Normative aging results in degradation of gene networks in a zebra finch basal ganglia nucleus dedicated to vocal behavior

Aging increases brain susceptibility to neurodegenerative diseases, but the mechanisms are not clear. Vocal behavior provides an accessible, reliable, and sensitive biomarker to address this because voice changes in middle age can be early indicators of neurodegenerative diseases. The adult male zebra finch is an excellent model organism for these studies due to well-characterized vocal brain circuitry and strong homology to human brain centers. We performed RNA sequencing of song-dedicated basal ganglia nucleus Area X followed by weighted gene co-expression network analyses to examine changes in gene patterns across younger adult, middle, and older ages. Song-correlated gene networks degrade with age, with modules losing their coherence and migrating to different sets of genes, and changes in connection strength particularly for hub genes including those associated with human speech, Parkinson’s, and Alzheimer’s diseases. Gene pathway enrichment analyses reveal a lack of ongoing metabolic and biogenic processes in older finches. Our findings provide a robust platform for targeting network hubs in the treatment of neurologically driven human vocal disorders.