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

基本信息

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
项目类别：
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

项目摘要

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）：帕金森氏病的认知症状正在成为一个巨大的公共卫生问题。多达80％的PD患者在其疾病过程中会遭受衰弱的认知症状。在PD患者中，认知障碍预测了恶性疾病病程，从而导致就业，独立性，驾驶赤字，疗养院安置和死亡的丧失。由于PD与衰老密切相关，因此随着我们社会年龄的增长，这个问题将激增。几乎没有治疗可以改善与PD相关的认知症状。因此，对于PD的认知症状开发新的机械治疗迫切需要。开发新疗法的一个挑战是，关于与PD相关的认知症状机制存在知识差距。 PD患者的认知缺陷包括工作记忆力受损，注意力，推理，计划和时机。 PD患者可靠地受损的一项基本认知任务是间隔时间。在此任务中，对受试者进行了刺激，并在几秒钟内估算其持续时间。间隔时间是PD认知的理想窗口，因为此任务取决于多巴胺，并且可以在动物模型中很容易研究。阐明间隔时间的神经回路可能有助于缩小有关PD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的间隔时间安排。但是，目前尚不清楚如何前额叶神经元会影响间隔时间。在这里，我们将高度选择性和特定的技术结合在一起，例如光遗传学，局灶性药物输注和神经元集合记录，以系统地详细介绍前额叶D1神经元的神经活动，并绘制这些神经元的预测。在AIM 1中，我们确定前额叶D1神经元的控制间隔时间。在AIM 2中，我们确定前额叶D1神经元控制间隔时间的投影。最后，在AIM 3中，我们通过刺激前额叶D1神经元及其预测来挽救PD动物模型中的间隔时间缺陷。这项工作将确定PD患者受损的认知过程的关键驱动因素。我们的发现可以将大脑区域和受体系统与PD损害的认知过程联系起来，并可能刺激有针对性的药理，遗传或脑刺激疗法的发展。这项工作的见解可能与PD以及其他涉及额叶多巴胺回路（例如精神分裂症，ADHD，成瘾和亨廷顿氏病）的疾病有关。