Environmental Enrichment and Cholinergic Mechanisms after TBI

描述（由申请人提供）：将大鼠暴露于复杂，刺激和社会住房（即丰富的环境；EE）可改善创伤性脑损伤（TBI）后的认知和运动表现。尽管有证据表明情感表达增强了大脑皮层的可塑性，但其具体机制尚不清楚。此外，皮层下胆碱能传入事件在激发大鼠特定形式的可塑性中起关键作用，如海马中雌激素介导的可塑性，额叶皮层中去神经传导介导的可塑性，以及视觉和听觉皮层中与经验相关的可塑性。本研究将验证脑外伤后胆碱能神经元是脑电诱导改变的重要介质，且该介质存在性别差异的假设。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，例如对TBI患者的行为增强（即康复）。提出了五个具体目标来检验总体假设。目的1将确定破坏基底前脑胆碱能神经元（BFCNs）是否会削弱EE改善脑外伤后行为表现的能力，该脑外伤是由成熟的可控皮质撞击损伤模型与皂苷（SAP）损伤联合造成的。Aim 2将确定在这些相同的动物中，eeg诱导的突触可塑性（即Aim 1）被改变的程度，以及可塑性是否与表现相关。由于已知激素可以调节胆碱能功能，而且雄性和雌性对脑外伤后情感表达的反应不同，Aim 3将评估性腺完整与卵巢切除（OVX）雌性大鼠在脑外伤+/-SAP病变后情感表达对皮质可塑性和功能改善的影响，并将结果与Aims 1-2中的雄性大鼠进行比较。目的4将评估延迟和慢性治疗方案（损伤后1-20天）在雄性、完整和OVX雌性大鼠TBI后使用经fda批准的乙酰胆碱酯酶抑制剂多奈哌齐的效果，以确定多奈哌齐+EE的加性或协同效应是否能促进运动和空间学习和记忆的获得。最后，Aim 5将扩展Aim 4的康复策略，确定受试者在接受和不接受持续药物治疗的情况下恢复标准生活条件后，多奈哌齐+EE的效果是否持续。我们的长期目标是开发促进人类脑外伤后功能恢复的治疗方法。公共卫生相关性：创伤性脑损伤是一个重大的卫生保健问题，每年仅在美国就影响数百万人。患者通常会留下长期的身体和认知障碍，而目前还没有公认的治疗方法。影响胆碱能系统的药物治疗已被证明可以提供一些益处，环境富集也是如此。本研究旨在评估多奈哌齐和富集对脑外伤后功能结局的影响。本研究进一步试图验证胆碱能神经元是脑外伤后行为诱导改变的重要介质的假设，并且这种介质存在性别差异。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.