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

PACAP信号通路作为恐惧泛化背后的神经回路的新型调节器

基本信息

批准号：
10163069
负责人：
Briana Kaying Chen
金额：
$ 4.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163069
关键词：
Address Affect Affinity Anxiety Disorders Applications Grants Award Behavior Behavioral Behavioral Assay Binding Biological Assay Brain Brain imaging Brain region Cells Data Development Discrimination Discrimination Learning Disease Enterobacteria phage P1 Cre recombinase Exposure to Extinction (Psychology)Freezing Fright G-Protein-Coupled Receptors General Population Generalized Anxiety Disorder Goals Hippocampus (Brain)Image Imaging Techniques Implant Individual Intervention Jaw Knowledge Measures Mediating Mental disorders Methods Modeling Mus National Research Service Awards Neurons Neuropeptides Output PACAPR-1 protein Parahippocampal Gyrus Pattern Population Post-Traumatic Stress Disorders Principal Investigator Refractory Research Research Training Role Scientist Shock Signal Pathway Signal Transduction Signal Transduction Pathway Stimulus Stress Symptoms System Techniques Testing Therapeutic Time Viral Virus anxiety symptoms calmodulin-dependent protein kinase II cellular imaging conditioned fear dentate gyrus effective intervention in vivo indexing inhibitory neuron insight lens neural circuit neuronal excitability neuropsychiatric disorder neurotransmission novel novel therapeutics optogenetics pituitary adenylate cyclase activating polypeptide prevent programs receptor relating to nervous system response selective expression skills stress resilience vasoactive intestinal peptide 2 receptor

项目摘要

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.

项目概要/摘要焦虑症，例如广泛性焦虑症（GAD）和创伤后应激障碍（PTSD），美国最常见的精神疾病，影响高达 18% 的总人口。一个明确的症状这些疾病的一个特点是恐惧泛化，其中习得的恐惧反应被转移到类似但新颖的刺激。因此，检查调节恐惧泛化和情境辨别的神经回路是一个研究课题。了解压力恢复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）被认为是大脑和外周恐惧反应的关键调节因子。 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 I 型多肽受体 (PAC1) 和血管活性肠肽受体 2 (VPAC2)。这个 Kirschstein-NRSA F31 申请提供了一个研究和培训计划，它将支持我走上发展之路成为专注于研究 PACAP 和 VPAC2 的独立研究科学家所需的技能使用全脑成像等尖端技术来研究信号传导及其对恐惧泛化的影响，以及同步光遗传学操作和体内 Ca2+ 成像。在这个提案中，我将研究如何全脑 VPAC2 表达与恐惧泛化的行为输出相关（目标 1），并评估 VPAC2 在改变恐惧泛化背后的神经回路活动方面的贡献（目标 2）。瞄准 1，将使用情境恐惧辨别（CFD）任务对小鼠进行分析。全脑成像技术将然后用于可视化和比较高恐惧人群和低恐惧人群之间的全脑 VPAC2 表达概括老鼠。在目标 2 中，我将利用 Inscopix nVoke 系统同时进行体内光遗传学和实时 CFD 行为期间的 Ca2+ 成像，以研究 VPAC2 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型信号传导的作用介导恐惧泛化的神经基质的途径。最终，这些知识可能有助于制定更有针对性、更具体的干预措施，以更好地治疗和预防恐惧和焦虑症。这些数据以及通过 F31 奖项开发的研究和科学专业知识将支持我的研究成功转型为独立神经科学家。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

小鼠脑外伤引起的恐惧泛化涉及海马记忆痕迹功能障碍，(R,S)-氯胺酮可缓解这种情况。

DOI：
发表时间：
2024-01-01
期刊：
影响因子：
10.6
作者：
McGowan, Josephine C;Ladner, Liliana R;Shubeck, Claire X;Tapia, Juliana;LaGamma, Christina T;Anqueira;DeFrancesco, Ariana;Chen, Briana K;Hunsberger, Holly C;Sydnor, Ezra J;Logan, Ryan W;Yu, Tzong;Kernie, Steven G;Denny
通讯作者：
Denny

Propranolol Decreases Fear Expression by Modulating Fear Memory Traces.

普萘洛尔通过调节恐惧记忆痕迹来减少恐惧表达。

DOI：
发表时间：
2021
期刊：
影响因子：
10.6
作者：
Leal Santos, Sofia;Stackmann, Michelle;Muñoz Zamora, Andrea;Mastrodonato, Alessia;De Landri, Allegra V;Vaughan, Nick;Chen, Briana K;Lanio, Marcos;Denny, Christine A
通讯作者：
Denny, Christine A

Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits.

氟乙基去甲美金刚是美金刚的一种新型衍生物，可促进消退学习，且不会出现感觉运动缺陷。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Chen, Briana K;Le Pen, Gwenaëlle;Eckmier, Adam;Rubinstenn, Gilles;Jay, Therese M;Denny, Christine A
通讯作者：
Denny, Christine A