Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats

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Current pharmacological treatments for PTSD and comorbid depression are inadequate. These stress- related psychiatric illnesses of high significance and impact to the veteran population, and finding more effective treatments would satisfy a tremendous gap in veterans’ health care. Evidence-based behavioral therapies, such as exposure therapy, are promising, but they also have limited efficacy. The lack of effective treatment arises, in part, from our lack of knowledge of the neurobiological mechanisms underlying these illnesses, the altered regulatory processes that lead to pathology, the neural systems that mediate the dimensions of cognition and adaptive coping behavior that are disrupted in these illnesses, and the mechanisms responsible for effective therapeutic response in any modality, pharmacological or behavioral. Such knowledge may inform a more targeted approach to increase therapeutic efficacy. To better study these processes, in the previous grant period we developed, validated and characterized extinction learning in rats as a model of exposure therapy in comorbid PTSD and depression. We demonstrated the efficacy of extinction in reversing behavioral and physiological deficits following chronic unpredictable stress. We showed that these effects were dependent upon activity in the medial prefrontal cortex (mPFC) during extinction for the therapeutic effects seen 24 hrs after treatment. And we showed that the therapeutic effects of extinction were dependent on the induction of de novo protein synthesis in the mPFC, which we believe represents the initiation of processes related to plasticity and changes in circuit function in this brain region. In this proposal for renewal, we will characterize the precise circuit-level plasticity and signaling mechanisms that underlie the therapeutic effects of extinction on a range of behavioral measures modeling different dimensions of comorbid PTSD and depression after chronic unpredictable stress exposure. In aim 1, using a virogenetic inhibitory DREADD strategy, we will investigate the role of specific efferent projections of the infralimbic (IL) and prelimbic (PL) sub-regions of mPFC to target regions that mediate specific behavioral response domains relevant to comorbid PTSD and depression, and to the therapeutic efficacy of exposure therapy. In aim 2, we will investigate the role of afferent projections to the IL and PL cortices arising from the mediodorsal thalamus and the ventral hippocampus in the therapeutic effects of extinction. We will also test the hypothesis that BDNF signaling during extinction, induced specifically by activity in ventral hippocampal afferent, initiates signal transduction processes in the mPFC necessary for the plasticity that is ultimately responsible for the beneficial behavioral effects seen 24 hours after extinction. With this knowledge, in aim 3, we will then test a rational adjunct treatment strategy combining a sub-effective extinction protocol with a sub- effective dose of a novel candidate pharmacotherapeutic agent, L-655,708, that activates signaling pathways and/or neural circuits convergent with those activated by extinction, to determine if this strategy can increase the efficacy of extinction. We have established the utility of the adjunct therapy strategy to detect enhanced efficacy using ketamine, an established therapeutic agent. The proposed investigation of potential therapeutic utility of L-655,708 is a high-risk high-gain undertaking, as the likelihood of success is less clear. L-655,708 is a selective negative allosteric modulator of the a5 subtype of the GABA-A receptor that is relatively specifically expressed in the ventral hippocampus, a major afferent to the IL cortex that we believe plays an important role in therapeutic efficacy after chronic stress. The ultimate goal of this research is to inform the development of more effective treatments for PTSD and comorbid depression, to improve the quality of life for veterans and their families. The PI and the MPI are well established VA investigators with a long history of productive collaboration and complementary expertise in stress neurobiology, psychopharmacology, animal models and systems neurobiology. They and their labs are ideally suited to the successful conduct of this project.