Harnessing the Cholinergic Inflammatory Reflex to Alter Neuroinflammation and Neuropsychiatric Consequences Following Traumatic Brain Injury

在世界范围内，创伤性脑损伤（TBI）造成的死亡和残疾比其他创伤相关疾病更多。 受伤最近的统计数字表明，有6 900万人受到这种“无声的流行病”的影响， 居住在美国和加拿大的受影响人员。军事人员特别容易受到创伤性脑损伤的影响， 被认为是最近战争的标志性损伤。这些闭合头部冲击波诱发爆炸性TBI（bTBI）， 由于接近爆炸装置，导致神经精神损害，严重影响了 受伤后的生活神经炎症与一般人群中的神经精神疾病有关，因此， 可以调节这些损伤。目前迫切需要有效的抗炎治疗， TBI，一个积极调查的领域。广泛的研究表明，选择神经调节和 药物治疗工具可用于激活胆碱能炎性反射以调节 神经炎症，但目前还不清楚是否可以使用后bTBI的方法。当前应用程序 我将通过确定迷走神经刺激（一种神经调节）的效用来解决这些知识空白 工具，和anatabine，一种全胆碱能激动剂，使用bTBI的啮齿动物模型。迷走神经刺激（VNS）， 一种FDA批准的神经调节治疗选择神经精神疾病，目前正在探索 用于各种炎症和神经康复。Anatabine也同样被检查， 神经康复，但这两种治疗都没有用于爆炸相关的闭合性头部损伤。当前 研究旨在通过在临床前研究中完成以下短期目标来解决这一知识差距 bTBI（小鼠）模型：1）了解是否可以靶向胆碱能途径来改变 对bTBI的炎症反应，以及2）了解靶向该途径是否可以减少 严重影响损伤后生活质量的神经精神缺陷。这些目标将通过以下方式实现： 完成三个具体目标：1）表征对bTBI的神经炎症反应，因为它与脑损伤相关。 损伤的神经精神后果，2）确定VNS改变免疫反应的有效性 改善bTBI的神经精神后果，以及3）确定胆碱能激动剂的有效性 改变免疫反应以改善bTBI的神经精神后果。我们的初步数据和 最近的VISN 1CDA支持我们的假设和进行拟议的研究的可行性。当前 该项目旨在扩展我们的原理验证工作，以明确定义这些新疗法的效用。 如果成功，这种有前途的神经调节治疗可以提高军队的护理标准 提高退伍军人及其家属的生活质量。当前职业发展 Award-2将在白河交汇处VA医疗中心进行，并将现有的 基础设施和设备，包括爆炸管装置，重现战场的独特设备 受伤候选人具有临床前模型评估功能障碍的科学经验， 自主神经系统和免疫系统。她有超过十年的研究经验，包括 疾病和神经创伤的动物模型，显微外科手术，神经调节，免疫组织化学， 组织学和显微镜检查。Noller博士组建了一个由退伍军人事务部领先的科学家组成的指导团队， 具有丰富经验的医生指导早期职业研究者走向独立。科学 小组还包括当地专家，就工作的具体方面进行咨询。即时研究 这些活动将支持Noller博士成为一名翻译VA科学家的长期职业目标。具体地说， CDA-2将在她接受神经炎症指导培训时提供受保护的时间， 啮齿动物的神经解剖学、定量神经病理学和神经行为评估。集体 完成研究活动和指导和专业培训将建立她在该领域的专业知识 并最终作为VA研究科学家完全独立研究。

Worldwide, traumatic brain injury (TBI) contributes to more death and disability than other trauma-related injuries. Recent statistics indicate that 69 million people are affected by this “silent epidemic,” with 4.6 million affected persons residing in the United States and Canada. Military personnel are especially vulnerable to TBI, considered a signature injury of recent wars. These closed-head, shockwave-induced blast TBIs (bTBI), caused by proximity to explosive devices, lead to neuropsychiatric impairment that significantly affects the quality of life after injury. Neuroinflammation is linked to neuropsychiatric illness in the general population and thus, may mediate these impairments. There is a critical need for effective anti-inflammatory treatments for blast TBI, an area of active investigation. Extensive research shows that select neuromodulatory and pharmacotherapy tools can be used to activate the cholinergic inflammatory reflex to modulate neuroinflammation, but it is unknown whether either approach can be used after bTBI. The current application will address these gaps in knowledge by determining the utility of vagus nerve stimulation, a neuromodulation tool, and anatabine, a full-cholinergic agonist, using a rodent model of bTBI. Vagus nerve stimulation (VNS), an FDA-approved neuromodulation treatment for select neuropsychiatric disorders, is currently being explored for various inflammatory conditions and neurorehabilitation. Anatabine is similarly being examined for neurorehabilitation, but neither treatment has been used for blast-related, closed-head injuries. The current study aims to address this knowledge gap by completing the following short-term goals in a pre-clinical (mouse) model of bTBI: 1) understand whether the cholinergic pathway can be targeted to alter the inflammatory response to bTBI, and 2) understand whether targeting this pathway can reduce neuropsychiatric deficits that substantially affect the quality of life after injury. These goals will be achieved by completing three specific aims: 1) Characterize the neuroinflammatory response to bTBI as it relates to the neuropsychiatric consequences of injury, 2) Determine the effectiveness of VNS to alter the immune response to improve neuropsychiatric consequences of bTBI, and 3) Determine the effectiveness of a cholinergic agonist to alter the immune response to improve neuropsychiatric consequences of bTBI. Our preliminary data and recent VISN1CDA support our hypotheses and the feasibility of carrying out the proposed research. The current project is designed to extend our proof-of-principle work to clearly define the utility of these novel treatments. If successful, this promising neuromodulation treatment could advance the standard of care for military personnel and improve the quality of life for Veterans and their families. The current Career Development Award-2 will be performed at the White River Junction VA Medical Center and incorporates existing infrastructure and equipment, including a blast tube apparatus, unique equipment that recapitulates battlefield injuries. The candidate has scientific experience with pre-clinical models evaluating dysfunction in the autonomic nervous system and immune system. She has over ten years of research experience, including animal models of disease and neurotrauma, microsurgery, neuromodulation, immunohistochemistry, histology, and microscopy. Dr. Noller has assembled a mentoring team consisting of leading VA scientists and physicians with extensive experience mentoring early career investigators towards independence. The scientific team also includes local experts for consultation on specific aspects of the work. The immediate research activities will support Dr. Noller’s long-term career goal of becoming a translational VA scientist. Specifically, the CDA-2 will provide protected time while she receives mentored training in neuroinflammation, neuroanatomy, quantitative neuropathology, and neurobehavioral assessment of rodents. Collectively completing the research activities and mentored and specialized training will establish her expertise in the field and culminate in full research independence as a VA Research Scientist.