Orexin regulation of responses to brain injury

项目摘要 创伤性脑损伤（TBI）对受影响个体的生活质量具有破坏性后果。 轻度TBI（mTBI）非常常见，影响全世界约4200万人（NINDS.gov; 2015）。主要症状包括白天过度嗜睡，记忆力和注意力差以及精神病 症状包括焦虑[1，2]。mTBI的恢复可能是不平衡的，有些人会发展成 长期症状[3]。一个因素可能是个体之间mTBI严重程度差异的基础， 症状是压力暴露压力暴露在导致TBI的环境中很常见[4]，压力可以 加重mTBI结果并导致长期mTBI结果，而心理压力导致 从mTBI可以加剧症状，并导致精神问题[7]，先前的压力， 对随后的mTBI的增加的脆弱性不太清楚[5]。这些结果表明， 应激可改善mTBI后的临床结局。本提案的目的是确定 神经肽食欲素是应激通过其发挥作用的神经底物。食欲素具有 主要研究它们在损伤后调节行为结果中的作用。然而，食欲素是否 在先前的压力暴露过程中的行为，以调节随后的mTBI的结果研究甚少。基于我们 根据初步数据，该提议的中心假设是食欲素神经元活动是 慢性应激对轻度侧向液压冲击伤（LFPI）引起的焦虑相关性的影响 食欲素的行为和这些作用依赖于性别。两个目标旨在验证这一点 假说.具体目标1中的实验将检验对CSDS敏感的小鼠将 在LFPI后食欲素神经元的神经递质调节中表现出性别特异性改变。实验 在具体目标2中，将检验以下假设：在应激期间降低食欲素活性将促进 恢复力和减少LFPI对焦虑结果的影响。这些实验将提供 关于食欲素细胞活性作为减少应激对mTBI影响的机制的重要新信息- 诱导焦虑这些实验汇集了PI在应激神经生物学和mTBI方面的专业知识。 建议使用的工具和范例在我们的实验室中得到了很好的验证。

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.