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

点击翻译按钮获取中文摘要

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.