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，奖励和喂养。 多巴胺对正常睡眠和病理性睡眠的影响还不太被认识和理解。帕金森氏病中发生的多巴胺细胞死亡与清醒-睡眠状态的深刻改变有关，这种改变可以广泛地分类为脑运动和丘脑皮质节律性的障碍。 前者包括睡眠周期性腿部运动和快速眼动睡眠（REM睡眠）行为障碍，而后者包括睡眠纺锤波和慢波睡眠的丧失、白天嗜睡和白天侵入REM睡眠，表现为幻觉行为。疾病的启发式模型在很大程度上限制了DA对丘脑皮层回路的间接作用，而不是直接作用，并且还限制了DA参与清醒行为，而不是丘脑皮层唤醒状态（例如，睡眠）。 我们最近描述了一种新的起源于黑质纹状体通路的轴突侧支的中脑丘脑多巴胺通路，并在PD中退化。 因此，中脑多巴胺神经元具有调节正常和病理行为（包括睡眠）的潜力，不仅通过传统的黑质纹状体通路，而且还通过丘脑的轴突侧支。 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。 S.A.数字1采用显微技术来建立DA神经支配在“运动”、“前额”、“边缘”和网状（即，丘脑起搏器）丘脑核。S.A.第2号将通过表征相同核团对局灶性拟多巴胺药物的反应性，扩展我们对丘脑神经活动的DA调制的初步电生理学证明。S.A.编号3检查了基于其丘脑靶点识别的中脑DA神经元的状态相关放电，以及DA从功能同源纹状体区域的状态相关释放。这些研究是促进我们对伴随一系列神经精神疾病的唤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高（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).