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: 10426388
• 负责人: Cole Vonder Haar
• 金额: $ 31.65万
• 依托单位: OHIO STATE 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426388
• 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.

项目摘要/摘要 每年发生超过280万次创伤性脑损伤（TBI），这使得这是最紧迫的 医学界面临的挑战。 TBI的幸存者经常经历慢性精神病症状 例如增加风险的决策和冲动性，但是没有针对这一大型的治疗方法 人口。这些赤字会影响日常生活各个方面的个人，通常会导致质量降低 护理人员或周围人的生活。导致这种持久功能障碍的潜在主要贡献者 减少了多巴胺神经传递，它介导了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功效和 在这方面，治疗药物使TBI患者成为特殊人群。因此，这个项目的目标是 调查慢性TBI引起的精神病样缺陷的潜在治疗方法，重点是调节 多巴胺系统的假设是增强多巴胺将改善功能。这将是 使用TBI的大鼠模型进行了三个目标，每个目标都具有不同的治疗方式。建议的 研究将使用爱荷华州赌博任务（称为啮齿动物赌博任务）的类似物来同时 评估TBI之后有风险的决策和冲动。 AIM 1将调查敏感性的变化 了解人类康复培训功效的转变的环境意外事件。一系列 实验将确定结果的提示是否是一种刺激多巴胺反应的已知手段， 可以挽救决策能力。 AIM 2将测试多种治疗药物的功效。它将比较 将有效的受体特异性药物与一般多巴胺能特异性药物进行比较 在慢性损伤时期，多巴胺相关蛋白的大脑水平发生变化。 AIM 3将评估 经颅直流刺激（TDC）的功效和机制作为神经调节的一种形式。事先的 研究表明，TDCS增加了多巴胺水平，但尚未探索参数 脑损伤的受试者。为了验证多巴胺正在推动TDC的有益作用 多巴胺细胞将在额叶皮层中进行。这些研究将提高基本理解 TBI后功能障碍的机制，确定三种不同的治疗方式的功效，并确定 确定多巴胺在多巴胺中代表慢性功能障碍的相关临床目标 受伤。