Thalamo-insular pathway regulates tic generation via motor-limbic crosstalk

SUMMARY Tic disorders accompanied by premonitory urges are hallmark symptoms of Tourette syndrome (TS), yet the underlying neuronal mechanisms remain elusive. Here, we establish a mouse model of motor tics by unilateral striatal injection of a GABA A receptor antagonist. This model induces c-Fos activation in both motor and limbic structures, including the insular cortex (IC). Fiber photometry reveals tic-associated activity in IC as well as the primary motor cortex (M1). Viral tracing demonstrates that basal ganglia outputs from the substantia nigra pars reticulata are transmitted to IC via the intralaminar thalamic nuclei (ITN). Chemogenetic inhibition of IC or the thalamo-insular pathway suppresses tic-related cortical activity and alleviates tic-like behaviors. These findings identify IC as a key node in tic generation and highlight ITN as critical relay stations linking motor and limbic circuits. Aberrant thalamo-insular signaling thus contributes to the pathophysiology of tic disorders and represents a potential therapeutic target in TS. Highlights c-Fos activation occurs in both motor and limbic structures in a mouse tic model Basal ganglia outputs are transmitted to insula via intralaminar thalamic nuclei Chemogenetic inhibition of thalamo-insular pathway suppresses motor tics Thalamo-insular inhibition diminishes tic-associated activity in primary motor cortex In brief Abnormal basal ganglia activity originating from the striatum drives dysfunction of the insular cortex via the intralaminar thalamic nuclei, leading to motor tics. Chemogenetic inhibition of this pathway suppresses tic-like behaviors, highlighting motor-limbic circuit pathology in tic disorders.