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.

项目概要/摘要 认知障碍会影响记忆、执行功能和时间安排。 大多数帕金森病患者在患病期间的某个阶段会出现轻度认知障碍。 尽管对质量产生负面影响，但损伤最终会演变成帕金森病痴呆。 这些症状引起的生活，目前尚无有效的疗法来治疗这些症状的认知障碍 因此，开发针对帕金森病相关认知的新疗法的需求尚未得到满足。 这需要确定认知功能障碍背后的基本神经生物学机制。 在帕金森病中。 黑质纹状体通路中的多巴胺神经元变性不仅与运动相关 帕金森病的症状，同时也伴有帕金森病患者的认知症状。 可靠地损害间歇计时任务的表现以及损伤或操纵多巴胺神经元 啮齿类动物也会损害间歇计时任务的表现。此外，纹状体神经元会进行时间编码。 我提出的研究的总体目标是通过在一定的时间间隔内增加他们的活动来获取相关信息。 的目的是确定在认知任务期间黑质纹状体多巴胺信号如何影响纹状体微电路。 总体假设是纹状体时间编码取决于多巴胺。 我将通过两个不同的实验来检验这个总体假设，首先，我将检验以下假设： 调节纹状体多巴胺活动预测纹状体投射神经元在 我将通过使用纹状体 dLight 和纤维记录局部多巴胺动态来测试这一点。 其次，我将测试以下假设： 多巴胺神经元控制纹状体时间相关的斜坡活动，我会通过光遗传学沉默或刺激。 多巴胺神经元在任务期间的关键行为事件，同时记录纹状体神经元整体活动。 总之，所提出的实验将有助于建立一个模型，建立黑质纹状体多巴胺如何 这些知识将为新疗法的开发提供信息。 通过确定治疗地点和方式来治疗帕金森病的认知障碍，这一点非常重要。 与帕金森病和其他多巴胺相关疾病相关，因为这项工作将揭示基础 多巴胺的基础科学机制的完成不仅会扩展我的技术。 和研究技能，同时也提高了我的专业发展技能，因此，这个奖项将会进步。 我的职业目标是在一个有竞争力的研究机构运营一个独立的实验室，专注于 关于认知引导行动的多巴胺和基底神经节回路机制。