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：
10586138
负责人：
Nandakumar Narayanan
金额：
$ 46.01万
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/10586138
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 Methods Midbrain structure 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 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 time interval

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).

抽象的帕金森病 (PD) 的认知症状可影响高达 80% 的 PD 患者，并导致这些症状涉及工作记忆等执行功能受损。注意力、行为灵活性和时机，并可能发展为精神病、幻觉和痴呆。改善帕金森病认知功能的疗法很少，因此迫切需要更好的疗法。了解帕金森病中认知功能障碍的基本机制是我们的长期目标。旨在阐明PD患者认知功能障碍发生的机制，以便开发新的靶向治疗。 PD 涉及腹侧被盖区 (VTA) 中脑多巴胺能神经元的死亡。发送中皮层投射到关键的认知皮层区域，例如前额叶皮层，目前尚不清楚。 VTA 多巴胺神经元如何参与人类 PD 患者功能障碍的认知过程。我们在本提案中的目标是利用细胞类型特定的啮齿动物模型来表征 VTA 多巴胺我们的初步数据表明，与 PD 相关的认知过程中的神经功能。我们的啮齿动物研究表明，时间变异与 PD 相关的认知功能障碍相关。 VTA 多巴胺对于间隔计时、前额叶计时相关调制和前额叶 4 Hz 是必需的在这里，我们将结合光遗传学、光纤光度测量和神经系统记录。转基因小鼠以细胞类型特异性和毫秒来询问 VTA 多巴胺预测我们将检验 VTA 多巴胺神经元参与认知处理的总体假设。在目标 1 中，我们将确定沉默 VTA 多巴胺神经元如何影响前额皮质。在目标 2 中，我们将定义 VTA 多巴胺神经元动态如何预测认知。在目标 3 中，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 VTA 多巴胺何时以及如何参与前额叶具有广泛的意义。尽管这是一个专注于 VTA 多巴胺神经元的基础科学提案，但我们的研究研究结果将指导人类帕金森病的新疗法。这项工作可能有助于开发帕金森病和帕金森病的生物标志物。其他阿尔茨海默病和相关痴呆症 (ADRD)，例如路易体痴呆 (DLB)。