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

利用胆碱能炎症反射改变脑外伤后的神经炎症和神经精神后果

• 批准号: 10537766
• 负责人: Crystal M Noller
• 金额: --
• 依托单位: WHITE RIVER JUNCTION VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537766
• 关键词: Acute; Address; Affect; Amygdaloid structure; Animal Disease Models; Anterior; Anti-Inflammatory Agents; Anxiety; Anxiety Disorders; Area; Autonomic nervous system; Behavior; Behavioral Assay; Blast Phase; Brain; Brain Injuries; Brain region; Canada; Center for Translational Science Activities; Cessation of life; Cholinergic Agonists; Chronic; Chronic Phase; Closed head injuries; Cognitive deficits; Consultations; Data; Devices; Epidemic; Epilepsy; Equipment; FDA approved; Family; Fright; Functional disorder; General Population; Goals; Head; Health; Health Services Research; Healthcare; Hippocampus (Brain); Histology; Human; Immune; Immune response; Immune system; Immunohistochemistry; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Injury; Insula of Reil; Investigation; K-Series Research Career Programs; Knowledge; Lead; Link; Mediating; Medical center; Mental Depression; Mentors; Microscopy; Microsurgery; Military Personnel; Modeling; Nervous System Trauma; Neuroanatomy; Neuroimmune; Pathway interactions; Peripheral; Persons; Pharmacotherapy; Physicians; Positioning Attribute; Post-Traumatic Stress Disorders; Pre-Clinical Model; Quality of life; Recovery of Function; Reflex action; Research; Research Activity; Research Personnel; Research Priority; Research Support; Rivers; Rodent; Rodent Model; Safety; Scientist; Severities; Standardization; System; TBI treatment; Testing; Time; Training; Translations; Trauma; Traumatic Brain Injury; Tube; United States; Veterans; War; Work; battlefield injury; blood-brain barrier permeabilization; career; cholinergic; cingulate cortex; combat veteran; cytokine; design; disability; effective intervention; effectiveness evaluation; experience; immune activation; improved; mouse model; negative affect; neurobehavioral; neuroinflammation; neurological rehabilitation; neuropathology; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; neuroregulation; novel; pre-clinical; rehabilitation research; research and development; response; service member; standard of care; statistics; stress disorder; targeted treatment; tool; vagus nerve stimulation

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.

在世界范围内，创伤性脑损伤 (TBI) 比其他创伤相关疾病导致更多的死亡和残疾 受伤。最近的统计数据表明，6900万人受到这种“无声流行病”的影响，其中460万人受到影响。 居住在美国和加拿大的受影响人士。军事人员特别容易遭受 TBI， 被认为是最近战争的标志性伤害。这些封闭头、冲击波引发的爆炸 TBI (bTBI) 由于接近爆炸装置，会导致神经精神损伤，从而显着影响安全质量 受伤后的生活。神经炎症与普通人群的神经精神疾病有关，因此， 可能会调解这些障碍。迫切需要有效的抗炎治疗 TBI，一个正在积极研究的领域。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症反射来调节 神经炎症，但尚不清楚这两种方法是否可以在 bTBI 后使用。当前应用 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差距 使用 bTBI 啮齿类动物模型。迷走神经刺激（VNS）， 目前正在探索 FDA 批准的针对特定神经精神疾病的神经调节疗法 用于各种炎症和神经康复。 Anatabine 也正在接受类似的检查 神经康复，但这两种治疗方法均未用于治疗爆炸相关的闭合性头部损伤。目前的 研究旨在通过在临床前完成以下短期目标来解决这一知识差距 bTBI（小鼠）模型：1）了解胆碱能通路是否可以靶向改变 bTBI 的炎症反应，2) 了解靶向该途径是否可以减少 严重影响受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）描述 bTBI 的神经炎症反应，因为它与 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 VISN1CDA 支持我们的假设以及开展拟议研究的可行性。目前的 该项目旨在扩展我们的原理验证工作，以明确定义这些新颖疗法的效用。 如果成功，这种有前途的神经调节治疗可以提高军事护理标准 人员并改善退伍军人及其家人的生活质量。目前的职业发展 Award-2 将在 White River Junction VA 医疗中心进行，并结合了现有的 基础设施和设备，包括爆破管装置、再现战场的独特设备 受伤。候选人具有评估临床前功能障碍的科学经验 自主神经系统和免疫系统。她拥有十多年的研究经验，包括 疾病和神经创伤动物模型、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 博士组建了一支由退伍军人事务部顶尖科学家和 拥有丰富经验的医生指导早期职业调查人员走向独立。科学的 团队还包括当地专家，就工作的具体方面进行咨询。立即研究 这些活动将支持 Noller 博士成为一名转化型 VA 科学家的长期职业目标。具体来说， CDA-2 将在她接受神经炎症方面的指导培训期间提供受保护的时间， 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 完成研究活动以及指导和专门培训将建立她在该领域的专业知识 并最终以退伍军人管理局研究科学家的身份获得完全的研究独立性。