Prefrontal D1 signaling and cognitive symptoms of Parkinson's disease

描述(由申请人提供)：帕金森氏症的认知症状正在成为一个巨大的公共卫生问题。高达80%的帕金森病患者在疾病过程中会出现衰弱的认知症状。在PD患者中，认知障碍预测恶性疾病过程，导致失去就业、独立、驾驶缺陷、养老院安置和死亡。由于帕金森病与老龄化密切相关，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帕金森病相关的认知症状。因此，迫切需要开发治疗帕金森病认知症状的新的机械性治疗方法。开发新的治疗方法面临的一个挑战是，对帕金森病相关认知症状的机制存在知识缺口。帕金森病患者的认知缺陷包括工作记忆、注意力、推理、计划和时间安排的损害。帕金森病患者的一个基本认知任务是间歇计时。在这项任务中，受试者被呈现一种刺激，并估计其持续时间超过几秒钟。间期计时是了解帕金森病认知的理想窗口，因为这项任务依赖于多巴胺，而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弥合关于帕金森病认知功能障碍的知识差距。我们的初步数据强烈暗示D1型多巴胺受体在大脑皮层前额叶区域的锥体神经元上存在间隔时间。然而，目前还不清楚到底是如何做到的 前额叶神经元影响间期计时。在这里，我们结合了高选择性和特定的技术，如光遗传学，焦点药物注射，和神经元集合记录，系统地详细询问前额叶d1神经元的神经活动，并绘制 这些神经元的投射。在目标1中，我们确定了前额叶D1神经元是如何控制间隔时间的。在目标2中，我们确定了控制间期计时的前额叶D1神经元的哪些投射。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帕金森病动物模型中的时间间隔缺陷。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帕金森病患者受损的认知过程联系起来，并可能刺激有针对性的药物、遗传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、ADHD、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.