Lost in translation: No effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

BACKGROUND The orbitofrontal cortex-ventromedial striatum (OFC-VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. METHODS 27 male Long-Evans rats implanted with optical-fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC-VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after and one hour after each stimulation, one and two weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC-VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional setshifting. RESULTS OFC-VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the mouse protocol did alter OFC-VMS synaptic weighting. CONCLUSIONS In sum, although physiological changes were observed in the OFC-VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. If optogenetic effects on behavior do not reliably transfer between rodent species, this may have important implications for designing rodent-to-human translational pipelines.