FOCUSED REVIEW Edited by: Gal Richter-Levin, University of Haifa, Israel Reviewed by: Edward S. Brodkin, University of Pennsylvania School of Medicine, USA Jacqueline N. Crawley, National Institute of Mental Health, USA Gal Richter-Levin, University of Haifa, Israel *Correspondence: Jonathan L. Brigman received his Ph.D. in Cognitive Neuroscience from The George Washington University, where he worked with Lawrence Rothblat investigating the functional specialization of the mouse prefrontal cortex. He is currently working with Andrew Holmes in the Section on Behavioral Science and Genetics at the National Institute on Alcohol Abuse and Alcoholism. His current research focuses on the molecular mechanisms and neural circuits underlying well learned action and executive control of behavioral ﬂexibility, and the role of the glutamate system in learning, memory and addiction. brigmanj@mail.nih.gov Frontiers in Neuroscience Predictably irrational: assaying cognitive inﬂexibility in mouse models of schizophrenia Jonathan L. Brigman*, Carolyn Graybeal and Andrew Holmes Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD, USA The development of sophisticated, translatable mouse-based assays modeling the behavioral manifestations of neuropsychiatric diseases, such as schizophrenia, has lagged the advances in molecular and genomic techniques. Our laboratory has made efforts to ﬁll this gap by investing in the development of novel assays, including adapting a touchscreen-based method for measuring cognitive and executive functions for use in mice. As part of these efforts, a recent study by Brigman et al. (2009) investigated the effects of subchronic phencyclidine treatment on mouse touchscreen-based pairwise visual discrimination and reversal learning. Here, we summarize the results of that study, and place them in the larger context of ongoing efforts to develop valid mouse “models” of schizophrenia, with a focus on reversal learning and other measures of cognitive ﬂexibility. Touchscreen-based systems could provide a tractable platform for fully utilizing the mouse to elucidate the pathophysiology of cognitive inﬂexibility in schizophrenia and other neuropsychiatric disorders. Keywords: mouse, schizophrenia, gene, prefrontal cortex, executive function INTRODUCTION The last decade has seen the mouse become one of the model species of choice for researchers studying brain function and neuropsychiatric diseases. This trend has been catalyzed by two key scientific advances during this period: the emergence of techniques for precisely manip- ulating the mouse genome, such as gene-tar- geting (Capecchi, 2005), and the sequencing of the human genome (International Human Genome Sequencing Consortium, 2004). In addition, the mouse lends itself to the appli- cation of other techniques, both traditional (e.g., drug treatments, brain lesions) and cutting-edge (e.g., RNA interference, optico- genetics), for manipulating molecules, neuro- transmitters and circuits in the brain. As such, the mouse-based laboratory is now equipped with a potent armamentarium of techniques to tackle the study of neuropsychiatric disor- ders. By joining forces with increasingly pow- erful techniques for studying human subjects, such as genome-wide association studies and brain imaging (Harrison and Weinberger, 2005; Robbins, 2005; Hariri and Holmes, 2006), the hope is that research using mice can allow us to make some truly novel insights into the patho- physiology and treatment of neuropsychiatric diseases, including schizophrenia. Arguably, the development of sophisti- cated, translatable mouse-based assays for the behavioral manifestations of schizophrenia has lagged the advances in molecular and genomic techniques. Contrary to a commonly voiced opinion, we do not believe that this is because mice are “not smart enough” to perform com- plex behavioral, particularly cognitive, assays, but rather that an adequate investment of time and effort has not been put into adapting and validating procedures for the mouse. May 2010 | Volume 4 | Issue 1 | 19