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.T he gene encoding the transcription factor forkhead box P2 (FOXP2) is a promising candidate for investigating the evolutionary basis of human speech and language capabilities. Humans carrying only one functional copy of this transcription factor experience difficulties in learning and performing complex orofacial movements and have receptive and expressive deficits in oral and written language, whereas other cognitive skills are less affected. These speech and language deficits are associated with functional impairments in cortico-basal ganglia and corticocerebellar circuits (1). Since the time that the human and chimpanzee lineages separated, approximately 6 Mya, two amino acid substitutions have occurred in FOXP2, a higher rate of change than expected given its conservation in mammals (2, 3). Mice in which the endogenous Foxp2 gene has been "humanized" for these two amino acid changes (Foxp2 hum/hum mice) exhibit prominent neurochemical, neurophysiological, and neuroanatomical alterations in the striatum and related cortico-basal ganglia circuits (4, 5). These circuits are known to be essential for acquiring habits and other motor and cognitive behaviors (6), including vocal learning in songbirds (7) and speech and language capabilities in humans (8). However, whether learning behavior depending on these circuits is affected in Foxp2 hum/hum mice has so far not been investigated.A key functional distinction has been made between subregions of the striatum that underlie modes o...

Enhanced Procedural Learning of Speech Sound Categories in a Genetic Variant ofFOXP2

“…In the rodent model, FoxP2 mutations impair auditory-motor learning (Kurt et al, 2012). A humanlike FoxP2 gene induced in mice models altered plasticity in the medium-spiny neurons within the striatum and induced faster switching from declarative to procedural learning strategies (Enard, 2011;Schreiweis et al, 2014).…”

“…Behaviorally, these mice show an advantage in learning stimulus-response associations relative to controls when place-based (comparable to a declarative strategy in humans) and response-based (comparable to a procedural strategy in humans) strategies compete for control . Given that human language learning is also hypothesized to be mediated by declarative and procedural systems, Schreiweis et al (2014) posit that FOXP2 may have affected language evolution by tuning corticostriatal systems differentially, leading to faster proceduralization of complex learned sequences.…”

Components of the Language-Ready Brain

“…Knockdown (in finches) or haploinsufficiency (in mice) of Foxp2 leads to altered or inaccurate vocalizations (Shu et al, 2005;, and in the finch this is associated with the altered density of spiny neurons in Area X (Schulz et al, 2010). Interestingly, the human version of Foxp2 has strong effects on the plasticity of the striaum and accelerates learning when introduced into mice (Schreiweis et al, 2014). Mice with certain point mutations in one copy of Foxp2, including those that cause developmental verbal dyspraxia in humans, are developmentally delayed, somatically weak, and have impaired auditory-motor association learning owing to strongly altered activity in the striatal circuits, but they make the expected range of acoustically normal vocalizations (Gaub et al, 2010;Kurt et al, 2012).…”

The Biology and Evolution of Speech: A Comparative Analysis

“…Comparisons of humanized and wild-type mice allow a precise dissection of these effects: The human FOXP2 allele leads to increased complexity in the dendritic arbors of medium spiny neurons in the striatum in the basal ganglia (Enard et al 2009). These changes appear to affect the balance between hippocampal-and striatal-based motor learning, leading to earlier "proceduralization" of motor knowledge in humanized mice (Schreiweis et al 2014). Ideally, similar genetic experiments will be carried out in mammalian vocal learners (e.g., bats or seals) to investigate what this might mean for vocal learning in particular.…”