Isles Anthony R, Humby Trevor, Wilkinson Lawrence S
Laboratory of Cognitive and Behavioural Neuroscience, Neurobiology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Psychopharmacology (Berl). 2003 Dec;170(4):376-82. doi: 10.1007/s00213-003-1551-6. Epub 2003 Aug 30.
The increasing use of genetically modified mice to probe genetic contributions to normal and abnormal behaviours requires the development of sensitive and selective behavioural tasks.
To develop a discrete trial assay of impulsivity (delayed reinforcement) that is tractable in mice utilising a mouse operant nine-hole box apparatus and to specify the task with respect to behavioural and pharmacological manipulations.
Mice were trained to respond with a nose-poke to one of two visual stimuli; one response resulted in a small quantity of reinforcer, the other in a larger quantity of reinforcer. As the session proceeded increasing delay was introduced onto the response leading to the large reward. Hence, the nature of the choice was a small quantity of reinforcer immediately versus a larger but progressively delayed amount of reinforcer. At stable baseline performance the mice were challenged with a variety of task manipulations and systemic d-amphetamine in order to discern aspects of the underlying psychological and neurochemical substrates of the choice behaviour.
The mice showed a systematic shift in responding away from the large reinforcer with increasing delay (0, 2, 4, 8, 12 s), such that at the longest delay >80% of nose-pokes were for the smaller, immediate reinforcer. Task manipulations indicated that behaviour was controlled in a trial discrete manner by the contingency between delay and reward and was not due to non-specific factors such as satiation. d-Amphetamine had complex, dose dependent effects on choice behaviour which revealed dissociations between impulsive choice and hyperactivity.
We have successfully developed an assay of impulsivity in mice that will be of utility to examine impulsive behaviours and their genetic substrates. In addition, our data provided evidence of distinct dopaminergic mechanisms mediating aspects of impulsivity and hyperactivity.
为探究基因对正常和异常行为的影响，转基因小鼠的使用日益增多，这就需要开发灵敏且具选择性的行为任务。
利用小鼠操作性九孔箱装置，开发一种适用于小鼠的冲动性（延迟强化）离散试验测定法，并从行为和药理学操作方面明确该任务。
训练小鼠对两种视觉刺激之一进行鼻触反应；一种反应会得到少量强化物，另一种会得到大量强化物。随着实验进程推进，对导致获得大量奖励的反应引入越来越长的延迟。因此，选择的本质是立即获得少量强化物与延迟获得大量但逐渐增加的强化物之间的权衡。在稳定的基线表现时，用各种任务操作和系统性右旋苯丙胺对小鼠进行挑战，以辨别选择行为潜在心理和神经化学基础的各个方面。
随着延迟增加（0、2、4、8、12秒），小鼠的反应出现系统性转变，远离大量强化物，以至于在最长延迟时，超过80%的鼻触是为了获得较小的即时强化物。任务操作表明，行为以离散试验的方式由延迟与奖励之间的偶然性控制，而非诸如饱足等非特异性因素所致。右旋苯丙胺对选择行为有复杂的剂量依赖性影响，揭示了冲动性选择与多动之间的分离。
我们成功开发了一种小鼠冲动性测定法，这将有助于研究冲动行为及其基因基础。此外，我们的数据提供了证据，表明存在不同的多巴胺能机制介导冲动性和多动的各个方面。
