Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner

Matthijs C Dorst,Christian Broberger,Sotiris Masmanidis,Gilad Silberberg,Kwang Lee,Ming Zhou,Anna Tokarska,Stefanos Stagkourakis

doi:10.1038/s41467-020-18882-y

Abstract

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.

Highlights

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function
We show that striatal cholinergic interneurons (ChINs) are interconnected by a strong and prevalent polysynaptic inhibitory pathway that can affect their firing patterns and promote local synchrony within the ChIN population
We show that synchrony between TANs exists in the mouse striatum, as well as rewardrelated pauses, both of which were modulated by inhibition of striatal GABAergic neurons, suggesting a role for polysynaptic inhibition

Summary

Introduction

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Work suggested an antagonistic relationship in which elevated dopamine activity coincides with a decrease in the firing of ChINs3,9–12, yet more recent studies have shown an additional form of interaction, whereby synchronized ChIN activity promotes local dopamine release by acting on nicotine receptors of midbrain dopamine axons[1,13,14] This indicates that dopamine release shapes striatal acetylcholine levels while being reciprocally affected by them, depending on the degree of synchronicity between ChINs. Synchronized ChIN activity can inhibit medium spiny neurons (MSNs) by a feed-forward inhibitory pathway[15], shaping striatal output to downstream basal ganglia nuclei. Our results suggest a novel form of interaction between the dopaminergic and cholinergic systems, in which dopamine release shapes striatal acetylcholine dynamics by acting directly on the recurrent inhibition between ChINs, thereby tuning their level of synchronous activity

Methods

Results

Conclusion