Ventromedial prefrontal cortex regulation of fear memory expression

焦虑症，如创伤后应激障碍（PTSD）通常在个体经历高度创伤性事件时形成。创伤后应激障碍的一个标志是明显的恐惧表达和对抑制恐惧的行为疗法的抵抗。内侧前额叶皮层（mPFC）是重要的中介表达和抑制学习恐惧。具体而言，人类背侧前扣带回和腹内侧（vmPFC）的mPFC的亚部通常被认为是负责介导的表达和抑制恐惧，分别。然而，一些研究表明，除了抑制恐惧的作用外，vmPFC的活动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，对vmPFC的损害被认为可以防止PTSD的发展。尽管它与病理性恐惧行为有明确的相关性，但这种功能二分法的机制仍不清楚。啮齿类动物通常用于研究恐惧记忆调节的机制，因为它们与人类有许多相似的回路。与人类的vmPFC类似，啮齿类动物的vmPFC介导恐惧的抑制，并且可以分为两个解剖学上不同的子区域，包括边缘下（IL）和背脚（DP）皮质。虽然这两个vmPFC亚区被认为是介导的抑制恐惧，所有的研究都集中在IL和有没有明确的研究，研究DP在调节记忆的潜在贡献。相反，其假设的作用，在介导恐惧抑制，我的初步数据表明，DP是从事在表达条件性恐惧，并表现出证据的恐惧学习依赖的可塑性。基于这些数据，我建议DP编码学习恐惧通过学习依赖的兴奋性和抑制性可塑性。为了验证这个假设，我提出了以下两个目标：1。通过使用Miniscope在体DP钙成像，顺行回路追踪，并结合使用恐惧标记的DP神经元的体内光遗传学操作和靶脑区域的纤维光度学，解决恐惧激活的DP神经元的活动动力学和长程靶点。2.通过结合DP投射群体的体内光遗传学操纵和DP中的纤维光度测定，确定导致恐惧学习依赖性DP募集的电路机制。我们还将采用离体电生理学测量的经验依赖性可塑性的长期预测DP在细胞类型特异性的方式。从这个建议的结果将是第一个特点的DP在调节恐惧记忆的作用，概述它如何整合到现有的模型的恐惧电路，并描绘电路可塑性机制，确保是招聘后恐惧学习。

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.