Abstract
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. 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 1 h after each stimulation, 1 and 2 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 set-shifting. 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 stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes 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. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.
Highlights
Compulsions—maladaptive patterns of repetitive, inflexible cognition, and behavior—are a key feature of numerous mental health conditions, including obsessivecompulsive disorder (OCD), trichotillomania, skin picking disorder, eating disorders, addiction, anxiety, and depression[1,2,3,4]
Measuring orbitofrontal cortex–ventromedial striatum (OFC–VMS) connectivity via evoked potentials Repeated optogenetic stimulation of OFC terminals in VMS is believed to induce synaptic plasticity in mice. To determine whether this effect holds in rats, we evaluated the bidirectional OFC–VMS evoked response potential (ERP) before and after the 6day opto-stimulation protocol (Fig. 1B)
Discussion we carefully mimicked the technical details of the original study[20], and verified change in the targeted circuit, we could not reproduce in rats a model of compulsive behavior that has been previously reported in mice
Summary
Compulsions—maladaptive patterns of repetitive, inflexible cognition, and behavior—are a key feature of numerous mental health conditions, including obsessivecompulsive disorder (OCD), trichotillomania, skin picking disorder, eating disorders, addiction, anxiety, and depression[1,2,3,4]. Mental disorders associated with compulsive behaviors cause significant distress and, because they include various forms and degrees of manifestation, they still are difficult to diagnose and treat[3,5,6,7]. Clinical and preclinical studies suggest that compulsivity is governed by the frontal cortex in a complex interaction with subcortical systems that include midline thalamic nuclei, striatal regions, and the mesocorticolimbic dopamine system[11,12,13,14]. Abnormalities in the function of this cortico-striatal circuitry can contribute to compulsive/inflexible behavior, especially in complex and changing environments. Accumulating evidence points to dysregulation of the cortico-striatothalamo-cortical (CTSC) circuitry as a cause of OCD, one of the most common diseases of compulsive behavior[10,15,16,17]. Orbitofrontal cortex–ventromedial striatum de Oliveira et al Translational Psychiatry (2021)11:315
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