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The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.

Original publication

DOI

10.1073/pnas.1414542111

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

30/09/2014

Volume

111

Pages

14253 - 14258

Keywords

T-maze, cross maze, dorsolateral striatum, dorsomedial striatum, learning strategy, Amino Acid Substitution, Animals, Corpus Striatum, Dopamine, Female, Forkhead Transcription Factors, Humans, Learning, Long-Term Synaptic Depression, Male, Maze Learning, Mice, Mice, Transgenic, Motor Skills, RNA, Messenger, Recombinant Proteins, Repressor Proteins, Species Specificity, Transcriptome