TBI-induced Synaptic Plasticity: Effects on Ethanol Sensitivity

描述(由申请人提供)： 在军事战斗中，创伤性脑损伤占幸存伤亡人数的20%。在退伍军人中，临床研究已经确定脑外伤是酒精使用障碍的一个重要风险因素。是什么导致了创伤性脑损伤患者易受酒精中毒的影响？大脑对损伤的神经元反应可扰乱正常的神经元功能，如神经连通性改变、可塑性异常和神经元网络功能障碍。再次酗酒的脑损伤患者脑部损害的频率更高，涉及到调节成瘾行为的神经回路。在病理条件下，树突棘(神经元交流的主要部位)的重塑伴随着突触的改变，如脑外伤。对脑外伤后树突棘重塑和突触改变的临床前研究表明，脑外伤能够抑制神经元可塑性的解剖学表现。重要的是，在酒精敏感性改变的大鼠中也证明了树突结构被破坏的证据。同样，缺乏这种能力的大鼠 调节突触组织会降低乙醇耐受性。综上所述，这些数据证明了突触功能受损与酒精敏感性之间的关系，例如脑损伤后的突触功能受损。 显然，有必要找到有效的治疗方法来提高脑外伤患者的生活质量。在动物模型中，环境丰富(EE)调节树突复杂性、脊椎发育和行为改善的能力已经得到证实。EE暴露后，啮齿类动物的脑外伤后功能恢复加快，伴随着树突状细胞密度的增加。重要的是，EE已被证明对啮齿动物的酒精滥用易感性具有保护作用。综上所述，这些数据表明，使用EE重建突触信号可以对行为结果产生显著影响，并推动康复研究的进展。 目前应用的目的是检查非挫伤性脑损伤对突触功能和发育的影响，以及由此产生的与突触和行为对乙醇敏感性有关的后果。将探索使用环境浓缩作为一种干预措施，以减少/逆转TBI对乙醇敏感性的影响。 这一应用的总体假设是，非挫伤性脑损伤将损害突触功能，导致对乙醇的敏感性增加，而环境浓缩可以逆转这一点。 我们将使用以下具体目标来检验这一假设：1)确定非挫伤性脑损伤对介导酒精敏感性的脑区的树突分枝和突触形成和功能的影响(通过使用共聚焦分析和突触体准备来量化树突分支/复杂性和脊椎数量/密度，以及损伤后候选突触蛋白的激活、表达和分布)。确定非挫伤性脑损伤对急性和慢性酒精敏感性的影响(通过测量脑损伤后乙醇的激活、镇静和成瘾特性)，3.通过改善/恢复突触发育和功能，评估环境强化在逆转非挫伤性脑损伤对乙醇敏感性影响方面的有效性。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) accounts for up to 20% of surviving casualties during military combat. In the Veteran population, clinical studies have identified TBI as a significant risk facto for alcohol use disorders. What could underlie the propensity for TBI victims to become vulnerable to alcoholism? The neuronal response of the brain to injury can perturb normal neuronal function, e.g. alterations in neural connectivity, abnormal plasticity and neuronal network dysfunction. TBI patients who relapsed to alcohol abuse had a greater frequency of brain lesions involving neural circuits that mediate aspects of addictive behavior. Remodeling of dendritic spines (the major site of neuronal communication) accompanies synaptic modifications under pathological conditions, such as TBI. Preclinical studies of post-TBI dendritic spine remodeling and synaptic modification have indicated that TBI is capable of inhibiting anatomical manifestations of neuronal plasticity. Importantly, evidence of disrupted dendritic structure has also been demonstrated in rats with altered ethanol sensitivity. Likewise, rats lacking the ability to regulate synaptic organization have reduced ethanol tolerance. Together, these data demonstrate the relationship between impaired synaptic function, such as that occurring after TBI, and sensitivity to ethanol exposure. There is a clear need to find effective therapies to improve the quality of life of TBI victims. Th ability of environmental enrichment (EE) to modulate dendritic complexity, spine development and behavioral improvement in animal models has been well-established. Increased functional recovery from TBI in rodents has been demonstrated following EE exposure, with associated enhancement of dendritic density. Importantly, EE has been shown to provide protective effects against alcohol abuse susceptibility in rodents. Together, these data suggest that re-establishment of synaptic signaling using EE can have significant effect on behavioral outcome and advance the progress of rehabilitation research. The objective of the current application is to examine the effects of non-contusive TBI on synaptic function and development and the resulting consequences relating to synaptic and behavioral sensitivity to ethanol. The use of environmental enrichment will be explored as an intervention to reduce/reverse the effects of TBI on ethanol sensitivity. The overall hypothesis of this application is that non-contusive TBI will impair synaptic function leading to increased sensitivity to ethanol, which can be reversed by environmental enrichment. We will test this hypothesis using the following specific aims: 1.) Determine the effect of non-contusive TBI on dendritic arborization and synapse formation and function in brain regions that mediate ethanol sensitivity (by quantifying dendritic branching/complexity and spine number/density, as well as activation, expression and distribution of candidate synaptic proteins after injury using confocal analyses and synaptosome preparations) 2.) Determine the effect of non-contusive TBI on acute and chronic ethanol sensitivity (by measuring the activating, sedating and addictive properties of ethanol in the post-TBI period), 3.) Evaluate the efficacy of environmental enrichment in reversing the effects of non-contusive TBI on ethanol sensitivity by improving/restoring synaptic development and function.