Ventromedial Prefrontal Cortex Regulation of Fear Memory

腹内侧前额叶皮层对恐惧记忆的调节

基本信息

批准号：
10595725
负责人：
Kirstie Alyssa Cummings
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595725
关键词：
Amygdaloid structure Anatomy Anterior Anxiety Anxiety Disorders Area Behavior Behavior Therapy Behavioral Behavioral Mechanisms Brain region Data Development Disease Dorsal Electrophysiology (science)Ensure Exhibits Extinction (Psychology)Fiber Freezing Fright Head Human Individual Injury Insula of Reil Joints Knowledge Learning Link Measurement Medial Mediating Memory Mentors Modeling Monitor Mus Neurons Pathologic Pathological anxiety Patients Phase Photometry Physiological Play Population Post-Traumatic Stress Disorders Prefrontal Cortex Regulation Research Research Personnel Resistance Risk Factors Rodent Role Structure Sum Synapses Testing Training Work base calcium indicator cell type conditioned fear experience experimental study fear memory in vivo in vivo calcium imaging nonhuman primate optogenetics recruit skills traumatic event

项目摘要

Anxiety disorders such as post-traumatic stress disorder (PTSD) typically nucleate when individuals experience a highly traumatic event. One hallmark of PTSD is pronounced expression of fear and resistance to fear-suppressing behavioral therapies. The medial prefrontal cortex (mPFC) is important for mediating both the expression and inhibition of learned fear. Specifically, the human dorsal anterior cingulate and ventromedial (vmPFC) subdivisions of mPFC are generally believed to be responsible for mediating the expression and inhibition of fear, respectively. However, several studies have suggested that in addition to its fear-inhibiting role, activity in the vmPFC is associated with increased anxiety in non-human primates and humans. Moreover, vmPFC activity is elevated in a third of PTSD patients. More strikingly, damage to the vmPFC has been suggested to protect against the development of PTSD. Despite its clear relevance to pathological fear behaviors, the mechanisms underlying this functional dichotomy in vmPFC remain unclear. Rodents are routinely used to study the mechanisms of fear memory regulation due to their numerous circuit parallels with humans. Similar to the vmPFC in humans, the rodent vmPFC mediates the inhibition of fear and can be divided into two anatomically distinct subregions, including the infralimbic (IL) and dorsal peduncular (DP) cortices. While both vmPFC subregions are thought to mediate the inhibition of fear, all studies have centered on IL and there are no studies that explicitly examine the potential contributions of DP during the regulation of memory. In contrast to its hypothesized role in mediating fear inhibition, my preliminary data indicate that DP is engaged during the expression of conditioned fear and exhibits evidence of fear learning-dependent plasticity. Based on these data, I propose that DP encodes learned fear through learning-dependent excitatory and inhibitory plasticity. To test this hypothesis, I propose to pursue the following two aims: 1. Resolve the activity dynamics and long-range targets of fear-activated DP neurons by using Miniscope in vivo calcium imaging in DP, anterograde circuit tracing, and combining the use of in vivo optogenetic manipulation of fear-tagged DP neurons and fiber photometry in target brain regions. 2. Determine the circuit mechanisms leading to fear learning-dependent DP recruitment by combining in vivo optogenetic manipulation of DP-projecting populations and fiber photometry in DP. We will also employ ex vivo electrophysiological measurements of experience- dependent plasticity of long-range projections to DP in a cell type-specific manner. Results from this proposal will be the first to characterize the role of DP in the regulation of fear memory, to outline how it integrates into existing models of fear circuitry, and to delineate the circuit plasticity mechanisms ensuring is recruitment after fear learning.

当个体经历高度创伤事件时，诸如创伤后应激障碍（PTSD）之类的焦虑症通常会成核。 PTSD的一个标志是表达恐惧和抵抗恐惧行为疗法的表达。内侧前额叶皮层（MPFC）对于介导的表达和抑制恐惧很重要。具体而言，MPFC的人体前扣带回和腹侧（VMPFC）细分通常被认为分别负责介导表达和抑制恐惧。但是，一些研究表明，除了抑制恐惧的作用外，VMPFC的活性与非人类灵长类动物和人类的焦虑增加有关。此外，三分之一的PTSD患者的VMPFC活性升高。更引人注目的是，已经提出对VMPFC的损害，以防止PTSD的发展。尽管它与病理恐惧行为明显相关，但VMPFC中这种功能性二分法的基础机制仍不清楚。啮齿动物通常用于研究恐惧记忆调节机制，因为它们与人类的众多电路相似。与人类中的VMPFC相似，啮齿动物VMPFC介导了恐惧的抑制作用，并且可以分为两个解剖上不同的子区域，包括插度（IL）和背梗（DP）皮层。尽管两个VMPFC子区域都被认为可以介导恐惧的抑制作用，但所有研究都以IL为中心，并且没有研究明确检查DP在调节记忆过程中的潜在贡献。与它在介导恐惧抑制中的假设作用相反，我的初步数据表明，在有条件的恐惧表达时，DP参与并表现出恐惧依赖于学习依赖性可塑性的证据。基于这些数据，我建议DP通过依赖学习的兴奋性和抑制性可塑性来编码学习恐惧。为了检验这一假设，我建议追求以下两个目标：1。通过在DP中使用Miniscope在DP，Arterograde Cource跟踪中，解决恐惧激活DP神经元的活动动态和远程目标，并结合使用目标脑区域中恐惧标记的DP神经元和纤维光度法的体内光遗传学操纵。 2。确定导致恐惧学习依赖性DP募集的电路机制，通过结合体内光遗传学操纵DP项目种群和DP中的光纤光度法。我们还将以特定于细胞类型的方式对长期投影对DP的经验依赖性可塑性进行离体电生理测量。该提案的结果将是第一个表征DP在调节恐惧记忆中的作用，概述其如何集成到现有恐惧电路模型中的角色，并描绘出恐惧学习后确保电路可塑性机制的招募。