Environmental Enrichment and Cholinergic Mechanisms after TBI

描述(由申请人提供)：将大鼠暴露在复杂的、刺激的和社会住房(即丰富的环境；EE)中可以改善创伤性脑损伤(TBI)后的认知和运动表现。这种效应背后的具体机制尚不清楚，尽管有证据表明EE增强了皮质的可塑性。此外，皮质下胆碱能传入在诱发大鼠特定形式的可塑性中起关键作用，如雌激素在海马区的可塑性，在额叶皮质由去神经支配的可塑性，以及在视觉和听觉皮质中与经验相关的可塑性。建议的研究将检验这一假设，即胆碱能神经元是EE诱导的脑损伤后改变的重要中介，并且在这一中介中存在性别差异。因此，胆碱能增强可能是增强脑外伤患者行为强化(即康复)等“辅助”治疗有益效果的有效手段。本文提出了五个具体目标来检验总体假设。目的1确定破坏基底前脑胆碱能神经元(BFCNs)是否会削弱EE改善行为能力的能力。目标2将确定EE诱导的这些动物(即目标1)的突触可塑性在多大程度上发生变化，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，而且雄性和雌性在脑损伤后对EE的反应不同，因此Aim 3将评估在TBI+/-SAP损伤后性腺完整的雌性大鼠与去卵巢(OVX)雌性大鼠中EE对皮质可塑性和功能改善的影响，并将结果与AIMS 1-2中的雄性进行比较。目的4研究FDA批准的乙酰胆碱酯酶抑制剂多奈哌齐对脑损伤后雄性大鼠、正常大鼠和去卵巢雌性大鼠的延迟和慢性治疗方案(伤后1-20天)的影响，以确定是否可以通过多奈哌齐+EE的相加或协同作用促进两组大鼠的运动和空间学习和记忆的获得。最后，目标5将扩展目标4的康复策略，确定在受试者恢复到标准生活条件后，在继续药物治疗和不继续药物治疗的情况下，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医疗保健问题，仅在美国每年就影响数百万人。患者往往患有长期的身体和认知障碍，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提供了一些好处，环境浓缩也是如此。本研究旨在评估多奈哌齐和增强剂的疗效及其对脑外伤后功能预后的影响。这项研究进一步试图检验这一假设，即胆碱能神经元是脑外伤后行为诱导变化的重要中介，并且在这一中介中存在性别差异。这一结果有可能为脑外伤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.