Project description:A defining feature of our species is the ability to manipulate our environment through the fine control of our hands and to communicate with others through the rapid and complex motor orchestration of human speech. The courtship song of songbirds shares a number of neural and behavioral similarities with human speech and other learned motor skills, providing a powerful model for understanding how enhanced motor skills develop at molecular and cellular levels. Birdsong is controlled by a specialized neural circuit whose properties enable high precision and speed. In particular, glutamatergic neurons in the birdsong motor region RA (Glut-RA) have higher spike rates and narrower action potentials than projection neurons in an adjacent motor region that does not control song, the dorsal intermediate arcopallium (Glut-AId). To identify candidate gene regulatory networks that establish the specialized properties of Glut-RA neurons, we performed single-nucleus profiling of gene expression and chromatin accessibility across song and non-song motor regions. We found that Glut-RA projection neurons and fast spiking interneurons (FSIs), a GABAergic type also characterized by high spike rates and narrow action potentials, share several transcriptional similarities. In particular, the transcription factor MAFB, which is essential for the development and fast-spiking physiology of FSIs in mice, is expressed in Glut-RA but no other projection neuron type. We found that MAFB transcription factor binding sites have enhanced chromatin accessibility specifically in glutamatergic neurons in RA relative to AId. Furthermore, gene regulatory network inference and in silico knockdown of MAFB expression reveal common MAFB targets in Glut-RA neurons and FSIs, and suggest that the transcription factor is necessary to specialize song Glut-RA neurons from non-song Glut-AId neurons. These data support a model in which birdsong projection neurons co-opt an interneuron gene regulatory program to enable the rapid physiological properties required for fast and precise birdsong performance.

Project description:Sensory feedback is required for the stable execution of learned motor skills, and its loss can severely disrupt motor performance. The neural mechanisms that mediate sensorimotor stability have been extensively studied at systems and physiological levels, yet relatively little is known about how disruptions to sensory input alter the molecular properties of associated motor systems. Songbird courtship song, a model for skilled behavior, is a learned and highly structured vocalization that is destabilized following deafening. Here, we sought to determine how the loss of auditory feedback modifies gene expression and its coordination across the birdsong sensorimotor circuit. To facilitate this system-wide analysis of transcriptional responses, we developed a gene expression profiling approach that enables the construction of hundreds of spatially-defined RNA-sequencing libraries. Using this method, we found that deafening preferentially alters gene expression across birdsong neural circuitry relative to surrounding areas, particularly in premotor and striatal regions. Genes with altered expression are associated with synaptic transmission, neuronal spines, and neuromodulation and show a bias toward expression in glutamatergic neurons and Pvalb/Sst-class GABAergic interneurons. We also found that connected song regions exhibit correlations in gene expression that were reduced in deafened birds relative to hearing birds, suggesting that song destabilization alters the inter-region coordination of transcriptional states. Finally, lesioning LMAN, a forebrain afferent of RA required for deafening-induced song plasticity, had the largest effect on groups of genes that were also most affected by deafening. Combined, this integrated transcriptomics analysis demonstrates that the loss of peripheral sensory input drives a distributed gene expression response throughout associated sensorimotor neural circuitry and identifies specific candidate molecular and cellular mechanisms that support the stability and plasticity of learned motor skills.

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Analysis of the effects of deafening on gene expression in birdsong neural circuitry

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