Obsessive-compulsive disorder (OCD) is a leading cause of illness-related disability, but the neural mechanisms underlying OCD symptoms are unclear. One potential mechanism of OCD pathology is monoamine dysregulation. Because of the difficulty of studying monoamine signalling in patients, animal models offer a viable alternative to understanding this aspect of OCD pathophysiology. We used HPLC to characterize post-mortem monoamine levels in lateral orbitofrontal cortex (OFC), medial OFC, medial prefrontal cortex and dorsal and ventral striatum of SAPAP-3 knockout (KO) mice, a well-validated model of compulsive-like behaviours in OCD. As predicted from previous studies, excessive grooming was significantly increased in SAPAP-3 KO mice. Overall levels of the serotonin metabolite 5-hydroxyindoleacetic acid (HIAA) and the ratio of 5HIAA/serotonin (serotonin turnover) were increased in all cortical and striatal regions examined. In addition, dihydroxyphenylacetic acid/dopamine ratio was increased in lateral OFC, and HVA/dopamine ratio was increased in lateral and medial OFC. No baseline differences in serotonin or dopamine tissue content were observed. These data provide evidence of monoaminergic dysregulation in a translational model of OCD symptoms and are consistent with aberrant cortical and striatal serotonin and dopamine release/metabolism in SAPAP-3 KO mice. These results are guiding ongoing experiments using circuit and cell-type specific manipulations of dopamine and serotonin to determine the contributions of these monoaminergic systems to compulsive behaviours, and serve here as a touchstone for an expanded discussion of these techniques for precise circuit dissection.This article is part of the discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

Optogenetics is an extremely powerful tool for selective neuronal activation/inhibition and dissection of neural circuits. However, a limitation of in vivo optogenetics is that an animal must be tethered to an optical fiber for delivery of light. Here, we describe a new method for in vivo, optogenetic inhibition of neural activity using an internal, animal-generated light source based on firefly luciferase. Two adeno-associated viruses encoding luciferase were tested and both produced concentration-dependent light after administration of the substrate, luciferin. Mice were co-infected with halorhodopsin- and luciferase-expressing viruses in the striatum, and luciferin administration significantly reduced Fos activity compared to control animals infected with halorhodopsin only. Recordings of neuronal activity in behaving animals confirmed that firing was greatly reduced after luciferin administration. Finally, amphetamine-induced locomotor activity was reduced in halorhodopsin/luciferase mice pre-injected with luciferin compared to controls. This demonstrates that virally encoded luciferase is able to generate sufficient light to activate halorhodopsin and suppress neural activity and change behavior. This approach could be used to generate inhibition in response to activation of specific molecular pathways.

Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity drives compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced compulsive behavior. Together, these findings highlight the striatal indirect pathway as a potential new treatment target for compulsive behavior.

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