UC San Diego

Organizing actions into sequences, formally defined as action sequencing, is fundamental to complex behaviors that humans engage in daily, such as typing on a keyboard, singing a song, or playing sports. Many pieces of evidence suggest that the striatum is critical for initiation, termination and switching of action sequences. Striatal dysfunction has been linked to several neurological disorders, including Parkinson's disease and Tourette syndrome, which are characterized by impairments in motor control and the ability to execute complex action sequences. Among numerous synaptic inputs to the striatum from cerebral cortex and thalamus, the parafascicular (PF) nucleus of thalamus provides the strongest input to the striatum. However, how thalamostriatal synapses operate in vivo is understudied and the precise role for the PF nucleus in executing learned action sequences remains unidentified. In this dissertation, I begin by reviewing the literature on action sequencing and the neural circuits supporting sequence execution. Utilizing molecular genetics, in vivo and in vitro electrophysiology, pharmacology, and optogenetics in the “left-left-right-right” (LLRR) sequential lever-pressing task, I elucidate the pivotal role of PF neurons in transmitting sequence-related information. These neurons exhibit sustained activities during lever pressing, crucial for the proper execution of learned action sequences. Activation of striatum-projecting PF neurons promotes action repetition and increases action speed or ‘vigor’, via the dorsomedial striatum, influenced by a more pronounced synaptic input from the PF to D1 neurons compared to D2 neurons. I further reveal that PF extends its regulatory influence on action sequences through a non-canonical disynaptic pathway to the dorsolateral striatum through the thalamic reticular nucleus. These two complementary circuits cooperate in controlling action sequences, specifically modulating action speed and repetition. Collectively, this work provides a comprehensive evaluation of how PF-striatum circuits contribute to execution of complex action sequences and new insight into the circuit mechanisms underlying action sequence control.