TBI-induced Synaptic Plasticity: Effects on Ethanol Sensitivity

TBI 诱导的突触可塑性：对乙醇敏感性的影响

• 批准号: 8499092
• 负责人: ALANA C. CONTI
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499092
• 关键词: 21 year old; Accounting; Acute; Addictive Behavior; Address; Adult; Alcohol abuse; Alcohol dependence; Alcoholism; Animal Model; Attenuated; Behavioral; Brain; Brain region; Chronic; Clinical Research; Communication; Data; Dendritic Spines; Development; Drug usage; Ethanol; Face; Frequencies; Injury; Intervention; Lead; Lesion; Life; Long-Term Effects; Measures; Mediating; Metabolic; Military Personnel; Mission; Modification; Nervous system structure; Neuronal Plasticity; Neurons; Outcome; Patient Care; Patients; Population; Predisposition; Preparation; Property; Proteins; Quality of life; Rattus; Recovery; Recovery of Function; Regulation; Rehabilitation Research; Rehabilitation therapy; Relapse; Risk; Risk Factors; Rodent; Signal Transduction; Site; Structure; Symptoms; Synapses; Synaptic plasticity; Synaptosomes; Testing; Traumatic Brain Injury; Vertebral column; Veterans; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; behavior measurement; combat; density; effective therapy; environmental enrichment for laboratory animals; improved; injured; network dysfunction; neural circuit; preclinical study; prevent; protective effect; relating to nervous system; response; reward circuitry; synaptic function; synaptogenesis

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.

描述（由申请人提供）： 在军事战斗中，脑外伤（TBI）占尚存的伤亡的20％。在退伍军人人口中，临床研究已将TBI确定为饮酒障碍的重大风险。 TBI受害者容易受到酒精中毒的倾向是什么？大脑对损伤的神经元反应会扰动正常神经元功能，例如神经连通性，异常可塑性和神经元网络功能障碍的改变。转移到酗酒的TBI患者的脑部病变频率更高，涉及介导上瘾行为方面的神经回路。树突状棘的重塑（神经元通信的主要部位）在病理条件下（例如TBI）伴随着突触修饰。 TBI后树突状脊柱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学表现。重要的是，在乙醇敏感性改变的大鼠中也证明了树突状结构破坏的证据。同样，老鼠缺乏能力 调节突触组织的乙醇耐受性降低。总之，这些数据证明了突触功能受损（例如TBI后发生的）与对乙醇暴露的敏感性之间的关系。 显然需要寻找有效的疗法来改善TBI受害者的生活质量。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建立了良好的建立。在EE暴露后，已经证明了啮齿动物中TBI的功能恢复增加，并与树突密度相关联。重要的是，EE已被证明可以在啮齿动物中对酒精滥用敏感性产生保护作用。总之，这些数据表明，使用EE重新建立突触信号会对行为结果产生重大影响，并提高康复研究的进展。 当前应用的目的是检查非凸性TBI对突触功能和发育的影响以及与乙醇的突触和行为敏感性有关的后果。将探索环境富集的使用作为干预措施，以减少/扭转TBI对乙醇敏感性的影响。 该应用程序的总体假设是，非直率的TBI会损害突触功能，从而提高对乙醇的敏感性，这可以通过环境富集来逆转。 我们将使用以下特定目的检验这一假设：1。）确定非传染性TBI对介导乙醇敏感性的大脑区域中的树突状形成和突触形成和功能的影响对急性和慢性乙醇敏感性的无脑性TBI（通过测量TBI后乙醇的激活，镇静和成瘾性的特性），3。），3。）评估环境富集在反转非孔隙性TBI对乙醇对乙醇敏感性的影响中的疗效，通过提高/还原/还原/恢复/还原/还原/恢复性突发性开发和功能。