The PACAP signaling pathway as a novel regulator of the neural circuits underlying fear generalization

项目总结/摘要 焦虑症，如广泛性焦虑症（GAD）和创伤后应激障碍（PTSD），是一种严重的精神障碍。 这是美国最常见的精神疾病，影响了18%的普通人群。一个典型的症状 这些障碍之一是恐惧泛化，在这种情况下，习得的恐惧反应被转移到类似但新的恐惧反应中。 刺激。因此，检查调节恐惧泛化和上下文辨别的神经回路是一个很好的方法。 这是理解压力恢复力的神经基础的关键一步。神经肽垂体腺苷酸 环化酶激活肽（PACAP）是大脑和外周恐惧反应的重要调节因子。 PACAP作用于大脑中的几种不同受体，包括垂体腺苷酸环化酶激活受体。 多肽I型受体（PAC 1）和血管活性肠肽受体2（VPAC 2）。这个Kirschstein-NRSA F31应用程序提出了一个研究和培训计划，将支持我走上发展的道路 成为独立研究科学家所需的技能，专注于研究PACAP和VPAC 2 信号及其对恐惧泛化的影响，使用尖端技术，如全脑成像， 以及同时的光遗传学操作和体内Ca 2+成像。在本提案中，我将研究如何 全脑VPAC 2表达与恐惧泛化的行为输出相关（目的1），并评估 VPAC 2在改变恐惧泛化背后的神经回路活动中的作用（目标2）。在Aim中 1，将使用情境恐惧辨别（CFD）任务测定小鼠。全脑成像技术将 然后用于可视化和比较高度恐惧和低度恐惧人群之间的全脑VPAC 2表达， 概括小鼠。在目标2中，我将利用Insopix nVoke系统同时进行体内光遗传学和 实时CFD行为期间的Ca 2+成像，以研究VPAC 2如何调节神经活动以影响恐惧 泛化行为这项研究的成功完成将有助于阐明一种新的信号转导的作用， 通路在介导的恐惧泛化的神经基板。最终，这些知识可能有助于 制定更有针对性的具体干预措施，以更好地治疗和预防恐惧和焦虑症。 这些数据，沿着通过F31奖开发的研究和科学专业知识，将支持我 成功转型为独立的神经科学家

Project Summary / Abstract Anxiety disorders, such as generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD), are the most common mental illnesses in the US, affecting up to 18% of the general population. A defining symptom of these disorders is fear generalization, in which learned fear responses are transferred to similar but novel stimuli. Examining the neural circuits that modulate fear generalization and context discrimination is therefore a critical step to understanding the neural substrates of stress resilience. The neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) is known as a critical regulator of fear responses in the brain and periphery. PACAP acts on several different receptors in the brain, including pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1) and vasoactive intestinal peptide receptor 2 (VPAC2). This Kirschstein-NRSA F31 application presents a program for research and training that will support me on a path towards developing the skills necessary to become an independent research scientist focused on studying PACAP and VPAC2 signaling and their effects on fear generalization using cutting-edge techniques such as whole-brain imaging, and simultaneous optogenetic manipulation and in vivo Ca2+ imaging. In this proposal, I will investigate how whole-brain VPAC2 expression correlates with the behavioral output of fear generalization (Aim 1), and assess the contribution of VPAC2 in altering activity of the neural circuits underlying fear generalization (Aim 2). In Aim 1, mice will be assayed using a contextual fear discrimination (CFD) task. Whole-brain imaging techniques will then be used to visualize and compare brain-wide VPAC2 expression between populations of high- and low-fear generalizing mice. In Aim 2, I will leverage the Inscopix nVoke system for simultaneous in vivo optogenetic and Ca2+ imaging during real-time CFD behavior to investigate how VPAC2 modulates neural activity to affect fear generalization behavior. Successful completion of this study will help elucidate the role of a novel signaling pathway in mediating the neural substrates of fear generalization. Ultimately, this knowledge could contribute to the development of more targeted, specific interventions to better treat and prevent fear and anxiety disorders. These data, along with the research and scientific expertise developed through this F31 award, will support my successful transition into an independent neuroscientist.