Circuitry of Midbrain Dopamine in Sleep & Wake

多巴胺（DA）是一种神经递质，调节多种清醒行为，包括运动、动机、认知、奖励和进食。多巴胺对正常睡眠和病理性睡眠的影响较少受到重视和理解。多巴胺细胞死亡发生在帕金森病中，与清醒-睡眠状态的深刻改变有关，可大致分为夜间运动障碍和丘脑皮质节律性障碍。前者包括睡眠的周期性腿部运动和快速眼动睡眠（REM-sleep）行为障碍，后者包括睡眠纺锤波和慢波睡眠的缺失，白天嗜睡，白天快速眼动睡眠的侵入，表现为幻觉行为。疾病的启发式模型很大程度上局限于DA对丘脑皮质回路的间接作用，而不是直接作用，也局限于DA对清醒行为的参与，而不是对丘脑皮质觉醒状态的参与（例如，睡眠）。我们最近描述了一种新的中丘脑多巴胺通路，起源于黑质纹状体通路的轴突侧枝，并在PD中退化。因此，中脑多巴胺神经元不仅可以通过传统的黑质纹状体通路，还可以通过丘脑的侧轴突通路，调节包括睡眠在内的正常和病理行为。在这里，我们建议定义这些新的电路在非人类灵长类动物的解剖和生理特征。sa number 1采用显微技术建立了DA神经支配在“运动”、“前额叶”、“边缘”和丘脑网状核（即丘脑起搏器）中的分布、亚细胞靶点、地形和侧支。sa 2将扩展我们的初步电生理论证，通过表征相同核对局灶多巴胺模拟物的反应，DA调节丘脑神经活动。s.a.d 3研究了根据丘脑靶区识别的中脑DA神经元的状态相关放电，以及功能同源纹状体区域DA的状态相关释放。这些研究是推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理解的先决条件，特别是那些可以被广泛定义为亢进（例如，精神分裂症）和低多巴胺能（例如，PD和不宁腿/睡眠的周期性腿部运动）。

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).