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

多巴胺调节治疗创伤性脑损伤引起的慢性功能障碍

• 批准号: 10163928
• 负责人: Cole Vonder Haar
• 金额: --
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2021-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163928
• 关键词: Affect; Aggressive behavior; Agonist; American; Amphetamines; Animal Model; Animals; Area; Attention deficit hyperactivity disorder; Automobile Driving; Behavior Therapy; Behavioral Assay; Biological Assay; Brain; Brain Injuries; Caregivers; Cells; Chemicals; Chronic; Clinical; Communities; Cues; Data; Decision Making; Development; Disease; Dopamine; Dopaminergic Agents; Environment; Functional disorder; Gambling; General Population; Goals; Human; Impaired cognition; Impairment; Impulsivity; Incidence; Individual; Injury; Iowa; Knowledge; Life; Mediating; Mediator of activation protein; Medical; Modality; Modeling; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Population; Positioning Attribute; Predisposition; Prosencephalon; Proteins; Psychiatric therapeutic procedure; Psychological reinforcement; Publishing; Quality of life; Rattus; Rehabilitation Outcome; Rehabilitation therapy; Reporting; Research; Ritalin; Rodent; Role; Self Perception; Series; Signal Transduction; Special Population; Survivors; Symptoms; System; TBI Patients; TBI treatment; Therapeutic; Therapeutic Agents; Training; Translations; Traumatic Brain Injury; Treatment Efficacy; United States; Work; addiction; analog; associated symptom; base; clinically relevant; disability; dopamine system; efficacious treatment; efficacy evaluation; efficacy testing; experience; experimental study; frontal lobe; improved; improved functioning; motivated behavior; negative affect; neglect; neuroregulation; neurotransmission; pre-clinical research; psychiatric symptom; psychostimulant; receptor; recruit; relating to nervous system; response; therapeutic evaluation; therapeutic target; therapeutically effective

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.

项目概要/摘要 每年发生超过 280 万起创伤性脑损伤 (TBI)，这使其成为最紧迫的问题之一 医学界面临的挑战。 TBI 幸存者经常会出现慢性精神症状 例如风险决策和冲动的增加，但目前还没有专门针对这种大型疾病的治疗方法。 人口。这些缺陷影响个人日常生活的各个方面，往往导致质量下降 照顾者或患者周围人员的生活。造成这种持久功能障碍的潜在主要因素 减少多巴胺神经传递，介导人类的许多核心动机行为 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，该项目的目标是 研究慢性创伤性脑损伤引起的精神类缺陷的潜在治疗方法，重点关注调节 多巴胺系统的研究，假设增加多巴胺会改善功能。这将是 使用 TBI 大鼠模型对三个目标进行研究，每个目标都有不同的治疗方式。建议的 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 将调查敏感度的变化 环境突发事件，以了解人类康复训练效果的变化。一系列 实验将确定结果提示（刺激多巴胺反应的已知方法）是否 可以挽救决策能力。目标2将测试多种治疗药物的功效。它将比较 受体特异性药物与一般多巴胺能药物相比效果如何，具体有哪些 在慢性损伤期间，大脑中多巴胺相关蛋白的水平会发生变化。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功效和机制。事先的 研究表明 tDCS 可以增加多巴胺水平，但尚未探索参数 脑损伤的受试者。为了验证多巴胺正在驱动 tDCS 的有益作用，化学遗传学抑制 多巴胺细胞将在额叶皮层进行。这些研究将增进基本理解 TBI 后功能障碍的机制，确定三种不同治疗方式的功效，以及 确定多巴胺在多大程度上代表慢性功能障碍的相关临床目标 受伤。