Striosome Microcircuit Critical for Motor Skill Learning

National Institute On Aging

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Abstract

Since ALDH1A1+ SNc DANs are required for rotarod motor skill learning and striosome dSPNs provide major inhibitory presynaptic inputs and regulate the transition from tonic to burst firing of ALDH1A1+ SNc DANs, we decided to systematically examine the involvement of striosome dSPNs in motor skill leaning. To elucidate how striosome dSPNs participate in motor skill learning, we first performed fiber photometry live recording of striosome neural activity during 10 sequential rotarod training sessions. We injected Cre-dependent GCaMP6-axon and tdTomato viral vectors to the dorsal striatum of Sepw1-Cre mice (a transgenic mouse model with preferential expression of Cre recombinase in striosomes), which allows for selective expression of this genetically encoded calcium indicator in the axon terminals of striosome neurons. Then we implanted an optic fiber in SNr to record calcium transients specifically in the axon terminals of striosome dSPNs during the rotarod tests. In contrast to the fast improvement of rotarod performance, our fiber photometry recording revealed a large increase of presynaptic calcium transients in the first trial of the first training session, with calcium transients gradually decreasing in the subsequent nine trials. The same reverse correlation between rotarod performance and presynaptic calcium transients was also observed in the 10 trials of the second training sessions. The calcium transients diminished in the following four sessions. These observations suggest that the striosome dSPNs may promote a novelty or salience signal to initiate the motor learning process. Since striosomes are comprised with both dSPNs and indirect-pathway SPNs (iSPNs), and their axonal targets include SNr, globus pallidus internus (GPi), and globus pallidus externa (GPe), we will also record the presynaptic calcium transients in GPi and GPe regions during rotarod tests and reveal their activity patterns over different trials and sessions. To determine whether striosome SPNs are required for motor skill learning, we used chemogenetic approach to modulate the striosome neuronal activity during rotarod training sessions. We injected Cre-dependent Gq and Gi chemogenetic modulator DREADD, as well as control mCherry viral vectors to the dorsal striatum of Sepw1-Cre mice, to either activate (Gq) or inhibit (Gi) the striosome neuronal activity during motor skill learning. We found that inhibition of striosome neuronal activity completely disrupted the motor skill learning, whereas activation of striosome neurons substantially improved the learning in Sepw1-Cre mice when compared with the mCherry control group. These findings demonstrated that striosome neurons are required for rotarod motor skill learning. To determine which striosome SPN subtype(s) plays a role in motor skill learning, we will use an optogenetics approach to selectively inhibit the transmitter release in the corresponding axon terminals at SNr, GPe and GPi during rotarod training. Together, this combination of fiber photometry, chemogenetics and opogenetics approaches will help to establish a causal relationship between the activity of striosome SPN subtypes and motor skill learning. To determine whether the strisosome dSPN-induced rebound and burst firing in ALDH1A1+ SNc DANs is related to motor skill learning, we will conduct fiber photometry recording of calcium transients in the axon terminals of strisosome dSPNs and single unit electrophysiology recording of ALDH1A1+ SNc DANs simultaneously during rotarod training sessions. We will investigate whether genetic deletion of GABA-B receptors in ALDH1A1+ SNc DANs disrupts the dSPN-induced rebound and burst firing and impairs motor skill learning. This study will help to define a key physiological function of striosome dSPN and ALDH1A1+ SNc DAN microcircuit in regulating motor learning.