Neural Mechanisms of Impulsivity and Attention Following Traumatic Brain Injury

军事职业暴露在简易爆炸装置的爆炸超压下可导致 轻度创伤性脑损伤(BLAST-TBI)，导致衰弱的持续性脑震荡后症状(PPCS) 和心理障碍，但诊断和治疗选择有限。PPCS的常见投诉 有冲击波病史的退伍军人包括认知障碍和生理症状。同样，常见的 心理障碍包括冲动控制障碍，药物滥用，创伤后应激障碍， 抑郁和焦虑，但其原因仍不清楚。因此，临床前的增加 需要使用啮齿动物模型进行研究，以提供对潜在原因的迫切需要的见解 BLAST-TBI导致后续功能障碍的机制。而BLAST-TBI的啮齿动物模型 主要集中在潜在的记忆相关的认知影响，到目前为止还没有研究利用啮齿动物模型来 检查爆炸暴露对冲动或注意力的影响，这是常见和反复出现的症状 这是接触冲击波的退伍军人的主要特征，与平民人口的心理障碍有很大关系。 同样，神经调节剂多巴胺在奖赏处理和决策过程中起着关键作用，而且在 在平民群体中，时相性多巴胺释放的紊乱与多种 本质上类似于冲击性脑损伤后出现的心理障碍。令人惊讶的是，几乎没有人 到目前为止，研究已经调查了爆炸暴露后多巴胺功能障碍的作用。海流 提案寻求填补这些知识空白，并将结合冲击波诱导的脑损伤小鼠模型，快速扫描 循环伏安法(FSCV)测量亚秒伏核(NAC)时相多巴胺的释放，以及 冲动和注意力的行为测量。目标一将检查近期和长期的后果 应用FSCV和电刺激对中脑边缘多巴胺系统进行单次和重复冲击暴露 刺激离散的大脑区域。目标二将研究单一和长期的后果 反复暴露在冲动和注意力的测量上，并将确定 在这些行为中，BLAST后增强的时相多巴胺释放。在啮齿动物模型中，适应不良 对冲动和注意力的测量与NAC时相多巴胺的增加有关 神经传递。因此，基于大量BLAST-TBI退伍军人表现出的冲动 注意力障碍和我们的初步数据表明爆炸导致的冲动增加 相关行为和刺激时相多巴胺释放，我们假设爆炸暴露将导致 NAC多巴胺释放增加，进而推动冲动和注意力的不适应措施。这些 实验旨在加深我们对行为和神经化学机制的理解。 潜在的BLAST-TBI功能障碍，将是阐明潜在治疗方法的重要临床前步骤 目标和策略。 我对CDA2应用程序的总体目标是：(I)创建一个翻译研究计划，以 探讨BLAST-TBI对随后认知、心理和行为的近期和远期影响 多巴胺能功能障碍。(2)发展新的技能和对BLAST-TBI啮齿动物模型的理解 由于有和没有BLI病史的退伍军人面临的临床问题，所以我的研究都是知情的 通过并有可能为未来的临床前和临床研究提供信息。(三)争取工作 在高级行为分析和大型数据集使用的统计技术方面的知识和专业知识。 (四)最后，凭借这些目标，明确区分我是一名独立的退伍军人管理局调查员 这是我的导师们独一无二的，也是他们帮助退伍军人处理爆炸性脑损伤历史的努力的补充。

Military occupational exposure to blast overpressure from improvised explosive devices can lead to mild traumatic brain injury (blast-TBI), resulting in debilitating persistent post-concussive symptoms (PPCS) and psychological dysfunction, but diagnoses and treatment options are limited. Common PPCS complaints of Veterans with blast histories include both cognitive difficulties and physiological symptoms. Likewise, common psychological dysfunctions include impulse control disorders, substance abuse, post traumatic stress disorder, depression and anxiety, but the causal mechanisms remain unknown. Therefore, increases in preclinical research efforts using rodent models are required to provide much needed insight into the underlying mechanisms by which blast-TBI contributes to subsequent dysfunction. While rodent models of blast-TBI have largely focused on potential memory-related cognitive effects, no study to date has utilized rodent models to examine the effects of blast exposure on impulsivity or attention, which are common and recurring complaints of blast exposed Veterans and are highly implicated in psychological dysfunction among civilian populations. Likewise, the neuromodulator dopamine plays a critical role in reward processing and decision making, and in civilian populations, perturbations of phasic dopamine release have been implicated in a variety of psychological dysfunctions that are similar in nature to those seen following blast-TBI. Surprisingly, few studies to date have investigated a role for dopamine dysfunction following blast exposure. The current proposal seeks to fill these knowledge gaps and will combine a mouse model of blast-induced TBI, fast scan cyclic voltammetry (FSCV) to measure subsecond nucleus accumbens (NAc) phasic dopamine release, and behavioral measures of impulsivity and attention. Aim one will examine the near and long-term consequences of single and repetitive blast exposure on the mesolimbic dopamine system using FSCV and electrical stimulation of discrete brain regions. Aim two will examine the near and long-term consequences of single and repetitive blast exposure on measures of impulsivity and attention, and will determine a potential role for augmented phasic dopamine release following blast in these behaviors. In rodent models, maladaptive measures of impulsivity and attention have been linked to an increase in phasic NAc dopamine neurotransmission. Therefore, based on the large number of blast-TBI Veterans presenting with impulsivity and attention impairments and our preliminary data demonstrating a blast-induced increase in impulsivity related behaviors and stimulated phasic dopamine release, we hypothesize that blast exposure will result in increased NAc dopamine release that in turn drives maladaptive measures of impulsivity and attention. These experiments are intended to further our understanding of the behavioral and neurochemical mechanisms underlying blast-TBI dysfunction, and will be an important preclinical step in elucidating potential treatment targets and strategies. My overall goals of the CDA2 application are: (i) To create a translational research program to investigate the near and long term effects of blast-TBI on subsequent cognitive, psychological and dopaminergic dysfunction. (ii) To develop new skills and understanding of rodent models of blast-TBI, as well as the clinical issues facing Veterans with and without blast-TBI histories so that my research is both informed by and has the potential to inform future preclinical and clinical lines of research. (iii) To gain working knowledge and expertise in statistical techniques for use with advanced behavioral assays and large data sets. (iv) Lastly, by virtue of these goals, to clearly differentiate myself as an independent VA investigator who is both unique from my mentors and complementary to their efforts in helping Veterans with blast-TBI histories.