Orexin regulation of responses to brain injury

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PROJECT SUMMARY Traumatic brain injuries (TBI) have devastating consequences for the quality of life of affected individuals. Mild TBI (mTBI) is extremely common affecting approximately 42 million individuals worldwide (NINDS.gov; 2015). Key symptoms include excessive daytime sleepiness, poor memory and attention and psychiatric symptoms including anxiety [1, 2]. Recovery from mTBI can be uneven with some individuals developing long-term symptoms [3]. One factor that could underlie variations between individuals in mTBI severity of symptoms is stress exposure. Stress exposure is common in environments that lead to TBI [4], stress can exacerbate mTBI outcomes and result in protracted mTBI outcomes While psychological stress resulting from mTBI can exacerbate symptoms and lead to psychiatric problems [7], the role of prior stress in increasing vulnerability to subsequent mTBI is less clear [5]. These results suggest that mitigating the impact of stress could improve clinical outcomes after mTBI. The objective of this proposal is to determine whether the neuropeptides orexins are neural substrates through which stress exerts its effects. Orexins have primarily been studied for their role in regulating behavioral outcomes after injury. However, whether orexins act during prior stress exposure to regulate outcomes of subsequent mTBI is poorly studied. Based on our preliminary data, the central hypothesis of this proposal is that orexin neuron activity underlies the effects of chronic stress on mild lateral fluid percussion injury (LFPI)-induced anxiety-related behaviors and these actions of orexins are sex-dependent. Two Aims are designed to test this hypothesis. Experiments in Specific Aim 1 will test the hypothesis that mice susceptible to CSDS will exhibit sex-specific alterations in glutamatergic regulation of orexin neurons after LFPI. Experiments in Specific Aim 2 will test the hypothesis that reducing orexin activity during stress will promote resilience and reduce the effects of LFPI on anxiety outcomes. The proposed experiments will provide important new information on orexin cell activity as a mechanism to reduce the impact of stress on mTBI- induced anxiety. The experiments bring together the expertise of the PIs in stress neurobiology and mTBI. The tools and paradigms proposed for use are well-validated in our labs.