Ventromedial Prefrontal Cortex Regulation of Fear Memory

创伤后应激障碍(PTSD)等焦虑症通常在个人经历高度创伤事件时形成。创伤后应激障碍的一个特征是明显表现出恐惧和对抑制恐惧的行为疗法的抵抗。内侧前额叶皮质(MPFC)对调节习得性恐惧的表达和抑制起着重要作用。具体地说，人类背侧前扣带回和腹内侧(VmPFC)的分支通常被认为分别负责调节恐惧的表达和抑制。然而，一些研究表明，除了它抑制恐惧的作用外，vmPFC的活动还与非人类灵长类动物和人类的焦虑增加有关。此外，三分之一的创伤后应激障碍患者的vmPFC活性升高。更引人注目的是，损伤vmPFC被认为可以防止创伤后应激障碍的发展。尽管它与病理性恐惧行为明显相关，但vmPFC的这种功能二分法背后的机制仍不清楚。啮齿动物经常被用来研究恐惧记忆调节的机制，因为它们有许多与人类相似的回路。与人类的vmPFC类似，啮齿动物的vmPFC介导恐惧的抑制，在解剖学上可分为两个不同的亚区，包括边缘下皮质(IL)和脚背皮质(DP)。虽然这两个vmPFC亚区都被认为介导了对恐惧的抑制，但所有的研究都集中在IL上，还没有明确地研究DP在记忆调节中的潜在作用。与其在调节恐惧抑制中的假设作用相反，我的初步数据表明，DP参与了条件性恐惧的表达，并展示了恐惧学习依赖的可塑性证据。基于这些数据，我认为DP通过学习依赖的兴奋性和抑制性可塑性来编码获得性恐惧。为了验证这一假说，我建议追求以下两个目标：1.利用迷你示踪器体内钙成像、顺行电路示踪，结合体内对恐惧标记的DP神经元的光遗传操作和靶区的纤维光度测量，解析恐惧激活的DP神经元的活动动力学和远程靶点。2.结合对DP投射群体的体内光遗传操作和DP的纤维光度测定，确定导致恐惧学习依赖的DP重新募集的回路机制。我们还将使用体外电生理测量经验依赖的可塑性的长期投射到DP以细胞类型特定的方式。这一提议的结果将首次表征DP在调节恐惧记忆中的作用，概述它如何整合到现有的恐惧回路模型中，并描绘确保恐惧学习后IS重新招募的回路可塑性机制。

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.