Obsessive-compulsive disorder (OCD), a disabling and notoriously treatment-resistant neuropsychiatric disorder that affects 2-3% of the general population, is characterized by reoccurring, intrusive thoughts (obsessions) and repetitive, ritualistic behaviors (compulsions). Although OCD has long been associated with dysfunction within the cortico-striato-thalamic-cortical circuits, the thalamic role in OCD pathogenesis is highly understudied in the current literature. Here we identified a rat thalamic nucleus – the reuniens (NRe) – that mediates persistent, compulsive self-grooming behaviors. Optogenetic activation of this nucleus triggers immediate excessive grooming with a strong irresistibility and negative affective valence. A thalamo-hypothalamic pathway linking NRe to the dorsal premammillary nucleus was found to mediate excessive self-grooming behavior, which renders such grooming behavior as a defensive coping response to stress, reminiscent of obsessions faced by OCD patients. Given the close resemblance of this self-grooming behavior to clinical manifestations of OCD, the results gathered from this study highlighted the role of NRe in mediating OCD-like behaviors. This could be attributable to the fact that NRe is sitting at the nexus of an extensive frontal-striato-thalamic network regulating stress, emotion, and motor execution, and therefore putting forth NRe as a potential novel target for intervention. (This work is supported by an HMRF grant 09203236)