Neural Mechanisms of Impulsivity and Attention Following Traumatic Brain Injury

脑外伤后冲动和注意力的神经机制

• 批准号: 10265324
• 负责人: Abigail G Schindler
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265324
• 关键词: Animals; Anxiety; Attention; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain region; Cell Nucleus; Cells; Clinical; Cognitive; Conflict (Psychology); Data; Decision Making; Devices; Diagnosis; Dopamine; Electric Stimulation; Exposure to; Freedom; Functional disorder; Future; Goals; High Prevalence; Impairment; Impulse Control Disorders; Impulsivity; Injury; Investigation; Knowledge; Lead; Link; Long-Term Effects; Measures; Memory; Mental Depression; Mentors; Midbrain structure; Military Personnel; Mus; Nature; Neuromodulator; Neurons; Nucleus Accumbens; Occupational Exposure; Periodicity; Pharmacology Study; Pharmacotherapy; Phase; Physiological; Play; Population; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Presynaptic Terminals; Probability; Quality of life; Reaction Time; Recording of previous events; Reporting; Research; Research Personnel; Risk; Risk-Taking; Rodent Model; Role; Scanning; Substance abuse problem; Symptoms; System; Techniques; Testing; Time; Traumatic Brain Injury; Ventral Striatum; Ventral Tegmental Area; Veterans; base; behavior measurement; behavioral disinhibition; behavioral outcome; behavioral pharmacology; behavioral phenotyping; blast exposure; career; design; discounting; experience; experimental study; insight; large datasets; median forebrain bundle; mesolimbic system; mild traumatic brain injury; mouse model; neurochemistry; neuromechanism; neurotransmission; operation; postsynaptic; pre-clinical; pre-clinical research; preference; psychologic; response; reward processing; skills; stress related disorder; therapy development; trait; translational research program

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.

军事职业暴露于简易爆炸装置的爆炸超压可导致 轻度创伤性脑损伤（爆炸-TBI），导致持续性脑震荡后症状（PPCS） 和心理功能障碍，但诊断和治疗选择有限。常见的PPCS投诉 有爆炸史的退伍军人包括认知困难和生理症状。同样，共同 心理功能障碍包括冲动控制障碍，药物滥用，创伤后应激障碍， 抑郁症和焦虑症，但因果机制仍然未知。因此，临床前增加 使用啮齿动物模型的研究工作需要提供急需的洞察力， 爆炸性TBI导致随后功能障碍的机制。虽然啮齿类动物模型的冲击-创伤性脑损伤， 主要集中在潜在的记忆相关的认知影响，迄今为止还没有研究利用啮齿动物模型， 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投诉 爆炸暴露的退伍军人和高度牵连在平民人口的心理功能障碍。 同样，神经调节剂多巴胺在奖励处理和决策中起着关键作用， 在平民群体中，阶段性多巴胺释放的扰动与各种 心理功能障碍，在性质上类似于爆炸-TBI后所见。令人惊讶的是， 迄今为止的研究已经调查了冲击波暴露后多巴胺功能障碍的作用。当前 一项提案试图填补这些知识空白，并将联合收割机结合爆炸诱导TBI的小鼠模型，快速扫描 循环伏安法（FSCV）以测量亚秒级中脑核（NAc）阶段性多巴胺释放，以及 冲动和注意力的行为测量。第一个目标将研究短期和长期的后果 使用FSCV和电刺激， 刺激离散的大脑区域。第二个目标将审查单一和单一的短期和长期后果， 重复爆炸暴露的冲动和注意力的措施，并将确定潜在的作用， 增强的阶段性多巴胺释放爆炸后，这些行为。在啮齿动物模型中， 冲动和注意力的测量与相位NAc多巴胺的增加有关 神经传递因此，根据大量爆炸性创伤性脑损伤退伍军人表现出的冲动性， 以及注意力受损，我们的初步数据显示，爆炸导致冲动性增加 相关的行为和刺激的阶段性多巴胺释放，我们假设爆炸暴露将导致 增加NAc多巴胺的释放，进而驱动冲动和注意力的适应不良措施。这些 这些实验旨在加深我们对行为和神经化学机制的理解， 潜在的原始细胞-TBI功能障碍，并将是阐明潜在治疗的重要临床前步骤 目标和战略。 我的CDA 2应用程序的总体目标是：（i）创建一个翻译研究计划， 研究冲击波创伤性脑损伤对随后的认知、心理和 多巴胺能功能障碍(ii)发展新的技能和理解的啮齿动物模型的冲击-创伤性脑损伤，以及 作为临床问题面临的退伍军人与没有爆炸性创伤性脑损伤的历史，使我的研究都知情 并有可能为未来的临床前和临床研究提供信息。(iii)为了获得工作 在统计技术方面的知识和专业知识，用于高级行为分析和大型数据集。 (iv)最后，凭借这些目标，明确区分自己作为一个独立的VA调查员， 两者都是我的导师们所独有的，也是他们帮助有爆炸性TBI病史的退伍军人的努力的补充。