Striosome Microcircuit Critical for Motor Skill Learning

National Institute On Aging

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Abstract

Since ALDH1A1+ SNc DANs play a crucial role in rotarod motor skill learning and striosome dSPNs exert major inhibitory presynaptic inputs while regulating the transition from tonic to burst firing of ALDH1A1+ SNc DANs, we conducted a systematic examination of the involvement of striosome dSPNs in motor skill learning. To elucidate how striosome dSPNs participate in motor skill learning, we performed fiber photometry live recording of striosome neural activity during 10 sequential rotarod training sessions. We employed Cre-dependent GCaMP6-axon and tdTomato viral vectors, selectively expressing a genetically encoded calcium indicator in the axon terminals of striosome neurons in Sepw1-Cre mice (a transgenic mouse model with preferential Cre recombinase expression in striosomes67). This setup allowed us to specifically record calcium transients in the axon terminals of striosome dSPNs during the rotarod tests. Surprisingly, we observed a significant increase in presynaptic calcium transients during the first trial of the first training session, which gradually decreased in the subsequent nine trials. This reverse correlation between rotarod performance and presynaptic calcium transients persisted in the 10 trials of the second training sessions, with the calcium transients diminishing in the following four sessions. These intriguing observations suggest that striosome dSPNs may initiate the motor learning process by promoting a novelty or salience signal. Considering that striosomes comprise both dSPNs and indirect-pathway SPNs (iSPNs) and their axonal targets include SNr, globus pallidus internus (GPi), and globus pallidus externa (GPe), we plan to record presynaptic calcium transients in GPi and GPe regions during rotarod tests to reveal their activity patterns over different trials and sessions. To determine the necessity of striosome SPNs in motor skill learning, we adopted a chemogenetic approach to modulate striosome neuronal activity during rotarod training sessions. By injecting Cre-dependent Gq and Gi chemogenetic modulators (DREADD) along with control mCherry viral vectors into the dorsal striatum of Sepw1-Cre mice, we could either activate (Gq) or inhibit (Gi) striosome neuronal activity during motor skill learning. The results showed that inhibiting striosome neuronal activity completely disrupted motor skill learning, while activating striosome neurons substantially improved learning compared to the mCherry control group. These findings establish that striosome neurons are crucial for rotarod motor skill learning. To further investigate which striosome SPN subtype(s) are involved in motor skill learning, we will employ optogenetics to selectively inhibit transmitter release in the corresponding axon terminals at SNr, GPe, and GPi during rotarod training. This combination of fiber photometry, chemogenetics, and optogenetics will help establish a causal relationship between the activity of striosome SPN subtypes and motor skill learning. Moreover, to determine whether the striosome dSPN-induced rebound and burst firing in ALDH1A1+ SNc DANs is related to motor skill learning, we will conduct simultaneous fiber photometry recording of calcium transients in the axon terminals of striosome dSPNs and single-unit electrophysiology recording of ALDH1A1+ SNc DANs during rotarod training sessions. Additionally, we will investigate whether genetic deletion of GABA-B receptors in ALDH1A1+ SNc DANs disrupts the dSPN-induced rebound and burst firing, consequently impairing motor skill learning. These investigations will provide valuable insights into the critical physiological function of the striosome dSPN and ALDH1A1+ SNc DAN microcircuit in regulating motor learning.