VTA dopamine neurons and cognitive symptoms of Parkinson’s disease

VTA 多巴胺神经元和帕金森病的认知症状

基本信息

批准号：
10361526
负责人：
Nandakumar Narayanan
金额：
$ 43.28万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361526
关键词：
Affect Alzheimer&apos s disease related dementia Area Attention Attenuated Basic Science Behavior Behavioral Biological Markers Cessation of life Cognition Cognitive Data Dementia Dementia with Lewy Bodies Disease Dopamine Employment Executive Dysfunction Fiber Goals Hallucinations Human Impaired cognition Impairment Internal Ribosome Entry Site Knowledge Lead Methods Midbrain structure Modeling Morbidity - disease rate Motivation Mus Neurobehavioral Manifestations Neurons Nucleus Accumbens Nursing Homes Parkinson Disease Participant Patients Performance Photometry Prefrontal Cortex Psychoses Publishing RNA Interference Research Resolution Rewards Rodent Rodent Model Short-Term Memory Specificity Substantia nigra structure Symptoms Testing Time Training Transgenic Mice Tyrosine 3-Monooxygenase Ventral Tegmental Area Work base cell type cognitive function cognitive impairment in Parkinson&apos s cognitive performance cognitive process dopaminergic neuron effective therapy executive function flexibility improved millisecond mortality motor symptom mouse model novel novel therapeutics optogenetics reduce symptoms societal costs temporal measurement

项目摘要

Abstract Cognitive symptoms of Parkinson’s disease (PD) can affect up to 80% of PD patients and lead to enormous societal cost. These symptoms involve impaired executive functions such as working memory, attention, behavioral flexibility, and timing, and can progress to psychosis, hallucinations, and dementia. There are few therapies that improve cognitive function in PD. Thus, there is a critical need to better understand the fundamental mechanisms of cognitive dysfunction that occurs in PD. Our long-term goal is to elucidate the mechanisms by which cognitive dysfunction occurs in PD patients in order to develop new targeted treatments. PD involves death of midbrain dopaminergic neurons in ventral tegmental area (VTA). These neurons send mesocortical projections to key cognitive cortical areas such as the prefrontal cortex. It is unknown how VTA dopamine neurons are involved in cognitive processes that malfunction in human PD patients. Our goal in this proposal is to harness cell-type specific rodent models to characterize VTA dopamine neuronal function in cognitive processes relevant to PD. Our preliminary data demonstrates interval- timing variability correlates with PD-related cognitive dysfunction. Our rodent research demonstrates that VTA dopamine is necessary for interval timing, prefrontal timing-related modulations and prefrontal 4 Hz rhythms. Here, we will combine optogenetics, fiber photometry, and neuronal ensemble recordings in transgenic mice to interrogate VTA dopamine projections with cell-type-specificity and millisecond resolution. We will test the overall hypothesis that VTA dopamine neurons engage cognitive processing in the prefrontal cortex. In Aim 1 we will determine how silencing VTA dopamine neurons impacts cognitive processing. In Aim 2 we will define how VTA dopamine neuron dynamics predict cognitive processing. In Aim 3 we will determine how stimulating VTA dopamine neurons impacts cognitive processing. This proposal is broadly significant in determining when and how VTA dopamine engages prefrontal cognitive processing. Although this is a basic-science proposal focused on VTA dopamine neurons, our results will guide new therapies for human PD. This work could contribute to biomarkers for PD and for other Alzheimer’s disease and related dementias (ADRDs) such as dementia with Lewy bodies (DLB).

抽象的帕金森氏病（PD）的认知症状可影响多达80％的PD患者，并导致这些巨大的社会成本。注意，行为灵活性和时机，可以发展为精神病，幻觉和痴呆症。很少有疗法改善PD的认知功能。了解我们的长期目标中发生的认知功能障碍的基本机制是为了阐明PD患者发生认知功能障碍的机制新的目标治疗。 PD涉及中脑多巴胺能神经元（VTA）的死亡将中层预测发送到关键认知皮层区域，例如前额叶皮层。 VTA多巴胺神经元如何参与人类PD患者故障的认知过程。我们在此建议中的目标是利用细胞型特定的啮齿动物模型来表征VTA多巴胺与PD相关的认知过程中的神经元功能。正时变异性与与PD相关的认知功能障碍相关。 VTA多巴胺对于间隔时间，前额叶时机相关调制和前额叶4 Hz是必需的节奏。转基因小鼠以细胞特异性和毫秒为单位询问VTA多巴胺投影解决方案。在AIM 1中的前额叶皮质中，我们将确定沉默VTA多巴胺神经元如何影响认知处理。在AIM 3中进行处理。我们将确定刺激VTA多巴胺神经元如何影响认知加工。该提议对于确定何时以及如何与前额叶接合的何时以及如何与认知处理。结果将指导人类PD的新疗法。其他阿尔茨海默氏病和相关的痴呆症（ADRD），例如Lewy Bodies（DLB）。