How can preclinical mouse models be used to gain insight into prefrontal cortex dysfunction in obsessive-compulsive disorder?

Obsessive-compulsive disorder is a debilitating psychiatric disorder that is characterised by perseverative thoughts and behaviours. Cognitive and affective disturbances play a central role in this illness, and it is therefore not surprising that clinical neuroimaging studies have demonstrated widespread alterations in prefrontal cortex functioning in patients. Preclinical mouse experimental systems provide the opportunity to gain mechanistic insight into the neurobiological changes underlying prefrontal cortex dysfunction through new technologies that allow measurement and manipulation of activity in discrete neural populations in awake, behaving mice. However, recent preclinical research has focused on striatal dysfunction, and has therefore provided relatively little insight regarding the role of the prefrontal cortex in obsessive-compulsive disorder–relevant behaviours. Here, we will discuss a number of translational prefrontal cortex–dependent paradigms, including obsessive-compulsive disorder–relevant tasks that produce compulsive responding, and how they can be leveraged in this context. Drawing on recent examples that have led to mechanistic insight about specific genes, cell types and circuits that mediate prefrontal cortex contributions to distinct aspects of cognition, we will provide a framework for applying similar strategies to identify neural mechanisms underlying obsessive-compulsive disorder–relevant behavioural domains. We propose that research using clinically relevant paradigms will accelerate translation of findings from preclinical mouse models, thus supporting the development of novel therapeutics targeted to specific pathophysiological mechanisms.