Chattree, G. | bioRxiv Science

bioRxiv2025

Striatal neural ensemble codes for voluntary locomotor and involuntary dyskinetic movements

BackgroundIn the classical model of basal ganglia circuitry, striatal spiny projection neurons of the direct and indirect pathways (dSPNs, iSPNs) promote and suppress movement, respectively, and exhibit unbalanced activity levels during hypokinetic or hyperkinetic conditions. Most therapies for these conditions are thought to work by rebalancing the relative activity of dSPNs and iSPNs towards normal levels. However, the mechanism of amantadine, which uniquely improves both hypokinetic and hyperkinetic conditions, is poorly understood. ObjectiveTo determine whether amantadine restores motor function by normalizing the balance of dSPN and iSPN activity or through a distinct mechanism. MethodsWe used dual-color two-photon Ca2+ imaging in the 6-OHDA mouse model of Parkinsons disease to concurrently monitor dSPN and iSPN dynamics across healthy, hypokinetic (parkinsonian), and hyperkinetic (dyskinetic) conditions. ResultsWe evaluated both dSPN/iSPN activity balance and action-specific neural ensemble activity in the dorsolateral striatum. In hypokinetic conditions, L-DOPA rescued the dSPN/iSPN imbalance but failed to restore the disrupted activity of the locomotion-specific ensemble. Conversely, amantadine improved locomotion-specific ensemble activity without normalizing the dSPN/iSPN imbalance. In hyperkinetic conditions, forelimb dyskinesias were characterized by neural activity patterns distinct from those encoding locomotion. Amantadine selectively suppressed the resting activity of forelimb dyskinesia ensembles without affecting locomotion-coding ensembles or restoring pathway balance. ConclusionsL-DOPA and amantadine may act through distinct mechanisms, with L-DOPA normalizing pathway balance and amantadine modulating action-specific neural ensembles. These findings support the importance of action-coding disruptions during hypokinetic and hyperkinetic conditions and suggest that correcting them can restore motor function.

neuroscience↗

bioRxiv2017

A Basal Ganglia Circuit Sufficient to Guide Birdsong Learning

Learning complex vocal behaviors, like speech and birdsong, is thought to rely on continued performance evaluation. Whether candidate performance evaluation circuits in the brain are sufficient to guide vocal learning is not known. Here, we test the sufficiency of VTA projections to the vocal basal ganglia (Area X) in singing zebra finches, a songbird species that learns to produce a complex and stereotyped multi-syllabic courtship song during development. We optogenetically manipulate VTA axon terminals in singing birds contingent on how the pitch of individual song syllables are naturally performed. We find that optical excitation and inhibition of VTA terminals have opponent effects on future performances of targeted song syllables and are each sufficient to reliably guide learned changes in song, consistent with positive and negative reinforcement of performance outcomes. These findings define a central role for reinforcement mechanisms in learning vocalizations and provide the first demonstration of minimal circuit elements for learning vocal behaviors.

neuroscience↗