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Humanized Foxp2 Accelerates Learning by Enhancing Transitions from Declarative to Procedural Performance

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Humanized Foxp2 Accelerates Learning by Enhancing Transitions from Declarative to Procedural Performance Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance Christiane Schreiweisa,b,1, Ulrich Bornscheinb,1, Eric Burguièrea,c, Cemil Kerimoglub,d, Sven Schreiterb,e, Michael Dannemannb, Shubhi Goyala, Ellis Reaf, Catherine A. Frenchg,h, Rathi Puliyadih, Matthias Groszeri, Simon E. Fisherj,k, Roger Mundryl, Christine Winterf, Wulf Heversb, Svante Pääbob,2, Wolfgang Enardb,d,2,3, and Ann M. Graybiela,2,3 aMcGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; bDepartment of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany; cInstitut 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; dLaboratory of Anthropology and Human Genetics, Department of Biology II, Ludwig-Maximilians University Munich, 82152 Martinsried, Germany; eDFG Research Center for Regenerative Therapies, Technical University Dresden, 01307 Dresden, Germany; fDepartment of Psychiatry and Psychotherapy, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01187 Dresden, Germany; gChampalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal; hWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; iInstitut 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; jDepartment of Language and Genetics, Max Planck Institute for Psycholinguistics, 6525 XD, Nijmegen, The Netherlands; kDonders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 EN, Nijmegen, The Netherlands; and lDepartments of Developmental and Comparative Psychology and Primatology, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany Contributed by Svante Pääbo, August 6, 2014 (sent for review April 29, 2014) The acquisition of language and speech is uniquely human, but circuits (4, 5). These circuits are known to be essential for ac- how genetic changes might have adapted the nervous system to quiring habits and other motor and cognitive behaviors (6), in- this capacity is not well understood. Two human-specific amino cluding vocal learning in songbirds (7) and speech and language acid substitutions in the transcription factor forkhead box P2 capabilities in humans (8). However, whether learning behavior (FOXP2) are outstanding mechanistic candidates, as they could depending on these circuits is affected in Foxp2hum/hum mice has so have been positively selected during human evolution and as far not been investigated. NEUROSCIENCE FOXP2 is the sole gene to date firmly linked to speech and lan- A key functional distinction has been made between sub- guage development. When these two substitutions are introduced regions of the striatum that underlie modes of learning also hum into the endogenous Foxp2 gene of mice (Foxp2 ), cortico-basal considered to be crucial for speech and language development ganglia circuits are specifically affected. Here we demonstrate marked and performance: declarative learning and procedural learning effects of this humanization of Foxp2 on learning and striatal neuro- (9–12). These learning modes were first distinguished in human hum/hum plasticity. Foxp2 mice learn stimulus–response associations cognitive studies to differentiate between a conscious form of faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learn- Significance ing could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related The human form of forkhead box P2 (FOXP2) is the leading to these two modes of learning are affected differently in the genetic candidate for human speech and language proficiency. Foxp2hum/hum mice, as judged by measures of dopamine levels, gene We demonstrate that the introduction of the amino acid expression patterns, and synaptic plasticity, including an NMDA changes that occurred during human evolution into murine receptor-dependent form of long-term depression. These findings hum Foxp2 (Foxp2 ) profoundly affects learning and striatal raise the possibility that the humanized Foxp2 phenotype reflects hum/hum neuroplasticity. Foxp2 mice learn stimulus–response a different tuning of corticostriatal systems involved in declarative associations more rapidly than WT mice when declarative (i.e., and procedural learning, a capacity potentially contributing to place-based) and procedural (i.e., response-based) forms of adapting the human brain for speech and language acquisition. learning could interfere with one another. Dopamine levels, gene expression patterns, and synaptic physiology are oppo- dorsomedial striatum | dorsolateral striatum | T-maze | cross maze | sitely affected in the striatal districts underpinning these learning strategy learning forms, paralleling the behavioral change. We hy- pothesize that the human FOXP2 evolution led to differential he gene encoding the transcription factor forkhead box P2 tuning of corticostriatal systems involved in declarative and T(FOXP2) is a promising candidate for investigating the procedural learning and thus contributed to adapting the hu- evolutionary basis of human speech and language capabilities. man brain for speech and language acquisition. Humans carrying only one functional copy of this transcription factor experience difficulties in learning and performing complex Author contributions: C.S., E.B., M.G., C.W., W.H., W.E., and A.M.G. designed research; orofacial movements and have receptive and expressive deficits C.S., U.B., S.S., S.G., E.R., C.A.F., R.P., and W.H. performed research; C.S., U.B., E.B., C.K., M.D., R.M., C.W., W.H., W.E., and A.M.G. analyzed data; C.S., U.B., E.B., S.E.F., R.M., W.H., S.P., W.E., in oral and written language, whereas other cognitive skills are and A.M.G. wrote the paper; and E.B., M.G., S.E.F., R.M., W.H., S.P., and A.M.G. supervised less affected. These speech and language deficits are associated research. with functional impairments in cortico-basal ganglia and cortico- The authors declare no conflict of interest. cerebellar circuits (1). Since the time that the human and chim- Database deposition: Sequences have been deposited in the Gene Expression Omnibus panzee lineages separated, approximately 6 Mya, two amino acid (GEO), (accession no. GSE60659). substitutions have occurred in FOXP2, a higher rate of change 1C.S. and U.B. contributed equally to this work. than expected given its conservation in mammals (2, 3). Mice 2To whom correspondence may be addressed. Email: [email protected], enard@ in which the endogenous Foxp2 gene has been “humanized” bio.lmu.de, or [email protected]. hum/hum for these two amino acid changes (Foxp2 mice) exhibit 3W.E. and A.M.G. contributed equally to this work. prominent neurochemical, neurophysiological, and neuroanat- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. omical alterations in the striatum and related cortico-basal ganglia 1073/pnas.1414542111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1414542111 PNAS | September 30, 2014 | vol. 111 | no. 39 | 14253–14258 Downloaded by guest on September 26, 2021 learning that can be “declared” and nonconscious forms of AB learning that require repetitive exposure (13). Equivalents for these two forms of learning have been suggested for animals in many pioneering studies, and terminology has been adapted Start Start – depending on whether the motivational drive (action outcome Reward Reward vs. stimulus–response; goal-directed vs. habit) or the task objective Smooth Rough Smooth Rough (place-based vs. response-based) is more central to the learning. In rodents, the two learning systems are often probed by tasks requiring 90 *** 90 motor learning, a type of learning thought to be mainly procedural, 80 80 or by navigational maze tasks in which place-based learning is sug- gested to correspond to declarative learning and response-based 70 70 – learning is representative of procedural learning (13 17). 60 60 These systems are thought to interact dynamically to optimize Foxp2hum/hum 50 50 behavior (17–22). Evidence suggests that these interacting systems Foxp2wt/wt % correct response 0 % correct response 0 have the capacity to compensate for each other if key components 1 2 3 4 5 6 7 8 9 101112 123456789101112 are pathologically affected (23, 24), but can also compete with Days of training Days of training each other under normal circumstances (14, 15, 17, 19, 25). In Fig. 1. Foxp2hum/hum mice learn more rapidly than WT littermates in a con- situations in which such competition occurs, learning is lessened ditional T-maze paradigm when spatial cues are present. (Upper) T-maze but can be facilitated by attenuating one of the two competing task with spatial cues (A), promoting place-based/declarative learning; or learning strategies (19, 25). In a novel context, a fact-oriented, without spatial cues (B), promoting response-based/procedural learning. declarative type of learning predominates as the new environment (Lower) Average percent correct responses
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