Neurobiology and Experimental Treatment of TBI Pain and Anxiety

描述（由申请人提供）： 闭合性头部创伤性脑损伤（CH-TBI）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开发新信息的紧迫性水平，这些新信息可以增强CH-TBI的治疗。本研究提出了一个统一的假设，关于多发性发病率，经常以下CH-TBI。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基础。提出了四个目标，以调查特定的神经功能缺损引起的CH-创伤性脑损伤，这些是如何与去甲肾上腺素能损伤，以及这些赤字的潜力进行修改的三种治疗，靶向上调中央去甲肾上腺素能系统。第五个目标提出了一个原则研究的证明。目的1将确定在大鼠头部损伤模型中轻度/中度CH-TBI后三种神经学表现的严重程度和时间过程。目的2将CH-TBI后行为变化的幅度与主要涉及感兴趣的特定行为的脑区域中NA表达的测量（即，海马CA 1和CA 3、杏仁核中央核以及颈和腰背脊髓灰质）。第三个目标将测试三种疗法的安全性，可行性和有效性-活动轮运动（AWL）运动，经皮质磁刺激（TMS）和普瑞巴林单独或联合-对轻度和中度CH-TBI的认知，疼痛和焦虑结果。目的4将研究这些治疗如何影响区域NA表达质谱和去甲肾上腺素（NE）免疫细胞化学。目的5将通过评价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疗效（使用最佳治疗组合）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诱导的认知功能障碍，焦虑，疼痛残疾和慢性炎症; 2）这些残疾与中枢NA系统失调的关系; 3）特定治疗的价值，以降低长期残疾的严重程度;和4）治疗方案对显著改变中枢NA水平和降低CH-TBI诱导的慢性炎症的程度的影响。这些发现的翻译可以提供安全，及时，有效的干预策略，可以显着受益于退伍军人的医疗保健系统。

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.