Prefrontal D1 signaling and cognitive symptoms of Parkinson's disease

帕金森病的前额叶 D1 信号传导和认知症状

• 批准号: 8792297
• 负责人: Nandakumar Narayanan
• 金额: $ 28万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792297
• 关键词: Affect; Age; Aging; Animal Model; Area; Attention; Attention deficit hyperactivity disorder; Automobile Driving; Behavior; Brain; Brain region; Cerebral cortex; Cessation of life; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Dorsal; Employment; Genetic; Goals; Huntington Disease; Impaired cognition; Infusion procedures; Knowledge; Lead; Link; Malignant - descriptor; Maps; Modeling; Morbidity - disease rate; Mus; Neurobehavioral Manifestations; Neurons; Nursing Homes; Parkinson Disease; Patients; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Process; Public Health; Pyramidal Cells; Ramp; Rodent; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Societies; Stimulus; System; Techniques; Time; Transgenic Mice; Ventral Tegmental Area; Work; addiction; cognitive control; cost; dopaminergic neuron; effective therapy; hippocampal pyramidal neuron; improved; insight; mortality; neural circuit; optogenetics; public health relevance; receptor; relating to nervous system; research study; time interval

DESCRIPTION (provided by applicant): Cognitive symptoms of Parkinson's disease are emerging as an enormous public health problem. Up to 80% of PD patients will suffer debilitating cognitive symptoms in the course of their disease. In PD patients, cognitive impairments predict a malignant disease course leading to loss of employment, independence, driving deficits, nursing home placement, and death. Because PD is strongly associated with aging, this problem will surge as our society ages. There are few treatments that improve PD-related cognitive symptoms. Thus there is a critical need to develop new, mechanistic treatments for cognitive symptoms of PD. A challenge in developing new treatments is that there is a knowledge gap about the mechanism of PD-related cognitive symptoms. Cognitive deficits in PD patients include impaired working memory, attention, reasoning, planning, and timing. One elementary cognitive task in which PD patients are reliably impaired is interval timing. In this task, subjects are presented with a stimulus, and estimate its duration over several seconds. Interval timing is an ideal window into cognition in PD because this task depends on dopamine and can be readily studied in animal models. Elucidating the neural circuitry of interval timing could help close the knowledge gap about cognitive dysfunction in PD. Our preliminary data strongly implicate D1-type dopamine receptors on pyramidal neurons in the prefrontal area of the cerebral cortex in interval timing. However, it is unclear precisely how prefrontal neurons influence interval timing. Here we combine highly selective and specific techniques such as optogenetics, focal drug infusions, and neuronal ensemble recordings to systematically interrogate the neural activity of prefrontal D1 neurons in great detail, and to map the projections of these neurons. In Aim 1, we determine how prefrontal D1 neurons control interval timing. In Aim 2, we determine which projections of prefrontal D1 neurons control interval timing. Finally, in Aim 3 we rescue interval timing deficits in animal models of PD by stimulating prefrontal D1 neurons and their projections. This work will identify key drivers of a cognitive process impaired in PD patients. Our findings could link a brain region and a receptor system to cognitive processes impaired in PD, and could spur development of targeted pharmacological, genetic, or brain-stimulation therapies. Insights from this work could have relevance for PD as well as for other diseases involving prefrontal dopamine circuits, such as schizophrenia, ADHD, addiction, and Huntington's disease.

描述（由申请人提供）：帕金森病的认知症状正在成为一个巨大的公共卫生问题。高达 80% 的 PD 患者在病程中会出现认知衰弱的症状。在帕金森病患者中，认知障碍预示着恶性病程，导致失业、独立性、驾驶缺陷、疗养院安置和死亡。由于帕金森病与衰老密切相关，随着社会老龄化，这个问题将会激增。很少有治疗方法可以改善帕金森病相关的认知症状。因此，迫切需要开发针对帕金森病认知症状的新的机械治疗方法。开发新疗法的一个挑战是，对于帕金森病相关认知症状的机制存在知识差距。 PD 患者的认知缺陷包括工作记忆、注意力、推理、计划和时间安排受损。 PD 患者确实受到损害的一项基本认知任务是间隔计时。在此任务中，向受试者提供刺激，并估计其持续时间（几秒钟）。间隔计时是了解 PD 认知的理想窗口，因为这项任务依赖于多巴胺，并且可以很容易地在动物模型中进行研究。阐明间隔计时的神经回路有助于缩小有关帕金森病认知功能障碍的知识差距。我们的初步数据强烈表明 D1 型多巴胺受体在间隔计时的大脑皮层前额叶区域的锥体神经元上。但目前还不清楚具体如何 前额神经元影响间隔时间。在这里，我们结合了高度选择性和特定的技术，如光遗传学、局部药物输注和神经元整体记录，系统地详细询问前额叶 D1 神经元的神经活动，并绘制地图 这些神经元的投射。在目标 1 中，我们确定前额 D1 神经元如何控制间隔时间。在目标 2 中，我们确定前额叶 D1 神经元的哪些投射控制间隔时间。最后，在目标 3 中，我们通过刺激前额叶 D1 神经元及其投射来挽救 PD 动物模型中的间隔时间缺陷。这项工作将确定帕金森病患者认知过程受损的关键驱动因素。我们的研究结果可能将大脑区域和受体系统与帕金森病中受损的认知过程联系起来，并可能刺激靶向药理学、遗传或大脑刺激疗法的开发。这项工作的见解可能与帕金森病以及涉及前额叶多巴胺回路的其他疾病有关，例如精神分裂症、注意力缺陷多动症、成瘾和亨廷顿舞蹈症。