial hypothalamic defensive circuit mediates innate defensive responses to predators. Recent data have identified neurons in the ventromedial hypothalamic nucleus (VMH) expressing the transcription factor SF1 as necessary and sufficient for defensive behavioral and autonomic responses to a predator. However little is known about the precise role of these neurons, and their targets, in representing threatening stimuli, and transforming this representation into emotion states and defensive responses. To fill this gap, we are using state-of-the-art tools for recording, imaging and perturbing neural activity in this system, using SF1+ neurons as a point-of-entry. Our broad, long-term objective is to understand how emotional stimuli are represented and transformed into internal states and behavioral responses. The central objective of this proposal is to determine how VMHdm/c SF1+ neurons, and associated circuitry, represent multi-modal threatening stimuli, and generate defensive responses. The rationale for this research is that the study of evolutionarily ancient brain circuits that control conserved emotion states such as fear is likely to yield general principles of multidimensional emotional representation. To achieve our objective, we will characterize how SF1+ neurons represent multi-modal threatening sensory cues (Aim 1); determine the relationship of neuronal activity in VMHdm/c SF1+ neurons to observable responses to threatening stimuli (Aim 2); investigate meso-scale circuit interactions controlling defensive responses by recording simultaneously from multiple regions during exposure to threatening stimuli (Aim 3); and investigate the circuit-level mechanisms underlying experience-dependent influences on acute responses to threatening stimuli (Aim 4). The contribution will be to apply state-of-the-art genetically based tools to study the representation of multimodal threatening stimuli and their causal functions. This contribution is significant because it will advance our understanding of the micro- and meso-scale circuit dynamics underlying emotional representations and responses. The contribution is innovative, because it represents the first time that this circuitry has been studied using such multidimensional systems-level approaches. The work proposed in this application will therefore increase our understanding of fundamental brain mechanisms of emotion representation, with potential relevance to understanding and treating human psychiatric disorders.

项目摘要/摘要 定义介导情绪状态多维表示的大脑机制，例如 恐惧，是与人类健康相关的神经科学的重要问题，包括精神病学 焦虑和抑郁等疾病。动物模型中恐惧的研究一直由 帕夫洛维亚恐惧调节范式，并关注杏仁核。但是有必要扩展 研究恐惧电路到外杏仁核系统的研究，以及在情感状态的天生恐惧的范式 可以研究没有学习引入的其他复杂性的情况。还需要扩展 研究从关注单核到中尺度连通性和功能的此类电路的研究。内侧 下丘脑防御回路调节对捕食者的先天防御反应。最近的数据已经确定 必要 足以使防御行为和对捕食者的自主性反应。但是对 这些神经元及其目标的确切作用在代表威胁刺激和改变这一点方面 代表情绪状态和防御反应。为了填补这一空白，我们正在使用最先进的工具 用于记录，成像和使用SF1+神经元作为进入点的神经活动。 我们广泛的长期目标是了解情感刺激的代表和转化为 内部状态和行为反应。该提案的核心目的是确定VMHDM/c的方式 SF1+神经元和相关电路代表多模式威胁刺激，并产生防御性 回答。这项研究的理由是，控制进化的古老脑电路的研究 保守的情绪状态（例如恐惧）可能会产生多维情感的一般原则 表示。为了实现我们的目标，我们将表征SF1+神经元如何代表多模式 威胁感官提示（目标1）；确定VMHDM/C SF1+神经元中神经元活性与 对威胁刺激的可观察反应（AIM 2）；调查控制中级电路相互作用 暴露于威胁刺激期间，通过同时记录来自多个区域的防御反应 （目标3）;并研究经验依赖性影响急性的电路级机制 对威胁刺激的反应（目标4）。贡献将是采用基于遗传的最先进的 研究多模式威胁刺激及其因果功能的代表性的工具。这个贡献 之所以重要，是因为它将提高我们对微观和中尺度电路动力学的理解 潜在的情感表征和反应。贡献是创新的，因为它代表 第一次使用此类多维系统级方法研究了该电路。这 因此，在本应用中提出的工作将增加我们对基本大脑机制的理解 情感表征，与理解和治疗人类精神疾病有关。

项目成果

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.

• DOI: 10.1016/j.cell.2018.03.037
• 发表时间: 2018-05-17
• 期刊: Cell
• 影响因子: 64.5
• 作者: Zelikowsky M;Hui M;Karigo T;Choe A;Yang B;Blanco MR;Beadle K;Gradinaru V;Deverman BE;Anderson DJ
• 通讯作者: Anderson DJ

Multimodal Analysis of Cell Types in a Hypothalamic Node Controlling Social Behavior.

• DOI: 10.1016/j.cell.2019.09.020
• 发表时间: 2019-10-17
• 期刊: Cell
• 影响因子: 64.5
• 作者: Kim DW;Yao Z;Graybuck LT;Kim TK;Nguyen TN;Smith KA;Fong O;Yi L;Koulena N;Pierson N;Shah S;Lo L;Pool AH;Oka Y;Pachter L;Cai L;Tasic B;Zeng H;Anderson DJ
• 通讯作者: Anderson DJ

Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex.

• DOI: 10.1038/nature23885
• 发表时间: 2017-10-18
• 期刊: Nature
• 影响因子: 64.8
• 作者: Remedios R;Kennedy A;Zelikowsky M;Grewe BF;Schnitzer MJ;Anderson DJ
• 通讯作者: Anderson DJ