Identification and treatment of brain regions causing post-traumatic headache

 描述（由申请人提供）： 目标：本提案的主要目标是培养Sowers博士成为VA系统中的独立翻译神经科学家。为了实现这一目标，他准备了一项研究计划，该计划将允许进行最先进的光遗传学技术培训，以解决退伍军人面临的一个主要问题，即创伤后头痛。退伍军人从现役返回的风险增加创伤后头痛，包括偏头痛。美国军事人员在从伊拉克一年的战斗之旅返回后90天内进行了筛查，与平民相比，偏头痛的发病率是平民的2-4倍。创伤后头痛的一个使人衰弱的方面是并发的恐惧症，这会对退伍军人的日常生活产生负面影响。由于对相关神经解剖学相关性的理解不足，对创伤后头痛和头痛恐惧症的干预和治疗仍然不足。该提案旨在确定与创伤后头痛和光敏性的发展直接相关的大脑区域，并测试减轻光敏性的药理学药物。作为一个起点，我们计划把重点放在涉及光厌恶和神经肽降钙素基因相关肽（CGRP）调制的领域。我们的研究结果将克服两个主要障碍，在未来的治疗退伍军人创伤性脑损伤（TBI）的发展，通过确定：第一，大脑区域足以诱导恐惧症，第二，这些区域是否是必要的TBI诱导恐惧症的发展。这些研究的结果将指导未来的创新治疗干预，如深部脑刺激和经颅刺激，用于治疗这种使人衰弱的慢性TBI。这项研究将通过与他的多学科指导团队的临床互动来帮助，其中两个是VA系统内的执业精神病学家，以及神经眼科医生。Sowers博士将在视力丧失治疗和预防中心接触到大量的TBI人群。培训计划还将利用与VA中心的临床医生和基础科学家的互动。此外，Sowers博士的导师正在与两家制药公司（桤木和礼来公司）合作，这将有助于翻译预期的 临床试验的结果。这些临床观点不仅有助于申请人的培训，而且还将把研究计划集中在快速翻译的时间表上。方法：我们建立了一个临床前爆炸引起的光厌恶模型作为创伤后头痛的客观指标。在目标1中，我们将使用光遗传学应用来靶向我们假设与创伤后头痛的发展有关的特定脑区域。在目的2中，我们将使用CGRP的药理学操作来减轻C57 BL/6 J野生型小鼠的创伤后头痛。预期成果：该提案将有三个主要成果：1）它将使申请人成为临床前TBI模型的专家，这些模型与新疗法的转化测试密切相关。2)它将通过识别可能成为特定深部脑刺激或经颅刺激治疗靶点的脑区，大大促进我们对创伤后头痛和头痛恐惧症的神经解剖学基础的理解。3)拟议的工作将有利于退伍军人确定未来的药物治疗，以改善创伤后头痛。

 DESCRIPTION (provided by applicant): Objective: A major objective of this proposal is to train Dr. Sowers to become an independent translational neuroscientist in the VA system. To accomplish this, he has prepared a research plan that will allow training in state-of-the-art optogenetic techniques to address a major issue facing Veterans, post-traumatic headache. Veterans returning from active duty are at an increased risk for post-traumatic headache that includes migraine. U.S. military personnel screened within 90 days of returning from a one-year combat tour in Iraq had 2-4 times the rate of migraine compared to civilians. One debilitating aspect of post traumatic headache is concurrent photophobia which can negatively affect Veterans daily lives. Interventions and treatments for post- traumatic headache and photophobia remain inadequate due to a poor understanding of the relevant neuroanatomical correlates. This proposal aims to identify brain regions that are directly involved with the development of post-traumatic headache and photosensitivity and test pharmacological agents to mitigate light sensitivity. As a starting point we plan to focus on areas implicated in light aversion and modulated by the neuropeptide calcitonin gene-related peptide (CGRP). Our findings will overcome two major hindrances in the development of future treatments for Veterans with traumatic brain injury (TBI) by determining: first, which brain regions are sufficient to induce photophobia, and second, whether these regions are necessary for the development of TBI induced photophobia. The results from these studies will guide future innovative therapeutic interventions, such as deep brain stimulation and transcranial stimulation, for the treatment of this debilitating chronic condition of TBI. This stuy will be aided by clinical interactions with his multidisciplinary mentoring team, two of which are practicing psychiatrists within the VA system, as well as a neuro-ophthalmologist. Dr. Sowers will have access to a large TBI population at the Center for the Treatment and Prevention of Visual Loss. The training plan will also take advantage of interactions with clinicians and basic scientists in the VA Center. Moreover, Dr. Sowers' mentor has ongoing collaborations with two pharmaceutical companies (Alder and Eli Lilly) that will facilitate the translation of the expected findings to clinical trials. These clinical perspectives will not only aid with the applicant's traning, but will also focus the research plan on a fast translational timeframe. Methods: We have established a pre-clinical blast-induced light-aversion model as an objective indicator of post-traumatic headache. In Aim 1, we will use optogenetic applications to target specific brain regions we hypothesize to be involved with the development of post-traumatic headache. In Aim 2 we will use pharmacological manipulation of CGRP to alleviate post-traumatic headache in C57BL/6J wild type mice. Expected results: This proposal will have three main outcomes: 1) It will establish the applicant as an expert in pre-clinical TBI models that are closely linked to translational testing of novel therapeutics. 2) It will significantly advance our understanding of the neuroanatomy underlying post-traumatic headache and photophobia by identifying brain regions that could be targets for specific deep brain stimulation or transcranial stimulatory treatments. 3) The proposed work will benefit Veterans by identifying future pharmacological treatments to ameliorate post-traumatic headache.