Mild TBI: Effects on addiction-related phenotypes and mesocorticolimbic function

轻度 TBI：对成瘾相关表型和中皮质边缘功能的影响

• 批准号: 9059792
• 负责人: MATTHEW D BUDDE
• 金额: $ 0.72万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059792
• 关键词: Accounting; Addictive Behavior; Affect; Alcohol consumption; Animals; Anterograde Amnesia; Basic Science; Behavioral; Biological Markers; Blast Cell; Blast Injuries; Brain; Brain Injuries; Cocaine; Comorbidity; Correlative Study; Data; Development; Diffusion Magnetic Resonance Imaging; Disease; Drug Addiction; Drug Exposure; Drug abuse; Drug usage; Emotional Disturbance; Epidemiology; Functional Imaging; Goals; Health; Human; Image; Impaired cognition; Incidence; Injury; Intake; Intervention; Investigation; Knowledge; Lesion; Magnetic Resonance Imaging; Measures; Medial; Mental disorders; Microscopic; Military Personnel; Mission; Modeling; Nervous System Physiology; Neurologic; Organism; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Predisposition; Prefrontal Cortex; Public Health; Rattus; Recording of previous events; Relapse; Research; Research Design; Resolution; Risk; Rodent; Rodent Model; Role; Self Administration; Substance Use Disorder; Substance abuse problem; Symptoms; TBI Patients; Techniques; Testing; Time; Traumatic Brain Injury; Veterans; Work; addiction; brain circuitry; cocaine exposure; cocaine use; combat; drug seeking behavior; experience; field study; frontal lobe; human data; innovation; mild traumatic brain injury; neurobehavioral; neuroimaging; neuropsychological; patient population; pre-clinical; preclinical study; programs; psychologic; standard care; therapeutic development; therapy development

 DESCRIPTION (provided by applicant): Substance use disorder (SUD) is a frequent comorbidity following traumatic brain injury (TBI), even in patients without a previous history of drug use. However, the extent to which the neurological effects of TBI contribute to the development of SUD is unknown. The long-term goal is to understand how brain injury alters neurological and psychiatric function. The objective of the proposed research is to elucidate the relationship between mild TBI (mTBI), addictive phenotypes, and mesocorticolimbic function. The central hypothesis is that mTBI results in elevated risk for drug addiction and changes in mesocorticolimbic circuitry. This hypothesis is supported by correlative data from human studies and by preliminary imaging data using a preclinical mTBI model. The rationale for the proposed research is that understanding the neurological consequences of mTBI will aid in the development of therapeutic strategies for mTBI patients. To isolate neurological effects, we propose a rodent model to enable investigation of the effects of mTBI in drug naïve organisms with similar environmental histories. Our hypothesis is supported by epidemiological and preliminary data and will be tested in two specific aims: 1) Identify the impact of mTBI on drug self-administration, seeking, and relapse; and 2) Determine the effects of mTBI and cocaine on brain networks implicated in drug seeking. In Aim 1, cocaine self-administration and drug seeking will be measured in rats following mild TBI induced by blast forces. In Aim 2, structural and functional imaging studies will be performed before and after mTBI and cocaine self-administration. The approach is innovative because it will contribute translational imaging and behavioral data from a controlled and reproducible preclinical model to a field of study that has been dominated by human imaging and correlative studies. The project is significant because it will initiate a course of research that will reveal mechanisms of TBI sequelae and how these sequelae can influence drug intake and drug seeking behaviors. This work is expected to contribute to a body of basic research that will aid in the development of treatments for co-morbid psychological and psychiatric disorders following TBI.

 描述(由申请人提供)：物质使用障碍(SUD)是创伤性脑损伤(TBI)后的一种常见共病，即使在没有药物使用史的患者中也是如此。然而，颅脑损伤的神经效应在多大程度上促进了SUD的发展尚不清楚。长期目标是了解脑损伤如何改变神经和精神功能。本研究的目的是阐明轻度脑损伤(MTBI)、成瘾表型和中皮质边缘功能之间的关系。中心假设是mTBI导致药物成瘾风险增加和中皮质边缘回路改变。这一假设得到了来自人类研究的相关数据和使用临床前mTBI模型的初步成像数据的支持。这项拟议研究的基本原理是，了解mTBI的神经学后果将有助于制定mTBI患者的治疗策略。为了分离神经效应，我们提出了一个啮齿动物模型来研究mTBI在具有相似环境历史的药物幼稚生物中的影响。我们的假说得到了流行病学和初步数据的支持，并将在两个特定的目标下进行检验：1)确定mTBI对药物自我给药、寻求和复发的影响；2)确定mTBI和可卡因对与药物寻找有关的大脑网络的影响。在目标1中，将测量冲击力诱导的轻度脑损伤后大鼠的可卡因自我给药和药物寻找。在目标2中，将在mTBI和可卡因自身给药前后进行结构和功能成像研究。这种方法是创新的，因为它将把来自受控和可重复的临床前模型的翻译成像和行为数据贡献给一个一直由人体成像和相关研究主导的研究领域。该项目意义重大，因为它将启动一项研究进程，揭示脑外伤后遗症的机制，以及这些后遗症如何影响药物摄取和药物寻找行为。预计这项工作将有助于基础研究的主体，这些研究将有助于开发脑外伤后并发心理和精神障碍的治疗方法。