THE NEURAL BASIS OF HYPERACTIVE WHEEL RUNNING IN MICE

该项目的主要目标是在一种新的小鼠模型中研究多动的神经基础。通过人工选择，我们培育出了内部激励的小鼠品系，它们在车轮上跑得比随机饲养的对照组更快，导致在24小时内车轮转数增加了26倍。在过度活跃的动物中，轮子跑是由短时间的活动爆发和频繁的短休息组成的。轮子跑得高的老鼠在没有轮子的情况下，在家中的笼子里也更活跃。因此，高强度跑步的小鼠可能是注意力缺陷多动障碍(ADHD)的良好动物模型。多巴胺传递缺陷与ADHD之间有关联，初步的神经药理学结果与多巴胺能功能减退导致车轮过度活动的假说一致。为了进一步探索遗传性多动的神经基础，我提议检查：1)阿朴吗啡和利他林(TM)是否可以减弱高跑小鼠的滚轮行为，2)在给定速度跑步时，高跑小鼠的多巴胺代谢比对照小鼠慢，3)高跑小鼠腹侧被盖区域的多巴胺神经元较少或较小。总之，拟议的研究将有助于阐明遗传多动的神经化学和神经解剖学基础。

The major goal of the proposed project is to investigate the neural basis of hyperactivity in a novel mouse model. Through artificial selection we have produced lines of mice that are internally motivated to run faster on running wheels than randombred controls, resulting in a 26-fold increase in wheel revolutions in a 24 hour period. Wheel-running in the hyperactive animals is composed of short bursts of activity separated by frequent short rests. High wheel-running mice are also more active in their home cages when deprived of wheels. The high-running mice may, therefore, be a good animal model for attention deficit hyperactivity disorder (ADHD). An association between deficiencies in dopamine transmission and ADHD has been suggested, and preliminary neuropharmacological results are consistent with the hypothesis that the hyperactive wheel running is caused by diminished dopaminergic function. To further explore the neural basis of genetic hyperactivity, I propose to examine whether: 1) apomorphine, and Ritalin(TM) attenuate wheel-running behavior in the high-running mice, 2) dopamine metabolism is slower in the high-running mice compared to controls at a given speed of running, and 3) the high-running mice contain fewer or smaller dopamine neurons in the ventral tegmental area. Together the proposed studies will help clarify the underlying neurochemistry and neuroanatomy of genetic hyperactivity.