Dopamine modulation for the treatment of chronic dysfunction due to traumatic brain injury

项目总结/摘要 每年发生超过280万例创伤性脑损伤（TBI），使其成为最紧迫的问题之一。 医学界面临的挑战。创伤性脑损伤的幸存者通常会出现慢性精神症状 例如增加风险决策和冲动，但没有针对这种大规模的治疗方法。 人口这些缺陷影响到个人日常生活的各个方面，往往导致质量下降 照顾者或周围的人的生活。一个潜在的主要贡献者这种持久的功能障碍 多巴胺神经传递减少，多巴胺神经传递介导人类许多核心动机行为， 动物由于多巴胺的减少，这些变化可能会改变康复努力的效果， 治疗药物，使TBI患者成为这方面的特殊人群。因此，本项目的目标是 研究慢性TBI引起的精神病样缺陷的潜在治疗方法，重点是调节 多巴胺系统，假设增加多巴胺将改善功能。这将是 研究了三个目标，每个目标都有不同的治疗方式，使用TBI的大鼠模型。提出 研究将使用爱荷华州赌博任务的模拟，称为啮齿动物赌博任务，同时 评估TBI后的风险决策和冲动。目标1将研究对以下因素的敏感性变化： 环境突发事件，以了解人类康复训练的效果变化。一系列 实验将确定结果提示，一种已知的刺激多巴胺反应的方法， 可以拯救决策能力。目标2将测试多种治疗药物的疗效。它会比较 受体特异性药物与一般多巴胺能药物相比如何有效， 在慢性损伤期，多巴胺相关蛋白质的脑水平发生变化。目标3将评估 经颅直流电刺激（tDCS）作为一种神经调节形式的疗效和机制。之前 研究表明，tDCS增加多巴胺水平，但参数尚未探索， 脑损伤的实验对象为了证实多巴胺是tDCS的有益作用的驱动力， 多巴胺细胞将在额叶皮层进行。这些研究将促进对 TBI后功能障碍的机制，确定三种不同治疗方式的疗效， 确定多巴胺在多大程度上代表慢性功能障碍的相关临床靶点， 损伤

Project Summary/Abstract More than 2.8 million traumatic brain injuries (TBIs) occur annually, making this one of the most pressing challenges facing the medical community. Survivors of TBI often experience chronic psychiatric symptoms such as increased risky decision-making and impulsivity, yet there are no treatments specific to this large population. These deficits affect individuals across all aspects of everyday life, often leading to reduced quality of life for caregivers or those surrounding the person. A potential major contributor to this enduring dysfunction is reduced dopamine neurotransmission, which mediates many core motivated behaviors in humans and animals. Because of reductions in dopamine, these changes may alter the efficacy of rehabilitative efforts and therapeutic drugs, making patients with TBI a special population in this regard. Thus, the goal of this project is to investigate potential treatments for psychiatric-like deficits arising from chronic TBI, focusing on modulation of dopamine systems, with the hypothesis that augmentation of dopamine will improve function. This will be investigated across three aims, each with different treatment modalities, using a rat model of TBI. Proposed studies will use an analog of the Iowa Gambling Task, known as the Rodent Gambling Task, to concurrently assess risky decision-making and impulsivity after TBI. Aim 1 will investigate changes in sensitivity to environmental contingencies to understand shifts in efficacy of rehabilitative training in humans. A series of experiments will determine whether cueing of outcomes, a known means of stimulating dopamine responses, can rescue decision-making ability. Aim 2 will test the efficacy of multiple therapeutic drugs. It will compare how effective receptor-specific drugs are compared with general dopaminergic agents and what specific changes occur to brain levels of dopamine-related proteins in the chronic injury period. Aim 3 will evaluate the efficacy and mechanism of transcranial direct-current stimulation (tDCS) as a form of neural modulation. Prior research has suggested that tDCS increases dopamine levels, but parameters have not been explored for brain-injured subjects. To verify that dopamine is driving beneficial effects of tDCS, chemogenetic inhibition of dopamine cells will be performed in the frontal cortex. These studies will advance fundamental understanding of mechanisms of dysfunction after TBI, identify the efficacy of three different therapeutic modalities, and determine the degree to which dopamine represents a relevant clinical target for chronic dysfunction after injury.