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<p>Social competition exerts a diverse set of influences on neural development and behavior during adolescence and yet the precise underlying molecular mechanisms remain poorly understood. Here, we demonstrate that individual rodents that rank lower in social hierarchies are more vulnerable to drug abuse. Proteomic analysis revealed a crucial role of the mesocorticolimbic netrin-1/DCC/UNC5 pathway within the nucleus accumbens (NAc) in mediating the impact of social competition. We found that mice with a conditional knockout of the deleted in colorectal cancer (DCC) gene in dopamine neurons were more likely to achieve higher social rank but exhibited increased drug-seeking behaviors. Following dopamine fiber immunostaining, these outcomes were attributed to ectopic mesolimbic dopamine fibers, which enhanced risk-taking behavior in winners that had DCC knockout. Collectively, our work elucidates a molecular mechanism through which social competition influences adolescent brain development and behavior, particularly in relation to drug susceptibility.</p>

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Paradoxical role of the mesocorticolimbic Netrin1-DCC pathway in social competition and vulnerability to methamphetamine abuse during adolescence

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Wei Xu,
  • Jiafeng Zhong,
  • Lijie Ding,
  • Haiyang Jing,
  • Xiaoqing Chen,
  • Ting Pan,
  • Baofang Zhang,
  • Ruiyi Zhou,
  • Liang Xu,
  • Jian He,
  • Hanhe Liu,
  • Taian Liu,
  • Zhonghua Lu,
  • Wen Chen,
  • Yingjie Zhu

摘要

Social competition exerts a diverse set of influences on neural development and behavior during adolescence and yet the precise underlying molecular mechanisms remain poorly understood. Here, we demonstrate that individual rodents that rank lower in social hierarchies are more vulnerable to drug abuse. Proteomic analysis revealed a crucial role of the mesocorticolimbic netrin-1/DCC/UNC5 pathway within the nucleus accumbens (NAc) in mediating the impact of social competition. We found that mice with a conditional knockout of the deleted in colorectal cancer (DCC) gene in dopamine neurons were more likely to achieve higher social rank but exhibited increased drug-seeking behaviors. Following dopamine fiber immunostaining, these outcomes were attributed to ectopic mesolimbic dopamine fibers, which enhanced risk-taking behavior in winners that had DCC knockout. Collectively, our work elucidates a molecular mechanism through which social competition influences adolescent brain development and behavior, particularly in relation to drug susceptibility.