VTA dopamine neurons and cognitive symptoms of Parkinson’s disease

摘要 帕金森病(PD)的认知症状可影响多达80%的PD患者，并导致 巨大的社会代价。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，并可发展为精神病、幻觉和痴呆症。 改善帕金森病患者认知功能的治疗方法很少。因此，迫切需要更好地 了解帕金森病患者认知功能障碍的基本机制。我们的长期目标 目的是阐明帕金森病患者认知功能障碍的发生机制 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 将中皮质投射发送到关键的认知皮质区域，如前额叶皮质。这是未知的 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。 我们在这项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 与帕金森病相关的认知过程中的神经元功能。我们的初步数据显示间隔- 时间变异性与帕金森病相关的认知功能障碍有关。我们对啮齿动物的研究表明 VTA多巴胺是间期计时、前额计时相关的调制和前额4赫兹所必需的 节奏。在这里，我们将结合光遗传学、纤维光度学和神经元集合记录在 具有细胞类型特异性和毫秒级的VTA多巴胺投射的转基因小鼠 决议。我们将测试VTA多巴胺神经元参与认知处理的总体假设 在前额叶皮质。在目标1中，我们将确定静息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VTA多巴胺神经元动力学如何预测认知 正在处理。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 正在处理。 这一建议对于确定VTA多巴胺何时以及如何参与前额叶活动具有广泛的意义。 认知加工。虽然这是一项专注于VTA多巴胺神经元的基础科学建议，但我们的 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帕金森病的生物标记物和 其他阿尔茨海默病和相关痴呆(ADRD)，如路易体痴呆(DLB)。

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).