GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335426/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335426GEOGSEfalseE2F3a transcription factor mediates behavioral, cellular, and DNA-protein regulation of cocaine reward in the nucleus accumbensDrug addiction is characterized by orchestrated transcriptional changes in brain reward regions, including the nucleus accumbens (NAc). The transcription factor E2F3a has emerged as a novel regulator of cocaine’s rewarding effects, yet its sex- and cell-specific mechanisms, as well as its genome-wide targets, remain undetermined. Here, we investigated the motivational and reinforcing roles of E2F3a in cocaine reward using conditioned place preference (CPP) and self-administration, combined with behavioral economics and viral-mediated gene manipulation. Selective overexpression of E2F3a in D1-type medium spiny neurons (MSNs), but not D2-MSNs, increased cocaine CPP in both male and female mice, whereas knockdown produced the opposite effects. Genome-wide mapping revealed increased E2F3a binding to DNA at genes associated with cocaine exposure. Together, these results establish E2F3a as a central substrate of cocaine reward via the recruitment of D1-MSNs and proven molecular drivers2026/08/10GSE335426GSM9813513GSM9813502GSM9813512GSM9813501GSM9813515GSM9813504GSM9813514GSM9813503GSM9813498GSM9813497GSM9813511GSM9813500GSM9813510GSM9813499GSM9813509GSM9813506GSM9813517GSM9813505GSM9813516GSM9813508GSM9813518GSM981350721103335426Mus musculus[42552420]