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

• 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
• 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' 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' 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

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).

摘要 帕金森病（PD）的认知症状可影响高达80%的PD患者，并导致 巨大的社会成本。这些症状涉及受损的执行功能，如工作记忆， 注意力，行为灵活性和时间，并可能发展为精神病，幻觉和痴呆症。 很少有改善PD认知功能的疗法。因此，迫切需要更好地 了解PD中发生的认知功能障碍的基本机制。我们的长期目标 目的是阐明PD患者发生认知功能障碍的机制， 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。这些神经元 将中皮层投射发送到关键的认知皮层区域，如前额叶皮层。尚不清楚 腹侧被盖区多巴胺神经元如何参与人类帕金森病患者的认知过程。 我们的目标是利用特定细胞类型的啮齿动物模型来表征腹侧被盖区多巴胺 与PD相关的认知过程中的神经元功能。我们的初步数据显示- 时间变异性与PD相关的认知功能障碍相关。我们的啮齿动物研究表明， 腹侧被盖区多巴胺对间隔计时、前额叶计时相关的调制和前额叶4 Hz是必要的 节奏在这里，我们将结合联合收割机光遗传学，纤维光度学，和神经元合奏记录， 转基因小鼠以细胞类型特异性和毫秒询问VTA多巴胺投射 分辨率我们将测试腹侧被盖区多巴胺神经元参与认知处理的总体假设 大脑前额叶皮层在目标1中，我们将确定沉默VTA多巴胺神经元如何影响 认知加工在目标2中，我们将定义腹侧被盖区多巴胺神经元动力学如何预测认知能力。 处理.在目标3中，我们将确定刺激腹侧被盖区多巴胺神经元如何影响认知能力。 处理. 这一建议在确定腹侧被盖区多巴胺何时以及如何与前额叶皮层结合方面具有广泛的意义。 认知加工虽然这是一个基础科学的建议，重点是腹侧被盖区多巴胺神经元，我们的 结果将指导人类PD的新疗法。这项工作可能有助于PD的生物标志物， 其他阿尔茨海默病和相关痴呆（ADRD），如路易体痴呆（DLB）。