Circuitry of Midbrain Dopamine in Sleep & Wake

多巴胺(DA)是一种神经递质，调节各种清醒行为，包括运动、动机、认知、奖励和进食。人们对多巴胺对正常和病理性睡眠的影响认识和理解较少。帕金森病中的多巴胺细胞死亡与觉醒-睡眠状态的深刻变化有关，这些变化大致可分为夜间运动障碍和丘脑皮质节律性障碍。前者包括周期性腿部运动睡眠和快速眼动睡眠(REM睡眠)行为障碍，后者包括睡眠纺锤体丧失和慢波睡眠、白天嗜睡和白天侵入REM睡眠表现为幻觉行为。疾病的启发式模型主要局限于DA对丘脑皮质回路的间接作用而不是直接作用，也限于DA参与觉醒行为而不是丘脑皮质唤醒状态(例如睡眠)。我们最近描述了一种新的间丘脑多巴胺通路，它起源于黑质纹状体通路的轴突侧支，并在帕金森病中退化。因此，中脑多巴胺神经元不仅通过传统的黑质纹状体通路，而且通过丘脑的轴突侧支，具有调节包括睡眠在内的正常和病理行为的潜力。在这里，我们建议在非人类灵长类动物中定义这些新回路的解剖学和生理学特征。S.A.1号利用显微技术建立了DA神经在丘脑“运动”核、“前额核”、“边缘核”和网状核(即丘脑起搏器)的分布、亚细胞靶点、地形图和侧化。S.A.第2号将通过表征相同核团对局灶性多巴胺仿制药的响应性，扩展我们关于DA调节丘脑神经活动的初步电生理学演示。S.A.Numer3研究了根据丘脑目标识别的中脑DA神经元的状态相关放电，以及从功能上相同的纹状体区域释放DA的状态相关。这些研究是促进我们对伴随一系列神经精神疾病的觉醒障碍的病理生理学和治疗的了解的先决条件，特别是那些可以广泛定义为高(例如，精神分裂症)和低多巴胺(例如，帕金森病和不宁腿/周期性腿部睡眠运动)的疾病。

Dopamine (DA) is a neurotransmitter that modulates diverse waking behaviors including movement, motivation, cognition, reward, and feeding. Less appreciated and understood are dopamine's influences upon normal and pathologic sleep. Dopamine cell death which occurs in Parkinson's disease, is associated with profound alterations in wake-sleep state that can be broadly classified into disturbances of noctural movement and thalamocortical rhythmicity. The former include periodic leg movements of sleep and rapid-eye-movement sleep (REM-sleep) behavior disorder, while the later encompass loss of sleep spindles and slow-wave sleep, daytime sleepiness, and daytime intrusion of REM-sleep manifesting as hallucinatory behavior. Heuristic models of disease have limited themselves largely to DA's indirect, rather than direct actions upon thalamocortical circuits, and also to DA's participation in waking behaviors rather than thalamocortical arousal state (e.g., sleep). We have recently described a novel mesothalamic dopamine pathway originating via axon collaterals of the nigrostriatal pathway and which degenerates in PD. Mesencephalic dopamine neurons therefore have potential to modulate normal and pathologic behavior, including sleep, not only through traditional nigrostriatal pathways, but also by way of axon collaterals to the thalamus. Here we propose to define anatomical and physiological features of these novel circuits in non-human primates. S.A. number 1 employs microscopic techniques to establish the distribution, subcellular targets, topography, and collateralization of DA innervation in "motor", "prefrontal", "limbic" and the reticular (i.e., the thalamic pacemaker) thalamic nuclei. S.A. number 2 will extend our preliminary electrophysiological demonstration of DA modulation of thalamic neural activity, by characterizing the responsivity of the same nuclei to focal dopaminomimetics. S.A.number 3 examines the state-related firing of midbrain DA neurons identified on the basis of their thalamic targets, and the state-related release of DA from functionally homologous striatal regions. These studies are a prerequisite to advancing our understanding of the pathophysiology and treatment of arousal disorders that accompany an array of neuropsychiatric conditions, particularly those which can be broadly defined as hyper- (e.g., schizophrenia) and hypodopaminergic (e.g., PD and restless legs/periodic leg movements of sleep).