In our preclinical studies, we have found that the Tac2 pathway might be an attractive candidate to prevent the development of PTSD after exposure to a traumatic event. The Tac2 gene in rodents (Tac3 in humans) encodes the neurokinin B (NkB) neuropeptide which binds to the neurokinin 3 receptor (Nk3), a G-protein-coupled receptor. NkB and Nk3 are tachykinins, a family of neuropeptides widely distributed in the brain that act as neurotransmitters and neuromodulators having a variety of biological functions including modulation of emotion and learning. Previously, other tachykinin pathways, such as neurokinin 1 receptor (NK1) and substance P, have been described to be involved in fear processes. However, we provide the first evidence that Tac2, NkB and Nk3, all highly expressed in the central amygdala (CeA, a key substructure for the formation of fear memories) are involved in emotional learning processes. Specifically, using RNA microarray, qPCR and in situ hybridization approaches, we found that the Tac2 gene is dynamically regulated after cued-fear conditioning in the CeA. Moreover, a single systemic and intra-CeA dose of a Nk3 antagonist impaired cued-fear consolidation of memory. Thus, this Exploratory/Developmental R21 proposal is intended to gain a better understanding of the Tac2 pathway by overexpressing and silencing the Tac2 gene to further our understanding of its role in fear conditioning. Moreover, we aim to study the specific role of the Tac2 expressing cells within the CeA via optogenetic excitation and inhibition of Tac2-expressing cells during fear learning. Together these studies will provide a new understanding of the role of the Tac2/Nk3 pathway in the consolidation process underlying fear learning. These findings will energize and support a new research program aimed at translating the modulation of the Tac2/Nk3 pathway to provide novel approaches to intervention following fear and trauma exposure for the prevention of the PTSD.
Post-traumatic Stress Disorder (PTSD) is an anxiety disorder associated with altered fear learning that affects around 7.7 million American adults in a given year. The most common treatment for chronic PTSD is monotherapy with antidepressants alone, although limited significant benefits have been reported in clinical studies. In order to decrease the prevalence of PTSD, it is important to better understand the mechanisms of altered fear learning. Especially attractive and novel are early interventions after trauma exposure since they may prevent the development of PTSD by impairing fear memory consolidation. Our preliminary preclinical data and the proposed R21 study to understand the Tac2 pathway will have implications for novel therapeutic approaches for disorders with altered fear learning such as Post-traumatic Stress Disorder (PTSD).
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