Environmental Enrichment and Cholinergic Mechanisms after TBI

描述（由申请人提供）：将大鼠暴露于复杂的、刺激的和社会性的圈养环境（即，丰富的环境; EE）改善创伤性脑损伤（TBI）后的认知和运动表现。这种效应的具体机制尚不清楚，尽管有证据表明EE增强了皮质可塑性。此外，皮质下胆碱能传入神经在大鼠中引起特定形式的可塑性，如海马中雌激素介导的可塑性，额叶皮层中去神经介导的可塑性，以及视觉和听觉皮层中与经验相关的可塑性。拟议的研究将检验这样的假设：胆碱能神经元是TBI后EE诱导变化的重要介质，并且这种介质存在性别差异。因此，胆碱能增强可能是增强“辅助”治疗的有益效果的有效手段，例如行为富集（即，康复），在TBI患者。提出了五个具体目标来检验总体假设。目的1将确定是否破坏基底前脑胆碱能神经元（BFCNs）钝化EE的能力，以提高TBI后的行为表现与完善的控制皮质撞击损伤模型结合皂草素（SAP）-病变。目的2将确定EE诱导的突触可塑性在这些相同动物中的程度（即，目标1）被改变，如果可塑性与性能相关。由于已知激素可调节胆碱能功能，且TBI后雄性和雌性对EE的反应不同，因此目标3将评估TBI+/-SAP损伤后性腺完整与卵巢切除（OVX）雌性大鼠中EE的皮质可塑性和功能改善，并将结果与目标1-2的雄性进行比较。目标4将评估延迟和慢性治疗方案的效果（损伤后1-20天）与FDA批准的乙酰胆碱酯酶抑制剂多奈哌齐在TBI后的雄性大鼠以及完整和OVX雌性大鼠中进行比较，以确定是否可以通过多奈哌齐+EE的加和或协同效应在任一组中促进运动和空间学习和记忆的获得。目标5将通过确定在受试者恢复标准生活条件（有或无持续药物治疗）后多奈哌齐+EE的作用是否持续，扩展目标4的康复策略。我们的长期目标是开发促进人类TBI后功能恢复的疗法。创伤性脑损伤是一个重大的医疗保健问题，仅在美国每年就影响数百万人。患者往往留下长期持久的身体和认知残疾，对此没有公认的治疗方法。影响胆碱能系统的药物疗法已被证明提供一些益处，环境富集也是如此。本提案中的研究旨在评估多奈哌齐和富集的效果及其对TBI后功能结局的影响。这项研究进一步试图验证这一假设，即胆碱能神经元是TBI后行为诱导变化的重要介质，并且在这种介质中存在性别差异。该结果有可能为TBI患者的康复提供一种新的治疗策略。

DESCRIPTION (provided by applicant): Exposing rats to complex, stimulating, and social housing (i.e., enriched environment; EE) improves cognitive and motor performance after traumatic brain injury (TBI). The specific mechanisms that underlie this effect are unknown, although there is evidence suggesting that EE enhances cortical plasticity. Furthermore, subcortical cholinergic afferents are critically involved in eliciting specific forms of plasticity in rats, such as estrogen-mediated plasticity in the hippocampus, denervation-mediated plasticity in the frontal cortex, and experience-related plasticity in both visual and auditory cortices. The proposed studies will test the hypothesis that cholinergic neurons are important mediators of EE-induced change after TBI and that there are gender differences in this mediation. As such, cholinergic enhancement may be an effective means of augmenting the beneficial effects of `ancillary' treatments, such as behavioral enrichment (i.e., rehabilitation), in patients with TBI. Five specific aims are proposed to test the overall hypothesis. Aim 1 will determine whether disrupting basal forebrain cholinergic neurons (BFCNs) blunts the ability of EE to improve behavioral performance after TBI produced with the well-established controlled cortical impact injury model in conjunction with saporin (SAP)-lesions. Aim 2 will determine to what extent EE-induced synaptic plasticity in these same animals (i.e., Aim 1) is altered and if plasticity correlates with performance. Because hormones are known to modulate cholinergic function and males and females respond differently to EE after TBI, Aim 3 will assess cortical plasticity and functional improvement with EE in gonadally intact vs. ovariectomized (OVX) female rats after TBI+/-SAP lesions and compare the results to males from Aims 1-2. Aim 4 will assess the effect of a delayed and chronic treatment regimen (1-20 days post-injury) with the FDA-approved acetylcholinesterase inhibitor donepezil in male and both intact and OVX female rats after TBI to determine if motor and acquisition of spatial learning and memory can be facilitated in either group via an additive or synergistic effect of donepezil+EE. Lastly, Aim 5 will expand on the rehabilitative strategy of Aim 4 by determining whether the effects of donepezil+EE are sustained after the subjects are returned to standard living conditions with and without continued pharmacotherapy. Our long-term goal is to develop therapies that facilitate functional recovery after human TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a significant health care issue affecting millions of individuals each year in the US alone. Patients are often left with long lasting physical and cognitive disabilities for which there are no accepted treatments. Pharmacotherapies affecting the cholinergic system have been shown to provide some benefit, as has environmental enrichment. The studies in this proposal seek to evaluate the effects of donepezil and enrichment and their effect on functional outcome after TBI. The study further seeks to test the hypothesis that cholinergic neurons are important mediators of behaviorally induced change after TBI and that there are sex differences in this mediation. The outcome has the potential to provide a novel treatment strategy for rehabilitation of TBI patients.