Data from: Monoamine abnormalities in the SAPAP3 knockout model of obsessive-compulsive disorder-related behaviour

Obsessive-compulsive disorder (OCD) is a leading cause of illness-related disability, but the neuralmechanisms underlying OCDsymptoms 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 celltype 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

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Obsessive-compulsive disorder: insights from animal models

Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic test

Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)-ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology

Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior

Abstract 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 is associated with 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 grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior

Differential Control of Learning and Anxiety along the Dorsoventral Axis of the Dentate Gyrus

The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorsoventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders