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

 描述（由申请人提供）：物质使用障碍（SUD）是创伤性脑损伤（TBI）后常见的合并症，即使在既往无药物使用史的患者中也是如此。然而，TBI的神经效应在多大程度上促进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。该研究的目的是阐明轻度TBI（mTBI），成瘾表型和中皮质边缘功能之间的关系。中心假设是mTBI导致药物成瘾风险升高和中皮质边缘回路变化。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。拟议研究的基本原理是，了解mTBI的神经系统后果将有助于为mTBI患者制定治疗策略。为了分离神经学效应，我们提出了一种啮齿动物模型，以研究mTBI在具有相似环境历史的药物初始生物体中的效应。我们的假设得到了流行病学和初步数据的支持，并将在两个具体目标中进行测试：1）确定mTBI对药物自我管理，寻求和复发的影响; 2）确定mTBI和可卡因对与药物寻求有关的大脑网络的影响。在目标1中，将在由冲击力诱导的轻度TBI后在大鼠中测量可卡因自我给药和药物寻求。在目标2中，将在mTBI和可卡因自我给药前后进行结构和功能成像研究。该方法是创新的，因为它将从受控的和可重复的临床前模型中贡献平移成像和行为数据到由人类成像和相关研究主导的研究领域。该项目意义重大，因为它将启动一个研究过程，揭示TBI后遗症的机制以及这些后遗症如何影响药物摄入和药物寻求行为。这项工作预计将有助于基础研究的机构，这将有助于在开发治疗TBI后共病的心理和精神疾病。

 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.