Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance
Open accessAbstract
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.
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The cortico-striatal circuitry mediates speech and language in humans.
“These findings suggest that the cortico-striatal circuitry mediates speech and language in humans (Enard et al., 2009; Fujita et al., 2008; Schreiweis et al., 2014; Shu et al., 2005).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Schreiweis et al., 2014
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- Authors
- Schreiweis, C., Bornschein, U., Burguière, E., Kerimoglu, C., Schreiter, S., Dannemann, M., Goyal, S., Rea, E., French, C. A., Puliyadi, R., Groszer, M., Fisher, S. E., Mundry, R., Winter, C., Hevers, W., Pääbo, S., Enard, W., & Graybiel, A. M.
- Affiliations
- McGovern Institute for Brain Research (US)
- Max Planck Institute for Evolutionary Anthropology (DE)
- Technische Universität Dresden (DE)
- Centre for Human Genetics (GB)
- Inserm (FR)
- Radboud University Nijmegen (NL)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-09-15
- Volume
- 111
- Issue
- 39
- Pages
- 14253-14258
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4191787
- OpenAlex
- W2016974947
- Cited by
- 190
- References
- 54
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 26 · 2023: 6 · 2022: 10 · 2021: 28 · 2020: 8 · 2019: 10 · 2018: 25 · 2017: 21 · 2016: 19 · 2015: 18 · 2014: 5 · 2013: 1
- FWCI
- 13.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Wellcome Trust (075491, 080971, 075491/Z/04,)
- National Institute of Mental Health (R01MH060379)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- FOXP2, declarative learning, procedural learning, cortico-basal ganglia circuits, dopamine, synaptic plasticity
- MeSH terms
- Animals, Corpus Striatum, Dopamine, Female, Humans, Learning, Male, Mice, Transgenic, Motor Skills, Recombinant Proteins, Repressor Proteins, RNA, Messenger, Species Specificity, Maze Learning, Amino Acid Substitution, Long-Term Synaptic Depression, Mice, Forkhead Transcription Factors, Transcriptome
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