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

Abstract

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.

Disruption of prepulse inhibition is associated with compulsive behavior severity and nucleus accumbens dopamine receptor changes in Sapap3 knockout mice

“…The Sapap3-KO model therefore serves as a useful system for further dissection of the contributions of overlapping versus distinct circuits associated with different OCD-relevant behavioral domains. This is an important question given that distinct patterns of activity in striatum and prefrontal cortex are associated with symptoms vs cognitive deficits 44 . Better understanding of these behavior-specific neural changes may thus be valuable for guiding the development of more effective treatments.…”

The prefrontal cortex and OCD

“…With these caveats in mind, efforts have more recently been made to dissect contributions of PFC-homologous regions to OCD-relevant behaviors in rodents. Because we have recently performed comprehensive reviews of the OCD animal literature [169,170], here we will focus on studies that may yield mechanistic insights into the proposed alternative theories described above.…”

Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior

“…Obsessive compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that affects 1-3% of the population, and is characterized by persistent intrusive thoughts (obsessions) and uncontrollable repetitive rituals (compulsions) [1,2]. There is a remarkable convergence of abnormal functional neuroimaging findings in prefrontal cortex (PFC)-striatal circuits in OCD patients [3]; however, there are discrepancies in the directionality of these results [4]. Typically, hyperactivity has been reported at baseline and during symptom provocation in OCD patients in areas including orbitofrontal cortex (OFC) [5][6][7], anterior-cingulate cortex (ACC) [6,7], ventromedial PFC (vmPFC) [8], and caudate [5,7]; this activity is normalized following successful treatment [9,10].…”