Male Sapap3 knockout mice show threat bias under conflict during platform-mediated avoidance task: effects of extinction with response prevention and implications for obsessive compulsive disorder.

Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive thoughts (obsessions) and repetitive rituals aimed at avoiding aversive outcomes (compulsions), which interferes with patients' lives. This relationship between obsessions and compulsions highlights a potential role of impaired threat processing and avoidance in OCD symptoms. Platform mediated avoidance (PMA) has proven to be a useful rodent paradigm to examine avoidance neurobiology and OCD-relevant constructs, such as exposure with response prevention (ERP) and persistent avoidance. However, the ERP protocol has only been used in rats, and studies in OCD-relevant transgenic mouse models may shed further light on neural mechanisms relevant to the disorder. To address this gap, we tested male Sapap3 knockout (KO) mice, a leading preclinical model in OCD research, using PMA with ERP. We examined avoidance acquisition, expression, and extinction, as well as reward-seeking under motivational conflict, in separate cohorts conditioned using high or low intensity shock. Sapap3-KOs exhibited heightened suppression of lever pressing for rewards and elevated freezing during a warning tone signaling impending footshocks, suggesting greater threat sensitivity under motivational conflict. Avoidance responding was acquired more slowly and extinguished more robustly following ERP in Sapap3-KOs trained with lower-intensity shock only. c-Fos expression showed preliminary evidence for decreased activity of medial orbitofrontal cortex (mOFC) in KOs, which may mediate post-ERP reduction of threat responses. Together these findings suggest that mOFC changes may contribute to therapeutic effects in OCD, and that dysfunction in mOFC may contribute to increased influence of threats (vs rewards) over action selection in OCD.