Slitrk5 deficiency preserves reversal learning but alters orbitofrontal-striatal signaling and task-related responding in mice.

Abstract

Obsessive-compulsive disorder (OCD) is a debilitating condition associated with repetitive behaviors and cognitive inflexibility, often linked to abnormalities in cortico-striato-thalamo cortical (CSTC) circuitry. Although the Slitrk5 knockout (Slitrk5-/-, KO) mouse has been proposed as an OCD-related model, it remains unclear how Slitrk5 deficiency influences adaptive decision making, task-related behavioral organization, and orbitofrontal-dorsomedial striatum (OFC-DMS) signaling during reversal learning. To address this, Slitrk5-/- and wild-type (WT) mice were examined using probabilistic reversal-learning paradigms combined with licking-behavior analyses, fiber photometry recordings optogenetic inhibition of OFC-DMS projections, and open-field assessment. Across paradigms, Slitrk5-/- mice displayed largely preserved reversal-learning performance and adapted to changing reward contingencies similarly to WT mice. However, genotype-dependent differences emerged in how licking behavior was organized across behavioral epochs and reward contingencies, indicating altered anticipatory, choice-related, and reward-associated responding during task performance. Fiber photometry recordings further identified altered OFC-striatal signaling in Slitrk5-/- mice across anticipatory and reward-associated behavioral periods. In contrast, optogenetic inhibition of OFC-DMS projections produced no detectable effects on reversal-learning performance or licking behavior. Open-field assessment revealed age-dependent alterations in locomotor and exploratory behavior together with progressive grooming-related lesion development. Together, these findings demonstrate selective alterations in task-related behavioral organization and OFC-striatal signaling despite preserved reversal-learning performance in Slitrk5-/- mice, highlighting the heterogeneous behavioral and neural expression associated with corticostriatal dysfunction across OCD-related phenotypes.