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<p>Drug 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. Behavioral economics analyses further revealed that E2F3a regulates specific aspects of cocaine reinforcement. 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 coordinated expression of both proven and new molecular drivers.</p>

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E2F3a transcription factor mediates behavioral, cellular, and DNA-protein regulation of cocaine reward in the nucleus accumbens

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Freddyson J. Martínez-Rivera,
  • Yun Young Yim,
  • Leanne M. Holt,
  • Arthur Godino,
  • Angélica Minier-Toribio,
  • Solange Tofani,
  • Angélica Torres-Berrío,
  • Molly S. Estill,
  • Rita Futamura,
  • Caleb J. Browne,
  • Tamara Markovic,
  • Peter J. Hamilton,
  • Rachael L. Neve,
  • Li Shen,
  • Eric J. Nestler

摘要

Drug 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. Behavioral economics analyses further revealed that E2F3a regulates specific aspects of cocaine reinforcement. 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 coordinated expression of both proven and new molecular drivers.