Multimodal and Supramodal processing of threatening emotional stimuli

项目总结/摘要 定义调节情绪状态的多维表征的大脑机制，例如 恐惧，是神经科学中的一个重要问题，与人类健康高度相关，包括精神疾病。 比如焦虑和抑郁。在动物模型中对恐惧的研究一直由 巴甫洛夫恐惧条件反射范式，以及对杏仁核的关注。然而，有必要扩大 研究杏仁核外系统的恐惧回路，以及情绪状态下先天恐惧的范例 可以在没有额外复杂性的情况下进行研究。还需要扩大 研究这样的电路，从专注于单核到中尺度的连接和功能。内侧 下丘脑防御回路介导对捕食者的先天防御反应。最近的数据显示， 下丘脑腹内侧核（VMH）中的神经元必要时表达转录因子SF 1 并且足以对捕食者做出防御行为和自主反应。然而，我们所知甚少， 这些神经元和它们的目标在代表威胁性刺激，并将其转化为 情绪状态和防御性反应。为了填补这一空白，我们正在使用最先进的工具 用于记录，成像和干扰该系统中的神经活动，使用SF 1+神经元作为进入点。 我们广泛的，长期的目标是了解情绪刺激是如何表现和转化为 内部状态和行为反应。本提案的中心目标是确定VMHdm/c SF 1+神经元和相关电路代表多模式威胁刺激，并产生防御性 应答这项研究的基本原理是，研究进化上古老的大脑回路， 保守的情绪状态，如恐惧，很可能产生多维情绪的一般原则， 表示.为了实现我们的目标，我们将描述SF 1+神经元如何代表多模态 威胁性感觉线索（目的1）;确定VMHdm/c SF 1+神经元中神经元活动与 对威胁刺激的可观察反应（目标2）;研究控制中尺度电路相互作用 在暴露于威胁性刺激时，同时记录多个区域的防御反应 (Aim 3）;并研究经验依赖性影响急性脑梗死的回路水平机制。 对威胁性刺激的反应（目标4）。我们的贡献将是应用最先进的基于基因的 工具来研究多模态威胁刺激的表征及其因果函数。这一贡献 是重要的，因为它将促进我们的理解微观和介观尺度电路动力学 潜在的情绪表征和反应。这种贡献是创新的，因为它代表了 这是第一次使用这种多维系统级方法来研究这种电路。的 因此，本申请中提出的工作将增加我们对基本脑机制的理解 情绪表征的研究，与理解和治疗人类精神疾病有潜在的相关性。

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.