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

在帕金森病（PD）的非运动症状中，强迫进食是最常见的冲动控制障碍。这种疾病归因于PD患者多巴胺能神经变性和慢性DA替代治疗后多巴胺（DA）功能障碍。最近的证据强调了睡眠改变在促成代谢和觅食行为障碍方面的因果影响。基于这些发现，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量消耗联系起来方面的关键重要性。mPFC是一个对执行功能至关重要的额叶神经中枢。鉴于中脑DA神经元对mPFC有密集的投射，我们在本项目中旨在阐明DA神经传递在基于其营养和代谢影响的食物偏好介导中的确切作用。为了干扰DA神经传递，我们采用化学遗传学方法选择性抑制腹侧被盖区（VTA）的DA神经元。在习惯了我们的行为设置后，动物们可以自由地获得美味的食物（巧克力和奶酪）和标准的实验室食物。在基线12小时/12小时光照/黑暗（LD）周期和6小时睡眠剥夺下，每天监测食物偏好和摄入量。在LD条件下，对照动物表现出对美味脂肪食物（奶酪）的高度偏好，而不是富含碳水化合物的食物（巧克力和标准食物）。在抑制DA神经元后，动物仍然表现出对高脂肪食物的偏好。

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.