Expression of FoxP2 in the basal ganglia regulates vocal motor sequences in the adult songbird

Lei Xiao,Ashwinikumar Kulkarni,Mou Cao,Devin P Merullo,Genevieve Konopka,Todd F Roberts,Therese M I Koch,Marissa Co

doi:10.1038/s41467-021-22918-2

Lei Xiao, Ashwinikumar Kulkarni + Show 6 more

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https://doi.org/10.1038/s41467-021-22918-2

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Abstract

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. The basal ganglia are important for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements in songbirds, with implications for speech disorders.

Highlights

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds
We find that optogenetic excitation, but not inhibition, of ventral tegmental area (VTA) axon terminals in Area X during song production disrupts the fluent initiation and termination of adult song and that these changes in song are dissociable from reinforcement-based changes in song syllable acoustic structure[38]
These findings indicate that FoxP2 regulated expression of dopamine receptors and changes in dopaminergic signaling in the striatum work in concert to control the fluent production of learned vocalizations

Summary

Introduction

Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. We show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, impairing fluent initiation and termination of birdsong. Knockdown of FoxP2 in Area X of juvenile zebra finches causes a variety of vocal learning deficits, including inaccurate syllable imitation, reduced stereotypy of song syntax, and anomalous repetition of song syllables[10,11,20].

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