Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Mol Psychiatry. 2022 Sep;27(9):3864-3874. doi: 10.1038/s41380-022-01622-7. Epub 2022 May 20.
Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naive male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring.
尼古丁摄入，无论是通过吸烟还是电子烟，仍然是全球关注的健康问题。新兴的临床前文献表明，父母尼古丁暴露会在后代中产生行为、生理和分子变化。然而，自愿的父母尼古丁摄入的遗传效应尚不清楚。在这里，我们发现，雄性和雌性后代从自行摄入尼古丁的雄性亲鼠中获得尼古丁摄入的能力增强。相比之下，雄性和雌性后代自行摄入蔗糖和可卡因并没有改变，这表明父代尼古丁摄入的代际效应可能是特定于强化物的。进一步的特征分析显示，在没有接触过药物的雄性后代中，而不是在雌性后代中，有尼古丁暴露的亲鼠的雄性后代表现出记忆缺陷和焦虑样行为增加。通过一种无偏见的全基因组方法，我们发现这些表型与 Satb2 表达减少有关，Satb2 是一种已知在突触可塑性和记忆形成中发挥重要作用的转录因子，在尼古丁亲鼠雄性后代的海马体中发现。这种效应是性别特异性的，因为在尼古丁亲鼠的雌性后代中没有发现 Satb2 表达的变化。最后，增加海马体中的 Satb2 水平可以防止尼古丁摄入的增加，并挽救与父代尼古丁摄入相关的雄性后代的记忆缺陷。总的来说，这些发现表明，父代尼古丁摄入会产生可遗传的、性别特异性的分子变化，从而促进雄性后代产生类似成瘾的表型和记忆损伤。
