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: 8278709
• 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/8278709
• 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. PUBLIC HEALTH RELEVANCE: Armed forces personnel face a disproportionately increased risk of traumatic brain injury (TBI). Although TBI symptoms may be mild or even undetected, long-lasting behavioral consequences may result in the post-TBIperiod. Notably, among the Veteran population, those with TBI demonstrate increased rates of alcoholism and drug use. Alcohol sensitivity can be altered by TBI-induced disturbances in neural circuitry, making TBI a risk factor for alcohol use disorders. Thus, the proposed project aims to address the critical need to understandhow TBI can disrupt neuronal networks that lead to alcohol use disorders. More importantly, in order to uphold the mission for VA patient care and rehabilitation, the proposed project seeks to evaluate rehabilitation interventions that may effectively reverse the detrimental effects of TBI on neuronal communication and alcohol sensitivity.

描述（由申请人提供）： 军事战斗中幸存伤亡人员中，高达 20% 是由创伤性脑损伤 (TBI) 造成的。在退伍军人群体中，临床研究已确定 TBI 是酒精使用障碍的一个重要危险因素。 TBI 受害者容易酗酒的原因是什么？大脑对损伤的神经元反应会扰乱正常的神经元功能，例如神经连接的改变、可塑性异常和神经元网络功能障碍。再次酗酒的 TBI 患者出现大脑损伤的频率更高，涉及介导成瘾行为的神经回路。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，例如 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实了树突结构被破坏的证据。同样，老鼠缺乏这种能力 调节突触组织降低了乙醇耐受性。这些数据共同证明了突触功能受损（例如 TBI 后发生的突触功能受损）与乙醇暴露敏感性之间的关系。 显然需要找到有效的疗法来改善 TBI 受害者的生活质量。环境富集 (EE) 在动物模型中调节树突复杂性、脊柱发育和行为改善的能力已得到证实。暴露于 EE 后，啮齿类动物的 TBI 功能恢复已得到证实，并伴有树突密度的增强。重要的是，EE 已被证明可以对啮齿类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 重建突触信号传导可以对行为结果产生重大影响，并推动康复研究的进展。 当前应用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突触和行为对乙醇敏感性相关的后果。将探索使用环境浓缩作为减少/逆转 TBI 对乙醇敏感性影响的干预措施。 该应用的总体假设是，非挫伤性 TBI 会损害突触功能，导致对乙醇的敏感性增加，而这种情况可以通过环境富集来逆转。 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 TBI 对介导乙醇敏感性的脑区树突分枝、突触形成和功能的影响（通过使用共聚焦分析和突触体制剂量化树突分支/复杂性和树突棘数量/密度，以及损伤后候选突触蛋白的激活、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，评估环境富集在逆转非挫伤性 TBI 对乙醇敏感性影响方面的功效。 公共卫生相关性： 武装部队人员面临的创伤性脑损伤 (TBI) 风险不成比例地增加。尽管 TBI 症状可能很轻微甚至未被发现，但 TBI 后可能会产生长期的行为后果。值得注意的是，在退伍军人群体中，患有创伤性脑损伤的人酗酒和吸毒的比例有所增加。 TBI 引起的神经回路紊乱会改变酒精敏感性，这使得 TBI 成为酒精使用障碍的危险因素。因此，拟议的项目旨在解决了解 TBI 如何破坏导致酒精使用障碍的神经元网络的迫切需要。更重要的是，为了履行 VA 患者护理和康复的使命，拟议项目旨在评估康复干预措施，以有效扭转 TBI 对神经元通讯和酒精敏感性的不利影响。