Behavior-Linked FoxP2 Regulation Enables Zebra Finch Vocal Learning

Abstract

Mutations in the FOXP2 transcription factor cause an inherited speech and language disorder, but how FoxP2 contributes to learning of these vocal communication signals remains unclear. FoxP2 is enriched in corticostriatal circuits of both human and songbird brains. Experimental knockdown of this enrichment in song control neurons of the zebra finch basal ganglia impairs tutor song imitation, indicating that adequate FoxP2 levels are necessary for normal vocal learning. In unmanipulated birds, vocal practice acutely downregulates FoxP2, leading to increased vocal variability and dynamic regulation of FoxP2 target genes. To determine whether this behavioral regulation is important for song learning, here, we used viral-driven overexpression of FoxP2 to counteract its downregulation. This manipulation disrupted the acute effects of song practice on vocal variability and caused inaccurate song imitation. Together, these findings indicate that dynamic behavior-linked regulation of FoxP2, rather than absolute levels, is critical for vocal learning.

Bidirectional scaling of vocal variability by an avian cortico-basal ganglia circuit

“…Area X: Miller et al. – 7–10 birds; Heston and White – 7–10 birds; Goldberg and Fee – 7–12 birds; Burkett et al., – 7 birds). We thus used 7–9 birds per DREADDs construct (inclusive of HSV and AAV) for Area X experiments.…”

“…Custom designed AAVs (serotype 1) were produced by Virovek (Hayward, CA; Heston and White ) containing either iDREADDs4 or eDREADDs3 driven off of the α‐CaMKII promoter (AddGene). Both viruses had a titer of 1 × 10 13 vg/mL and were injected at a volume of 500 nL.…”

“…Moreover, manipulations of the language‐related gene FoxP2 within Area X interfere with rapid social context‐dependent (Murugan et al. ) and slower practice‐dependent (Heston and White ) changes in variability.…”

Understanding Language from a Genomic Perspective

“…Gene knockdown in adult birds coupled with electrophysiological recordings suggests that FoxP2 is important for switching between practice and performance modes because of a function in dopaminergic modulation of cortico-striatal signaling (100). FoxP2 overexpression during the critical period for song learning results in inaccurate imitation, similarly to gene knockdown, so it seems that the capacity to dynamically regulate FoxP2 levels is critical (64). Although zebra finch vocal learning is restricted to juveniles, species like the budgerigar exhibit vocal plasticity in adulthood.…”

Genoarchitecture of the extended amygdala in zebra finch, and expression of FoxP2 in cell corridors of different genetic profile

“…In addition, we investigated the expression of FoxP2 in the different components of the extended amygdala, since alterations in the gene encoding this transcription factor have been associated with language learning deficits in humans (Lai et al 2001; Haesler et al 2007; reviewed by Fisher and Scharff 2009, Fischer and Hammerschmidt 2011, and French and Fisher 2014), and may contribute (not alone, but combination with other genes) to the development of autism (Park et al 2014), which implies not only deficits in communication but also in social skills (Bacon and Rappold 2012). Songbirds like the zebra finch are excellent models for studying the role of FoxP2 in the brain, since learned songs are used for social communication, and this transcription factor is regulated by singing and in fact required for proper song learning and song maintenance (Scharff and Haesler 2005; Wohlgemuth et al 2014; Murugan et al 2013; Condro and White 2014; Heston and White 2015). In mice, FoxP2 is expressed in the extended amygdala, including the intercalated amygdalar cells and the medial amygdala (Campbell et al 2009; Kaoru et al 2010), but, other than that, the exact location of the expression within this mosaic-like complex structure is unknown.…”