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

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.

What Is the Role of Thalamostriatal Circuits in Learning Vocal Sequences?

“…Either the vector can be used directly, or the choline acetyltransferase (ChAT) promoter can be assembled into an AAV construct to drive the expression of Cre in ChIs in Area X. Similar conditional expression of the transgene has been demonstrated to be efficient in Area X when the Cre-loxP system is delivered by two separate AAV constructs (Xiao et al, 2021 ). Alternatively, anti-ChAT conjugated saporin toxins, which are well established to specifically target and ablate ChIs in rodent striatum (Laplante et al, 2011 ; Aoki et al, 2015 ; Crevier-Sorbo et al, 2020 ), may provide a virus-free tool to eliminate ChIs in Area X.…”

“…As a complementary approach to genetic lesioning experiments, closed-loop optogenetic manipulation in behaving birds can be used to examine the real time contribution of DLM X input in song learning and production with high temporal specificity. Similar approaches have been used to investigate the roles of the dopaminergic pathway in vocal learning and production in birds (Xiao et al, 2018(Xiao et al, , 2021.…”

“…Male zebra finches, for example, produce thousands of highly stereotyped song renditions daily which, when combined with neural recordings and/or circuit manipulations, permit detailed study of how brain circuits control behavioral learning and performance. Lastly, the neural circuits underlying song learning and production are well characterized and cellular homologies between song circuits and mammalian circuits are starting to be revealed (Farries, 2004 ; Pfenning et al, 2014 ; Gadagkar et al, 2016 ; Vallentin et al, 2016 ; Hisey et al, 2018 ; Xiao et al, 2018 ; Colquitt et al, 2021 ; Xiao et al, 2021 ).…”

“…Lesions of Area X in juvenile birds result in birds with variable song syntax as adults (Sohrabji et al, 1990 ; Scharff and Nottebohm, 1991 ; Goldberg and Fee, 2011 ). Knockdown of the speech-linked gene FoxP2, overexpression of the mutant gene fragment that causes Huntington’s disease, and optogenetic excitation of dopaminergic inputs in Area X all cause progressive disruptions in song syllable sequencing, including repetition of song syllables and disruptions in song syntax in adult birds (Tanaka et al, 2016 ; Xiao et al, 2021 ).…”

Molecular networks of the FOXP2 transcription factor in the brain

“…When mouse Foxp2 is constitutively replaced by a partially humanized version, medium spiny neurons in the striatum show increases in dendrite length and synaptic plasticity (Enard et al , 2009 ), consistent with multiple studies implicating the gene in development and function of corticostriatal circuitry (Vernes et al , 2011 ; French et al , 2012 ; Chen et al , 2016 ; Hachigian et al , 2017 ; van Rhijn et al , 2018 ; French et al , 2019 ). Moreover, knockdown and overexpression studies in the brains of zebra finches suggest that avian FoxP2 is important not only in auditory‐guided vocal learning during development, but also for maintenance of vocal behaviors in adulthood (Haesler et al , 2004 ; Heston & White, 2015 ; Day et al , 2019 ; Norton et al , 2019 ; Xiao et al , 2021 ).…”