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.
The ventromedial prefrontal cortex is generally believed to mediate the inhibition of fear, however it is also paradoxically activated in a large subset of post-traumatic stress disorder patients, where fear expression is greatly enhanced. The proposed work will investigate the mechanisms underlying fear encoding in the ventromedial prefrontal cortex. Overall, results will reveal new information regarding how the medial prefrontal cortex participates in the encoding and expression of learned fear with important implications for disorders of pathological fear and anxiety.
