Thalamus orchestrates local acetylcholine-dependent dopamine release in the learning striatum

Dopamine is essential for basal ganglia function, and the loss of dopamine function during Parkinson’s disease (PD) is fundamental to the motor symptoms of the disease. We studied how dopamine release is regulated in the striatum during motor learning. While dopamine release is usually thought to arise following dopamine neuron firing, we found that thalamic input can also trigger dopamine release at axon terminals in the striatum by activating acetylcholine signaling. Using simultaneous recordings of thalamic activity and dopamine signals in mice learning a demanding motor task, we found that thalamic-evoked dopamine transients occurred specifically in the dorsomedial striatum and depended on learning, task engagement, and recent dopamine history. These signals did not simply reflect motor errors. Our findings identify thalamic input as a natural driver of acetylcholine-dependent dopamine release and suggest that local dopamine signaling is dynamically regulated during learning. Our findings help resolve debates about how local mechanisms contribute to dopamine release during behavior. This work may have relevance for PD, where disruptions to dopamine release (e.g. as seen in our alpha-synuclein overexpression models) may incur compensation within striatal circuitry. Non-motor symptoms of PD, such as cognitive impairment, may result partially from compensation in dopamine-acetylcholine interactions occurring in response to neurodegenerative processes.