PACAP Signaling in Fear Circuitries Relevant to Post-Traumatic Stress Disorder

描述(由申请人提供)：了解精神疾病的生物机制和生物标记物对于了解、评估风险和设计创伤后应激障碍(PTSD)等疾病的治疗方法至关重要。在这方面，最近报道神经肽PACAP及其质膜受体PAC1在遗传和表观遗传水平上与创伤后应激障碍有关。这些发现补充了大量先前的证据，即PACAP/PAC1信号涉及应激和恐惧回路。该提案中的实验将使用基因打靶方法在细胞、分子和行为水平上剖析PACAP-PAC1信号在调节小鼠恐惧的电路中的参与。这些结果有望为基于PAC1信号及其下游作用的一套全新的创伤后应激障碍治疗靶点的开发奠定机制基础，并可能导致与这一途径相关的新的和强大的生物标志物的发现。

DESCRIPTION (provided by applicant): Understanding the biological mechanisms and biomarkers of psychiatric disease is critical for understanding, assessing risk, and designing treatments of disorders such as post traumatic stress disorder (PTSD). In this regard, it was recently reported that the neuropeptide PACAP and its plasma membrane receptor PAC1 are linked to PTSD at both genetic and epigenetic levels. These findings complement a considerable set of prior evidence implicating PACAP/PAC1 signaling in stress and fear circuitries. Experiments in the proposal will use gene targeting approaches to dissect at the cellular, molecular, and behavioral levels, the involvement of PACAP-PAC1 signaling in the circuitry regulating fear in mice. The results are hoped to lay a mechanistic foundation for the development of an entirely new set of therapeutic targets for PTSD based on PAC1 signaling and downstream actions, and may also lead to the discovery of novel and robust biomarkers associated with this pathway.