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

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.