Nigrostriatal dopamine mechanisms of cognitive control

黑质纹状体多巴胺认知控制机制

• 批准号: 10639280
• 负责人: Alexandra Shelly Bova
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10639280
• 关键词: Address; Affect; Area; Attention; Award; Basal Ganglia; Basic Science; Behavioral; Code; Cognition; Cognitive; Corpus striatum structure; Data; Dementia; Development; Diagnosis; Disease; Dopamine; Dorsal; Electrophysiology (science); Event; Exhibits; Fiber; Foundations; Goals; Impaired cognition; Impairment; Institution; Knowledge; Laboratories; Learning; Lesion; Link; Memory; Modeling; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurons; Parkinson Disease; Parkinson' s Dementia; Patients; Performance; Photometry; Prefrontal Cortex; Principal Investigator; Quality of life; Ramp; Reporting; Research; Resolution; Rodent; Running; Short-Term Memory; Signal Transduction; Substantia nigra structure; Symptoms; Technical Expertise; Techniques; Testing; Time; Training; Transgenic Mice; Work; career; cognitive control; cognitive function; cognitive impairment in Parkinson' s; cognitive process; cognitive task; dopaminergic neuron; effective therapy; executive function; experience; experimental study; improved; mild cognitive impairment; millisecond; motor symptom; neurobiological mechanism; neurophysiology; neurotransmission; nigrostriatal pathway; novel; novel therapeutics; optogenetics; pars compacta; prevent; programs; skill acquisition; skills; societal costs; targeted treatment; temporal measurement; therapeutic development; therapy development; time interval

Project Summary/Abstract Cognitive impairments, which affect memory, executive functioning, and timing, are experienced by the majority of Parkinson’s disease patients at some point during their disease. For many patients, mild cognitive impairments eventually devolve into Parkinson’s disease dementia. Despite the negative impact on quality of life caused by these symptoms, there are currently no effective therapies to treat cognitive impairment in these patients. Thus, there is an unmet need to develop new treatments for Parkinson’s disease-related cognitive decline. This requires identifying the fundamental neurobiological mechanisms underlying cognitive dysfunction in Parkinson’s disease. Dopamine neuron degeneration in the nigrostriatal pathway is associated not only with the motor symptoms of Parkinson’s disease, but also with cognitive symptoms. Parkinson’s disease patients have reliably impaired performance on interval timing tasks and lesioning or manipulating dopamine neurons in rodents also impairs performance on interval timing tasks. Furthermore, striatal neurons encode temporally relevant information by ramping their activity across timed intervals. The overall goal of my proposed research is to identify how nigrostriatal dopamine signals influence striatal microcircuitry during a cognitive task. My overall hypothesis is that striatal temporal encoding depends on dopamine. I will test this overall hypothesis with two distinct experiments. First, I will test the hypothesis that task- modulated striatal dopamine activity predicts temporal encoding by striatal projection neurons during an interval timing task. I will test this by recording local dopamine dynamics with striatal dLight and fiber photometry while simultaneously recording striatal neuronal ensembles. Second, I will test the hypothesis that dopamine neurons control striatal time-related ramping activity. I will optogenetically silence or stimulate dopamine neurons at key behavioral events during the task while recording striatal neuronal ensemble activity. Together, the proposed experiments will contribute to a model establishing how nigrostriatal dopamine neurons regulate striatal cognitive processing. This knowledge will inform development of novel therapies for cognitive impairments in Parkinson’s disease by identifying where and how to target treatments. This is highly relevant for Parkinson’s disease and other dopamine-linked disorders, as this work will reveal foundational basic science mechanisms of dopamine. Completion of the proposed work will not only expand my technical and research skillset, but also enhance my professional development skills. Therefore, this award will advance me towards my career goal of running an independent laboratory at a competitive research institution, focused on dopamine and basal ganglia circuitry mechanisms of cognitively-guided action.

项目摘要/摘要 影响记忆，执行功能和时机的认知障碍是由 大多数帕金森病患者在疾病中的某个时候。对于许多患者，轻度认知 障碍最终转变为帕金森氏病痴呆症。尽管对质量产生负面影响 这些症状引起的生活，目前尚无有效治疗认知障碍的疗法 患者。这是毫无满足的，​​需要为帕金森氏病相关的认知开发新的治疗方法 衰退。这需要确定认知功能障碍的基本神经生物学机制 在帕金森氏病中。 黑质纹状体途径中的多巴胺神经元变性不仅与电动机有关 帕金森氏病的症状，也有认知症状。帕金森氏病患者有 在间隔正时任务上的性能可靠地损害，并在 啮齿动物还会损害间隔正时任务的性能。此外，纹状体神经元暂时编码 相关信息通过在定时间隔中逐渐增加其活动。我拟议的研究的总体目标 是为了确定在认知任务期间，骨纹状体多巴胺信号如何影响纹状体微环路。我的 总体假设是纹状体临时编码取决于多巴胺。 我将通过两个不同的实验检验这一总体假设。首先，我将测试任务的假设 - 调制纹状体多巴胺活性预测在纹状体投影神经元暂时编码 间隔正时任务。我将通过录制纹状体和光纤的局部多巴胺动力学来测试这一点 光度法同时记录纹状体神经元集合。其次，我将检验以下假设 多巴胺神经元控制纹状体时间相关的渐变活性。我会在光源上静音或刺激 在任务期间，在关键行为事件中，多巴胺神经元在记录纹状体神经元合奏活动的同时。 共同提出的实验将有助于建立黑质纹状体的模型 神经元调节纹状体认知处理。这些知识将为开发新颖疗法的发展 帕金森氏病的认知障碍是通过确定靶向靶向疗法的位置和靶向。这是高度的 与帕金森氏病和其他多巴胺相关的疾病有关，因为这项工作将揭示基础 多巴胺的基础科学机制。拟议工作的完成不仅会扩大我的技术 和研究技能，但也提高了我的专业发展技能。因此，该奖项将提高 我致力于在竞争性研究机构运营独立实验室的职业目标， 关于认知引导作用的多巴胺和基本神经节电路机制。