What Causes Obsessive Compulsive Disorder?: Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by Rauch and Carlezon Jr. ). Ahmari et al. (p. 1234 ) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine. Burguière et al. (p. 1243 ) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming.

Increasing evidence implicates abnormalities in corticostriatal circuits in the pathophysiology of obsessive-compulsive disorder (OCD) and OC-spectrum disorders. Parallels between the emergence of repetitive, compulsive behaviors and the acquisition of automated behaviors suggest that the expression of compulsions could in part involve loss of control of such habitual behaviors. The view that striatal circuit dysfunction is involved in OC-spectrum disorders is strengthened by imaging and other evidence in humans, by discovery of genes related to OCD syndromes, and by functional studies in animal models of these disorders. We highlight this growing concordance of work in genetics and neurobiology suggesting that frontostriatal circuits, and their links with basal ganglia, thalamus and brainstem, are promising candidates for therapeutic intervention in OCD.

Significance: The human form of forkhead box P2 ( FOXP2 ) is the leading genetic candidate for human speech and language proficiency. We demonstrate that the introduction of the amino acid changes that occurred during human evolution into murine Foxp2 ( Foxp2 ^hum ) profoundly affects learning and striatal neuroplasticity. Foxp2 ^hum/hum mice learn stimulus–response associations more rapidly than WT mice when declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could interfere with one another. Dopamine levels, gene expression patterns, and synaptic physiology are oppositely affected in the striatal districts underpinning these learning forms, paralleling the behavioral change. We hypothesize that the human FOXP2 evolution led to differential tuning of corticostriatal systems involved in declarative and procedural learning and thus contributed to adapting the human brain for speech and language acquisition.

Symptom comorbidity is present amongst neuropsychiatric disorders with repetitive behaviours, complicating clinical diagnosis and impeding appropriate treatments. This is of particular importance for obsessive-compulsive disorder (OCD) and Tourette syndrome. Here, we meticulously analysed the behaviour of Sapap3 knockout mice, the recent rodent model predominantly used to study compulsive-like behaviours, and found that its behaviour is more complex than originally and persistently described. Indeed, we detected previously unreported elements of distinct pathologically repetitive behaviours, which do not form part of rodent syntactic cephalo-caudal self-grooming. These repetitive behaviours include sudden, rapid body and head/body twitches, resembling tic-like movements. We also observed that another type of repetitive behaviour, aberrant hindpaw scratching, might be responsible for the flagship-like skin lesions of this mouse model. In order to characterise the symptomatological nature of observed repetitive behaviours, we pharmacologically challenged these phenotypes by systemic aripiprazole administration, a first-line treatment for tic-like symptoms in Tourette syndrome and trichotillomania. A single treatment of aripiprazole significantly reduced the number of head/body twitches, scratching, and single-phase grooming, but not syntactic grooming events. These observations are in line with the high comorbidity of tic- and compulsive-like symptoms in Tourette, OCD and trichotillomania patients.