Tic disorders: Disruption of neuronal processing in the cortico-basal ganglia-thalamocortical motor and limbic circuits

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which are sudden, rapid, recurrent, non-rhythmic movements. The TS is also accompanied by cognitive and emotional dysfunctions such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). Dysfunction of the cortico-basal ganglia-thalamocortical circuits has been suggested to induce these symptoms in TS patients, but the details of neuronal mechanisms underlying tic disorders remain unknown. In this study, we generated drug-induced tic model mice by unilateral local injection of GABA antagonist, bicuculline, into the striatal motor region. In this tic mouse model, we detected c-Fos labeled cells not only in motor structures but also in limbic structures such as insular and cingulate cortices. We then investigated the anatomical route from the basal ganglia output structures to the limbic structures using anterograde and retrograde viral tracers. We found that the intralaminar thalamic nuclei are hub structures, which connect the basal ganglia with the limbic cortex. We also revealed that chemogenetic inhibition of the insular cortex or the thalamocortical (insular) pathway ameliorated the drug-induced tic symptoms. These data suggest that abnormal neuronal processing in motor and limbic domains of the cortico-basal ganglia-thalamocortical circuits might be responsible for the generation of tic symptoms.