SLEEP/DOPAMINE PHENOTYPES IN GENETICALLY DISTINCT MICE

一种知之甚少的状态神经调节剂是中纹状体多巴胺（DA）系统，其不仅促进动机/奖励和运动，而且促进唤醒（即，wakefulness）。 相反，DA阻断和中纹状体通路的中断减慢运动并促进嗜睡。 中纹状体DA对觉醒/睡眠节律和睡眠结构的影响的细节，以及涉及的细胞和亚细胞底物仍然定义不清。 昼夜节律和稳态觉醒/睡眠因素影响中纹状体回路的可塑性，但其功能的进口也是不确定的。 多巴胺转运蛋白（DAT-/-）基因缺失的小鼠，它们的杂合子（DAT+/-），野生型同窝仔，纯C57 BL/6和S129/sv株的转基因衍生，和DBA/2近交系与已知的下表达的中纹状体D2受体提供了一种手段，以探测DA的作用，在状态控制，并占觉醒/睡眠表型的遗传变异。 目的#1提出表征这些小鼠中与睡眠/觉醒结构相关的24小时运动活动模式。 主观夜间DAT -/-和DAT +/-的运动过度活跃导致主观白天的活动减退，表明在长期升高的突触DA面前睡眠/觉醒逆转（初步数据）。 体内平衡睡眠驱动的机制足以克服慢性DA升高-如果睡眠确实伴随着观察到的活动减退-可能存在于参与中纹状体DA传递的其他蛋白质中。 因此，目标#2提出在边缘系统和运动纹状体回路中测量24小时内的传统DA标志物、分子定义的D1受体、DAT和囊泡单胺转运蛋白（vMAT 2）表达，以增强对目标#1结果的解释。 目的#3研究通过物理手段、安非他酮（一种DAT阻断剂）和咖啡因（一种腺苷受体阻断剂）诱导的长时间觉醒对这些小鼠中纹状体DA系统的影响。 研究人员假设，这些转基因和近交系小鼠将表现出独特的昼夜节律的蛋白质介导DA神经传递和独特的反应，这些蛋白质的长期觉醒，可能是治疗方式的具体，很大程度上相同的方式，抑郁症不同，他们的反应REM睡眠剥夺，发作性睡病不同于抑郁症在他们的REM睡眠反应DAT封锁。 总之，这些发现将促进对状态如何调节失眠、抑郁和神经精神疾病的病程和治疗的理解，这些疾病的病理生理学根源于DA敏感的基底神经节回路。

DESCRIPTION (adapted from the applicants' absract) One poorly understood neuromodulator of state is the mesostriatal dopamine (DA) system, which not only promotes motivation/reward and movement, but also arousal (viz., wakefulness). Conversely, DA blockade and interruption of mesostriatal pathways slows movement and promotes sleepiness. The details of mesostriatal DA's effects upon wake/sleep rhythms, and sleep architecture, and the cellular and subcellular substrates involved remain poorly defined. Circadian and homeostatic wake/sleep factors affect mesostriatal circuit plasticity, but their functional import is also undefined. Mice with genetic deletions of the dopamine transporter (DAT-/-), their heterozygotes (DAT+/-), wild type littermates, the pure C57BL/6 and S129/sv strains from which the transgenics derive, and the DBA/2 inbred strain with known under expression of mesostriatal D2 receptors afford a means to probe DA's role in state control, and to account for genetic variation in wake/sleep phenotypes. Aim #1 proposes to characterize 24-hour motor activity patterns in relation to sleep/wake architecture in these mice. Motor hyperactivity in DAT -/- and DAT +/- during the subjective night yields to hypoactivity during subjective day suggesting a sleep/wake reversal in the face of chronically elevated synaptic DA (preliminary data). The mechanisms underlying a homeostatic sleep drive powerful enough to overcome chronic DA elevations - if indeed sleep attends the observed hypoactivity - may reside in other proteins involved in mesostriatal DA transmission. Aim #2 therefore proposes to measure traditional DA markers, and molecularly defined D1 receptor, DAT and vesicular monoamine transporter (vMAT2) expression across 24-hours in limbic and motor striatal circuits to enhance interpretation of Aim #1 findings. Aim #3 investigates the effects of prolonged wakefulness induced by physical means, bupropion (a DAT blocker), and caffeine (an adenosine receptor blocker), on the mesostriatal DA system in these same mice. The investigators postulate that these transgenic and inbred mice will exhibit unique circadian rhythms of proteins mediating DA neurotransmission and unique responses of these proteins to prolonged wakefulness that may be treatment modality specific, much the same way that depressives differ in their response to REM-sleep deprivation, and narcoleptics differ from depressives in their REM-sleep responses to DAT blockade. Taken together, the findings will advance an understanding of how state might modulate the course and treatment of insomnia, depression, and neuropsychiatric diseases whose pathophysiologies are rooted in DA sensitive basal ganglia circuits.