title: Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.
abstract: 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.
authors.affiliation: McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Christiane
authors.initials: C
authors.lastname: Schreiweis
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bornschein
authors.affiliation: McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de Recherche Scientifique Unité Mixte de Recherche 7225, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06 Unité Mixte de Recherche S 1127, Institut du Cerveau et de la Moelle épinière, F-75013 Paris, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Burguière
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; Laboratory of Anthropology and Human Genetics, Department of Biology II, Ludwig-Maximilians University Munich, 82152 Martinsried, Germany;
authors.forename: Cemil
authors.initials: C
authors.lastname: Kerimoglu
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; DFG Research Center for Regenerative Therapies, Technical University Dresden, 01307 Dresden, Germany;
authors.forename: Sven
authors.initials: S
authors.lastname: Schreiter
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Dannemann
authors.affiliation: McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Shubhi
authors.initials: S
authors.lastname: Goyal
authors.affiliation: Department of Psychiatry and Psychotherapy, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01187 Dresden, Germany;
authors.forename: Ellis
authors.initials: E
authors.lastname: Rea
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: French
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Rathi
authors.initials: R
authors.lastname: Puliyadi
authors.affiliation: Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S839, Université Pierre et Marie Curie, 75005 Paris, France;
authors.forename: Matthias
authors.initials: M
authors.lastname: Groszer
authors.affiliation: Department of Language and Genetics, Max Planck Institute for Psycholinguistics, 6525 XD, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands; and.
authors.forename: Simon E
authors.identifier: http://orcid.org/0000-0002-3132-1996
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Departments of Developmental and Comparative Psychology and Primatology, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany.
authors.forename: Roger
authors.initials: R
authors.lastname: Mundry
authors.affiliation: Department of Psychiatry and Psychotherapy, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01187 Dresden, Germany;
authors.forename: Christine
authors.initials: C
authors.lastname: Winter
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;
authors.forename: Wulf
authors.initials: W
authors.lastname: Hevers
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; paabo@eva.mpg.de enard@bio.lmu.de graybiel@mit.edu.
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; Laboratory of Anthropology and Human Genetics, Department of Biology II, Ludwig-Maximilians University Munich, 82152 Martinsried, Germany; paabo@eva.mpg.de enard@bio.lmu.de graybiel@mit.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Enard
authors.affiliation: McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; paabo@eva.mpg.de enard@bio.lmu.de graybiel@mit.edu.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D003342:Corpus Striatum / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007858:Learning / Q000502:physiology*; D036881:Long-Term Synaptic Depression; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D013045:Species Specificity; D059467:Transcriptome
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D004298:Dopamine
keywords: T-maze; cross maze; dorsolateral striatum; dorsomedial striatum; learning strategy