Prefrontal D1 signaling and cognitive symptoms of Parkinson'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患者在发病过程中会出现认知功能衰弱的症状。在PD患者中，认知障碍预示着恶性病程，导致失业、独立、驾驶缺陷、养老院安置和死亡。因为帕金森病与衰老密切相关，这个问题将随着我们社会的老龄化而激增。很少有治疗方法可以改善pd相关的认知症状。因此，迫切需要开发新的机制治疗PD的认知症状。开发新疗法的一个挑战是，关于pd相关认知症状的机制存在知识缺口。PD患者的认知缺陷包括工作记忆、注意力、推理、计划和时机受损。PD患者的一个基本认知任务是间隔时间。在这项任务中，受试者被呈现一个刺激，并在几秒钟内估计其持续时间。间隔时间是研究帕金森病认知的理想窗口，因为这一任务依赖于多巴胺，可以在动物模型中很容易地进行研究。阐明间隔时间的神经回路有助于缩小PD认知功能障碍的知识空白。我们的初步数据强烈暗示d1型多巴胺受体在间隔时间大脑皮层前额叶区锥体神经元。然而，目前还不清楚具体是如何做到的

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.