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Pathological repetitive behaviours are a common feature of various neuropsychiatric disorders, including compulsions in obsessive–compulsive disorder or tics in Gilles de la Tourette syndrome. Clinical research suggests that compulsive-like symptoms are related to associative cortico-striatal dysfunctions, and tic-like symptoms to sensorimotor cortico-striatal dysfunctions. The Sapap3 knockout mouse (Sapap3-KO), the current reference model to study such repetitive behaviours, presents both associative as well as sensorimotor cortico-striatal dysfunctions. Previous findings point to deficits in both macro-, as well as micro-circuitry, both of which can be affected by neuronal structural changes. However, to date, structural connectivity has not been analysed. Hence, in the present study, we conducted a comprehensive structural characterisation of both associative and sensorimotor striatum as well as major cortical areas connecting onto these regions. Besides a thorough immunofluorescence study on oligodendrocytes, we applied AxonDeepSeg, an open source software, to automatically segment and characterise myelin thickness and axon area. We found that axon calibre, the main contributor to changes in conduction speed, is specifically reduced in the associative striatum of the Sapap3-KO mouse, myelination per se seems unaffected in associative and sensorimotor cortico-striatal circuits.

Lack of behavioral flexibility has been proposed as one underlying cause of compulsions, defined as repetitive behaviors performed through rigid rituals. However, experimental evidence has proven inconsistent across human and animal models of compulsive-like behavior. In the present study, applying a similarly-designed reversal learning task in two different species, which share a common symptom of compulsivity (human OCD patients and Sapap3 KO mice), we found no consistent link between compulsive behaviors and lack of behavioral flexibility. However, we showed that a distinct subgroup of compulsive individuals of both species exhibit a behavioral flexibility deficit in reversal learning. This deficit was not due to perseverative, rigid behaviors as commonly hypothesized, but rather due to an increase in response lability. These cross-species results highlight the necessity to consider the heterogeneity of cognitive deficits in compulsive disorders and call for reconsidering the role of behavioral flexibility in the aetiology of compulsive behaviors., Nabil Benzina et al. use a reversal learning task to examine behavioral flexibility in human and mouse models of obsessive compulsive disorder (OCD). They report that only subsets of human patients or OCD-like mice show deficits in behavioral flexibility, highlighting the diverse presentation of cognitive deficits in compulsive disorders.

Genetic and clinical studies of speech and language disorders are providing starting points to unravel underlying neurobiological mechanisms. The gene encoding the transcription factorFOXP2has been the first example of a gene involved in the development and evolution of this human-specific trait. A number of autosomal-dominantFOXP2mutations are associated with developmental speech and language deficits indicating that gene dosage plays an important role in the disorder. Comparative genomics studies suggest that two human-specific amino acid substitutions in FOXP2 might have been positively selected during human evolution. A knock-in mouse model carrying these two amino acid changes in the endogenous mouseFoxp2gene(Foxp2hum/hum)shows profound changes in striatum-dependent behaviour and neurophysiology, supporting a functional role for these changes. However, how this affects Foxp2 expression patterns in different striatal regions and compartments has not been assessed. Here, we characterized Foxp2 protein expression patterns in adult striatal tissue inFoxp2hum/hummice. Consistent with prior reports in wildtype mice, we find that striatal neurons inFoxp2hum/hummice and wildtype littermates express Foxp2 in a range from low to high levels. However, we observe a shift towards more cells with higher Foxp2 expression levels inFoxp2hum/hummice, significantly depending on the striatal region and the compartment. As potential behavioural readout of these shifts in Foxp2 levels across striatal neurons, we employed a morphine sensitization assay. While we did not detect differences in morphine-induced hyperlocomotion during acute treatment, there was an attenuated hyperlocomotion plateau during sensitization inFoxp2hum/hummice. Taken together, these results suggest that the humanizedFoxp2allele in a mouse background is associated with a shift in striatal Foxp2 protein expression pattern.