Autism spectrum disorders (ASDs) are characterized by impaired learning of social skills and language. Memories of how parents and other social models behave are used to guide behavioral learning. How ASD-linked genes affect the intertwined aspects of observational learning and behavioral imitation is not known. Here, we examine how disrupted expression of the ASD gene FOXP1, which causes severe impairments in speech and language learning, affects the cultural transmission of birdsong between adult and juvenile zebra finches. FoxP1 is widely expressed in striatal-projecting forebrain mirror neurons. Knockdown of FoxP1 in this circuit prevents juvenile birds from forming memories of an adult song model but does not interrupt learning how to vocally imitate a previously memorized song. This selective learning deficit is associated with potent disruptions to experience-dependent structural and synaptic plasticity in mirror neurons. Thus, FoxP1 regulates the ability to form memories essential to the cultural transmission of behavior.
Disruption of the transcription factor FoxP2, which is enriched in the basal ganglia, impairs vocal development in humans and songbirds. The basal ganglia are important for the selection and sequencing of motor actions, but the circuit mechanisms governing accurate sequencing of learned vocalizations are unknown. Here, we show that expression of FoxP2 in the basal ganglia is vital for the fluent initiation and termination of birdsong, as well as the maintenance of song syllable sequencing in adulthood. Knockdown of FoxP2 imbalances dopamine receptor expression across striatal direct-like and indirect-like pathways, suggesting a role of dopaminergic signaling in regulating vocal motor sequencing. Confirming this prediction, we show that phasic dopamine activation, and not inhibition, during singing drives repetition of song syllables, thus also impairing fluent initiation and termination of birdsong. These findings demonstrate discrete circuit origins for the dysfluent repetition of vocal elements in songbirds, with implications for speech disorders.
Autism spectrum disorders (ASD) are characterized by impaired learning of culturally transmitted behaviors like 10 social skills, speech, and language 1-3 . These behaviors are learned by copying parents and other social models during 11 development, a two-stage process that involves forming memories of appropriate behaviors during social 12 experiences and then using those memories to guide imitation. How ASD-linked genes impair these often-13 intertwined aspects of learning is not known, thereby limiting our understanding of the developmental progression 14 of ASD and the targeting of therapeutic interventions. Here we show that these aspects of learning are dissociable 15 and that the ASD-linked gene FoxP1 selectively impairs learning from social experience, but not behavioral imitation. 16 Haploinsufficiency of FOXP1 in humans causes FOXP1 syndrome, a neurodevelopmental disorder typified by severe 17 disruptions in speech and language development, and other ASD-associated symptoms 4,5 . We tested how 18 knockdown of FoxP1 (FP1-KD) affects the cultural transmission of vocal behaviors in zebra finches, a songbird that 19 learns by memorizing and vocally copying the song of an adult 'song-tutor'. We find that FP1-KD blocks song learning20 in juvenile birds by selectively impairing their ability to encode a memory during social experiences with a song-21 tutor. These learning deficits are linked to disruptions in experience-driven structural and functional plasticity. 22However, if birds are exposed to tutor-song prior to FP1-KD, their ability to imitate that song during development is 23 unaffected. Thus, FP1-KD impairs cultural transmission of vocalizations by disrupting the ability to form appropriate 24 vocal memories, yet spares the ability to use previously acquired memories to guide vocal learning. This indicates 25 that learning from social experience may be particularly vulnerable in FOXP1 syndrome. 26 27 28Humans and other animals learn many of their complex and socially oriented behaviors by imitating more experienced 29 individuals in their environment. For example, development of spoken language is rooted in a child's ability to imitate 30 the speech patterns of their parent(s) and other adults 6-8 . This cultural transmission of behavior is impaired in many 31 neurodevelopmental disorders, most notably ASD 1-3 . However, how ASD risk genes impact behavioral imitation is still 32 not known. We sought to examine this issue by testing the role of FoxP1 in the cultural transmission of song between 33 adult and juvenile zebra finches ( Fig. 1a-d, Extended Data Fig. 1). 34 35 2 FOXP1 (forkhead-box protein 1) is one of the top ASD-associated genes, and its haploinsufficiency causes specific 36 language impairment and intellectual disability in children 5 . FoxP1 is expressed in many of the same areas of the pallium 37 and basal ganglia in mammals and songbirds 9-11 . In zebra finches, FoxP1 expression is enriched in many brain regions 38 that are known to be important for song learning [10][11][12] (Fig. ...
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