Characterization of periaqueductal grey circuits for top-down motor/autonomic control and bottom-up cardiac interoception in fear and anxiety.

面对威胁时，哺乳动物的大脑会产生情绪状态，比如恐惧和焦虑，进而引发防御反应，以避免或减少伤害。这种反应包括主动或被动的防御行为反应、镇痛、心输出量的快速变化，以及其他生理和神经内分泌调节。关于身体外围状态变化的信息依次传递到脑干，并从那里传递到前脑区域进行情绪调节，如杏仁核，而岛叶皮层和前额叶皮层则是最重要的目标。这个过程被称为内感受，因此可以强烈地影响大脑的情绪状态。尽管在了解前脑回路如何自上而下控制恐惧和焦虑状态下引发的防御行为方面取得了很大进展，但介导内感受的回路仍然缺乏特征。使用功能性神经成像的人类研究主要集中在皮层区域的内感受，尽管有研究表明，内感受信号的一级整合已经在脑干水平上实现。中脑导水管周围灰质（PAG）是自上而下控制防御反应的电路的一部分。已有研究表明，PAG在介导主动和被动防御行为、镇痛和心功能调节等方面具有重要作用。我之前的研究，使用最先进的电路解剖方法，已经阐明了PAG神经元亚群和回路的功能，介导冻结和逃跑，两种保守的防御反应。PAG也接受来自后脑内感受区（如孤束核）的强输入，孤束核是迷走神经传入的主要目标。PAG本身投射到与情绪处理有关的前脑区域。这一提议的中心假设是PAG回路内的内感受性与自上而下的信号的整合对于调节恐惧和焦虑状态至关重要。这一假设将通过以下目标来解决：目标1：表征PAG电路中运动/自主神经控制和心脏内感受的细胞特异性和解剖连通性。目的2：操纵PAG回路内的神经元活动，用于运动/自主控制和心脏内感受，以干扰恐惧和焦虑。目的3：分析PAG电路中运动/自主控制和心脏内感受的信号整合。拟议的研究项目将提供对神经元回路的见解，介导内脏自下而上的信号对中枢恐惧和焦虑状态的影响，以及相应的运动和自主反应。阐明这些基本的内感受过程及其整合到自上而下控制行为和自主活动的回路中，将有助于理解回路功能失调的精神疾病。

In the face of threat, the mammalian brain generates emotional brain states such as fear and anxiety that in turn trigger a defense reaction to avoid or reduce harm. This reaction encompasses active or passive defensive behavioral responses, analgesia, and rapid change of cardiac output, among other physiologic and neuroendocrine adjustments. In-formation about changes in peripheral bodily states are in turn signaled to the brainstem and from there to forebrain regions for emotional regulation, such as the amygdala, and the insular and prefrontal cortices as the top-most targets. This process, termed interoception, can thereby strongly influence emotional brain states. Although much progress has been made in understanding how forebrain circuits exert top-down control of defensive behavior evoked during fear and anxiety states, the circuits mediating interoception remain poorly characterized. Humans studies using functional neuroimaging have focused on cortical areas for interoception, although it has been suggested that a first-order integration of interoceptive signals is already achieved at the level of the brainstem.The midbrain periaqueductal grey (PAG) is part of the circuitry that underlies top-down control of the defense reaction. Previous research has demonstrated a role of the PAG in mediating active and passive defensive behavior, analgesia and regulation of cardiac functions. My previous research, using state-of-the-art circuit dissection methodology, has elucidated the function of PAG neuronal subpopulations and circuits that mediate freezing and flight, two conserved defensive responses. The PAG also receives strong inputs from interoceptive regions in the hindbrain, such as the nucleus tractus solitarius, which is a major target of vagal afferents. The PAG itself projects to forebrain regions involved in emotional processing. The central hypothesis of this proposal is that integration of interoceptive with top-down signaling within PAG circuits is crucial for regulating fear and anxiety states. This hypothesis will be addressed with the following objectives:Objective 1: Characterization of cellular specificity and anatomical connectivity within PAG circuits for motor/autonomic control and cardiac interoception.Objective 2: Manipulation of neuronal activity within PAG circuits for motor/autonomic control and cardiac interoception to interfere with fear and anxiety.Objective 3: Analysis of signal integration within PAG circuits for motor/autonomic control and cardiac interoception.The proposed research project will provide insights into the neuronal circuits that mediate the effects of visceral bottom-up signaling on central fear and anxiety states, and their corresponding motor and autonomic reactions. Elucidating these basic interoceptive processes and their integration into circuits for top-down control of behavior and autonomic activity will help to understand dysregulation of circuit functions psychiatric conditions.