Opposing thalamic and amygdalar projections to the dorsolateral striatum sculpt the grooming microstructure in stress and autism models

Self-grooming is an evolutionarily conserved behavior characterized by a stereotyped sequence that is often disrupted in neuropsychiatric disease models, such as obsessive‒compulsive disorder (OCD) and autism spectrum disorder (ASD). While the dorsolateral striatum (DLS) has been implicated in modulating the grooming microstructure, the underlying circuit mechanisms remain unclear. By combining automated behavioral analysis, whole-brain activity mapping, and circuit-specific manipulations, we identified two opposing DLS circuits governing this microstructure. The glutamatergic mediodorsal thalamus (MD)→DLS pathway facilitates the core motor program by specifically amplifying mid-sequence grooming phases. Conversely, the GABAergic basolateral amygdala (BLA)→DLS pathway couples grooming with anxiety states by modulating sequence initiation and termination. Relevant disease models show distinct alterations and treatment methods: in stressed mice, fragmented grooming with disrupted termination is rescued by inhibiting the BLA→DLS pathway, whereas in Shank3B knockout (KO) mice, hyperpersistent mid-sequence grooming is normalized by either the alleviation of MD→DLS hyperactivity or the activation of the BLA→DLS pathway. These findings reveal phase-specific circuits that coordinate stereotyped behavior, providing new insights into the pathophysiology of related disorders.