TBI-induced Synaptic Plasticity: Effects on Ethanol Sensitivity

描述（由申请人提供）： 创伤性脑损伤（TBI）占军事战斗中幸存伤亡人数的20%。在退伍军人群体中，临床研究已将TBI确定为酒精使用障碍的重大风险因素。TBI受害者容易酗酒的倾向是什么？脑对损伤的神经元反应可以扰乱正常的神经元功能，例如神经连接的改变、异常可塑性和神经元网络功能障碍。酒精滥用复发的TBI患者有更高频率的大脑损伤，涉及神经回路，介导成瘾行为的各个方面。树突棘（神经元通讯的主要部位）的重塑伴随着病理条件下的突触修饰，如TBI。TBI后树突棘重塑和突触修饰的临床前研究表明，TBI能够抑制神经元可塑性的解剖表现。重要的是，在乙醇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，缺乏这种能力的老鼠 调节突触组织的能力降低了乙醇耐受性。总之，这些数据表明受损的突触功能，如TBI后发生的，和乙醇暴露的敏感性之间的关系。 显然需要找到有效的治疗方法来改善TBI受害者的生活质量。在动物模型中，环境富集（EE）调节树突复杂性、脊柱发育和行为改善的能力已经得到很好的证实。啮齿类动物TBI的功能恢复增加已被证明EE暴露后，与树突状细胞密度的相关增强。重要的是，EE已被证明对啮齿动物的酒精滥用易感性提供保护作用。总之，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。 本申请的目的是检查非挫伤性TBI对突触功能和发育的影响以及与对乙醇的突触和行为敏感性相关的结果。将探索使用环境富集作为干预措施，以减少/逆转TBI对乙醇敏感性的影响。 本申请的总体假设是，非挫伤性TBI将损害突触功能，导致对乙醇的敏感性增加，这可以通过环境富集来逆转。 我们将使用以下具体目标来测试这一假设：1。确定非挫伤性TBI对介导乙醇敏感性的脑区域中的树突分支和突触形成和功能的影响（通过使用共聚焦分析和突触体制备定量树突分支/复杂性和棘数量/密度，以及损伤后候选突触蛋白的活化、表达和分布）2.）确定非挫伤性TBI对急性和慢性乙醇敏感性的影响（通过测量TBI后时期乙醇的激活、镇静和成瘾特性），3.）通过改善/恢复突触发育和功能，评价环境富集在逆转非挫伤性TBI对乙醇敏感性影响方面的疗效。

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.