Neurobiology and Experimental Treatment of TBI Pain and Anxiety

TBI 疼痛和焦虑的神经生物学和实验治疗

• 批准号: 8426001
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426001
• 关键词: Affect; Amygdaloid structure; Animals; Anxiety; Behavior; Behavioral; Brain region; Cell Nucleus; Cervical; Chronic; Cognition; Cognitive; Community Services; Craniocerebral Trauma; Development; Dorsal; Exercise; Functional disorder; Head; Healthcare Systems; Hippocampus (Brain); Immune; Impaired cognition; Inflammation; Injury; Intervention; Lesion; Magnetism; Mass Spectrum Analysis; Measures; Modeling; Morbidity - disease rate; Neurobiology; Neurologic; Neurologic Manifestations; Neurons; Norepinephrine; Outcome; Outcome Measure; Pain; Rattus; Severities; Societies; Spinal; System; TBI treatment; Testing; Therapeutic; Time; Translations; Traumatic Brain Injury; Treatment Efficacy; Up-Regulation; Veterans; base; disability; effective intervention; gray matter; immunocytochemistry; interest; knowledge base; multiple disability; noradrenergic; pregabalin; programs; safety testing

DESCRIPTION (provided by applicant): Closed head traumatic brain injury (CH-TBI) results in a broad spectrum of neurological deficits. Recently, those involving cognition, pain sensitivity, and anxiety, have risen to the level of urgency for the development of new information that can enhance therapy for CH-TBI. This study proposes a unifying hypothesis regarding the multiple-morbidity that frequently following CH-TBI. It proposes that that dysfunction of the central noradrenergic (NA) system is a common underlying denominator of these multiple disabilities. Four aims are proposed to investigate specific neurological deficits induced by CH-TBI, how these are correlated with noradrenergic injury, and the potential for these deficits to be modified by three treatments that target upregulation of the central noradrenergic system. A fifth aim proposes a proof of principle sudy. Aim 1 will determine the severity and time-course of the three neurological manifestations following mild/moderate CH-TBI in a rat head injury model. Aims 2 will correlate the magnitude of behavioral changes after CH-TBI with measures of NA expression in regions of the brain predominantly involved in the specific behaviors of interest (i.e., hippocampus CA1 and CA3, central nucleus of the amygdala, and cervical and lumbar dorsal spinal gray matter). The third Aim will test the safety, feasibility, and efficacy of three therapies - activity wheel locomotor (AWL) exercise, transcortical magnetic stimulation (TMS), and pregabalin alone or in combination - on cognitive, pain, and anxiety outcomes of mild and moderate CH-TBI. Aim 4 will examine how these treatments affect regional NA expression using mass spectrometry and norepinephrine (NE) immunocytochemistry. Aim 5 will further test the central hypothesis by evaluating treatment efficacy (using the best treatment combination) in animals following selective immune-lesion of central noradrenergic neurons. The proposed studies will increase our knowledge base of: 1) CH-TBI-induced cognitive dysfunctions, anxiety, pain disabilities, and chronic inflammation; 2) the relationship of these disabilities with dysregulation of the central NA system; 3) the value of specific treatments to decrease the severity of long term disabilities; and 4) the impact of therapeutic program to significantly alter central NA levels and decrease the magnitude of CH-TBI-induced chronic inflammation. Translation of these findings may provide safe, timely, and effective intervention strategies which can significantly benefit the veterans' health care system.

描述（由申请人提供）： 闭合性头部创伤性脑损伤 (CH-TBI) 会导致广泛的神经功能缺损。最近，那些涉及认知、疼痛敏感性和焦虑的问题已经上升到迫切需要开发新信息来增强 CH-TBI 治疗的程度。本研究提出了关于 CH-TBI 后经常出现的多种发病情况的统一假设。它提出，中枢去甲肾上腺素能（NA）系统的功能障碍是这些多重残疾的共同根本特征。提出了四个目标来研究 CH-TBI 引起的特定神经缺陷、这些缺陷如何与去甲肾上腺素能损伤相关，以及通过三种针对中枢去甲肾上腺素能系统上调的治疗来改变这些缺陷的潜力。第五个目标提出了原理研究证明。目标 1 将确定大鼠头部损伤模型中轻度/中度 CH-TBI 后三种神经系统表现的严重程度和时间进程。目标 2 将 CH-TBI 后行为变化的程度与主要涉及特定行为的大脑区域（即海马 CA1 和 CA3、杏仁核中央核以及颈椎和腰椎背侧）的 NA 表达测量值相关联。脊髓灰质）。第三个目标将测试三种疗法——活动轮运动（AWL）运动、经皮质磁刺激（TMS）和普瑞巴林单独或组合——对轻度和中度认知、疼痛和焦虑结果的安全性、可行性和有效性。 CH-TBI。目标 4 将使用质谱和去甲肾上腺素 (NE) 免疫细胞化学检查这些治疗如何影响区域 NA 表达。目标 5 将通过评估中枢去甲肾上腺素能神经元选择性免疫损伤后动物的治疗效果（使用最佳治疗组合）来进一步检验中心假设。拟议的研究将增加我们的知识基础：1）CH-TBI 引起的认知功能障碍、焦虑、疼痛障碍和慢性炎症； 2）这些残疾与中枢NA系统失调的关系； 3）特定治疗对于降低长期残疾严重程度的价值； 4) 治疗方案对显着改变中枢 NA 水平并降低 CH-TBI 诱导的慢性炎症程度的影响。这些发现的转化可以提供安全、及时和有效的干预策略，从而显着有利于退伍军人的医疗保健系统。