Neuronal mechanisms of sleep alterations in Parkinson's Disease: A circuit based investigation

帕金森病睡眠改变的神经机制：基于回路的研究

• 批准号: 18F18073
• 负责人: ラザルス ミハエル
• 金额: $ 1.54万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2018
• 资助国家: 日本
• 起止时间: 2018-04-25 至 2020-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18F18073/
• 关键词: Parkinson disease; Parkinson's disease

Among the well-established non-motor symptoms of Parkinson disease (PD), compulsive eating stands among the most frequent impulse control disorder. This disorder is attributed to dopamine (DA) dysfunction following both dopaminergic neurodegeneration and chronic DA replacement therapy in PD patients. Recent evidence highlighted the causal impact of sleep alterations in precipitating metabolic and food-seeking behavioral disorders. Building on these findings, we have recently revealed the crucial importance of the medial prefrontal cortex (mPFC) in linking sleep quality with food preference and energy consumption. The mPFC is a frontal neuronal hub that is crucial for executive functions. Given that midbrain DA neurons have dense projections to the mPFC, we aimed in this project to elucidate the precise role of DA neurotransmission in mediating food preference based on their nutritional and metabolic impact. To interfere with DA neurotransmission, we employed chemogenetic to selectively inhibit DA neurons in the ventral tegmental area (VTA).After habituation into our behavioral settings, animals were given free access to highly palatable food (Chocolate and cheese) and standard laboratory chow. Food preference and intake was monitored daily under both baseline 12h/12h light/dark (LD) cycle and following 6h sleep deprivation. Under LD conditions, control animals showed high preference for palatable fatty items (cheese) over carbohydrate-rich food (chocolate and standard chow). After inhibition of DA neurons, animals still show a preference for fatty food over sweet food.

在帕金森氏病（PD）的良好成熟的非运动症状中，强迫性饮食是最常见的冲动控制障碍之一。这种疾病归因于PD患者多巴胺能神经变性和慢性DA替代疗法后多巴胺（DA）功能障碍。最近的证据强调了睡眠改变在沉淀代谢和寻求食物的行为障碍中的因果影响。在这些发现的基础上，我们最近揭示了内侧前额叶皮层（MPFC）在将睡眠质量与食物偏好和能源消耗联系起来的关键重要性。 MPFC是一个额叶神经元中心，对执行功能至关重要。鉴于中脑DA神经元对MPFC有密集的预测，因此我们旨在阐明DA神经传递在基于其营养和代谢影响的粮食偏好中的确切作用。为了干扰DA神经传递，我们采用化学生成来有选择地抑制腹侧段段区域（VTA）的DA神经元（VTA）。习惯习惯我们的行为环境后，可以免费获得高度可口的食物（巧克力和奶酪）和标准实验室粮食。每天在基线12h/12h光/黑色（LD）周期和6h睡眠剥夺之后，每天都监测食物偏好和摄入量。在LD条件下，对照动物对可口的脂肪含量（奶酪）高于富含碳水化合物的食物（巧克力和标准食物）。在抑制DA神经元之后，动物仍然表现出对脂肪食物而不是甜食的偏爱。