Izquierdo Alicia, Wiedholz Lisa M, Millstein Rachel A, Yang Rebecca J, Bussey Timothy J, Saksida Lisa M, Holmes Andrew
Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute of Alcohol Abuse and Alcoholism, NIH, Rockville, USA.
Behav Brain Res. 2006 Aug 10;171(2):181-8. doi: 10.1016/j.bbr.2006.03.029. Epub 2006 May 19.
Mice are uniquely suited as experimental subjects for various approaches to the study of the molecular and genetic basis of behavior, and there has been a corresponding explosion in the use of mice in behavioral neuroscience. Rats and monkeys, however, remain the preferred species for high-order cognitive models largely due to the unavailability of valid, reliable and translatable endpoint measures of behavior in the mouse. Here we present further development and validation of a touchscreen-based operant method for measuring cognition that is comparable to methods used in other species and human patients. C57BL/6J mice were found to show good performance on visual discrimination and reversal learning using this method. Demonstrating the sensitivity of the paradigm to genetic factors, C57BL/6J and DBA/2J mice exhibited marked differences in discrimination and reversal learning. Systemic treatment with the selective D1-like agonist, SKF81297, produced an impairment in the early phase of reversal learning, but did not alter visual discrimination, in C57BL/6J mice. The same treatment impaired spatial working memory on the T-maze delayed alternation task, but did not alter control measures of behavior including motivation and locomotor activity. These data demonstrate the sensitivity of visual discrimination and reversal learning measured by this method to genetic factors and pharmacological challenge, and thereby provide an extension and further validation of the method for measuring cognition in mice. When combined with emerging molecular techniques uniquely suited to this species such as genetic engineering and RNA modification this paradigm could provide a powerful new tool for behavioral neuroscience.
小鼠非常适合作为实验对象，用于研究行为的分子和遗传基础的各种方法，并且行为神经科学中对小鼠的使用也相应激增。然而，大鼠和猴子仍然是高阶认知模型的首选物种，这主要是因为小鼠缺乏有效、可靠且可转化的行为终点测量方法。在此，我们展示了一种基于触摸屏的用于测量认知的操作性方法的进一步发展和验证，该方法可与用于其他物种和人类患者的方法相媲美。使用这种方法，发现C57BL/6J小鼠在视觉辨别和逆向学习方面表现良好。C57BL/6J和DBA/2J小鼠在辨别和逆向学习方面表现出显著差异，这证明了该范式对遗传因素的敏感性。在C57BL/6J小鼠中，用选择性D1样激动剂SKF81297进行全身治疗会在逆向学习的早期阶段产生损伤，但不会改变视觉辨别能力。相同的治疗会损害T迷宫延迟交替任务中的空间工作记忆，但不会改变包括动机和运动活动在内的行为控制指标。这些数据证明了通过这种方法测量的视觉辨别和逆向学习对遗传因素和药理学挑战的敏感性，从而为测量小鼠认知的方法提供了扩展和进一步验证。当与基因工程和RNA修饰等特别适用于该物种的新兴分子技术相结合时，这种范式可为行为神经科学提供一种强大的新工具。
