Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics

Abstract

The precise causal factors for obsessive-compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo-cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive-repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive-repetitive behaviors.

Figure 1. Central role of the CSTC circuitry in obsessive-compulsive disorder in humans and compulsive-repetitive behaviors in mice

A. Diagram of a human brain section (coronal) illustrating a simplified CSTC loop. Right panel, zoom view of the CSTC loop illustrating the intermingled but functionally distinct “direct” and “indirect” projection pathways of the basal ganglia that are thought to exert opposing control over selection of motor behaviors. B. Diagram of a mouse brain section (sagittal) illustrating the equivalent CSTC loop in the corresponding rodent brain structures. Abbreviations: CTX, cortex; STR, striatum; CAU, caudate; PUT, putamen; HIP, hippocampus; THAL, thalamus; STN, sub-thalamic nucleus; SNr, substantia nigra pars reticulata; GPe, globus pallidus externa; GPi, globus pallidus interna; SC, superior colliculus; BS, brain stem; CB cerebellum. C. Highly simplified diagram of candidate OCD gene expression patterns throughout the mouse brain demonstrating extensive overlap of expression in brain regions composing the CSTC circuitry. NOTES: The Sapap3 expression pattern is based on in situ data as reported in [17]. The Slitrk5 expression pattern is based on LacZ activity as reported in [25]. The Hoxb8 expression pattern was inferred from [28], and importantly this pattern is intended merely to reflect the regions of highest concentration of Hoxb8-expressing microglia rather than all Hoxb8-expressing microglia in the brain. The EAAC1 expression pattern is based on anti-EAAC1 antibody staining in brain slices as reported in [35].

Figure 2. Compulsive-repetitive behavior is a core feature that is shared between obsessive-compulsive spectrum disorders and autism spectrum disorders

Specific features of obsessive-compulsive spectrum disorders include obsession and excessive anxiety; whereas specific features of autism spectrum disorders include social interaction defects and language deficits.