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患者在疾病过程中会出现使人衰弱的认知症状。在PD患者中，认知障碍预示恶性疾病病程，导致失业、独立性、驾驶缺陷、养老院安置和死亡。由于PD与老龄化密切相关，随着我们社会的老龄化，这个问题将激增。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。开发新治疗方法的一个挑战是，对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、计划和时间安排受损。PD患者可靠受损的一个基本认知任务是间隔计时。在这项任务中，受试者被呈现一个刺激，并估计其持续时间超过几秒钟。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PD认知功能障碍的知识差距。我们的初步数据强烈牵连的D1型多巴胺受体在大脑皮层的前额叶区的锥体神经元的间隔时间。然而，目前还不清楚如何 前额叶神经元影响间隔计时。在这里，我们结合联合收割机高度选择性和特异性的技术，如光遗传学，局灶性药物输注和神经元系综记录，系统地询问前额叶D1神经元的神经活动的非常详细，并映射 这些神经元的投射。在目标1中，我们确定前额叶D1神经元如何控制间隔时间。在目标2中，我们确定哪些预测的前额叶D1神经元控制间隔时间。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PD患者认知过程受损的关键驱动因素。我们的发现可以将大脑区域和受体系统与PD中受损的认知过程联系起来，并可以刺激靶向药理学，遗传学或脑刺激疗法的发展。这项工作的见解可能与帕金森病以及其他涉及前额叶多巴胺回路的疾病有关，如精神分裂症，多动症，成瘾和亨廷顿病。

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.