Aomine Yoshiatsu, Shimo Yuto, Sakurai Koki, Abe Mayuka, Macpherson Tom, Ozawa Takaaki, Hikida Takatoshi
Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
Research Fellow of Japan Society for the Promotion of Science, Suita, Japan.
J Neurochem. 2025 Jan;169(1):e16227. doi: 10.1111/jnc.16227. Epub 2024 Sep 17.
Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein-protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex-dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.
尼古丁是烟草中发现的一种成瘾性化合物，在大脑中作为烟碱型乙酰胆碱受体（nAChRs）的激动剂发挥作用。有趣的是，据报道尼古丁在人类受试者和实验动物中均作为一种认知增强剂。然而，其在动物研究中的效果并不总是一致的，并且已发现尼古丁对多种行为的影响存在性别差异。具体而言，性别在调节尼古丁对啮齿动物辨别学习和认知灵活性的影响中所起的作用仍不清楚。在此，我们评估了不同剂量（0.125、0.25和0.5 mg/kg）的尼古丁每日腹腔注射（i.p.）对小鼠视觉辨别（VD）学习和反转（VDR）学习影响的性别依赖性差异。在雄性小鼠中，0.5 mg/kg尼古丁显著改善了VDR任务的表现，但未改善VD任务的表现，而0.5 mg/kg尼古丁显著恶化了雌性小鼠VD任务的表现，但未恶化VDR任务的表现。此外，仅在雌性小鼠中，0.25 mg/kg尼古丁显著恶化了VD和VDR任务的表现。接下来，为了研究尼古丁对认知影响的性别差异背后的细胞机制，我们对连续3天或18天接受尼古丁给药的雄性和雌性小鼠的内侧前额叶皮质组织样本进行了转录组分析。通过使用差异表达基因的基因集进行通路富集分析和蛋白质-蛋白质相互作用分析，发现雄性中突触后相关基因的表达降低以及雌性中先天免疫相关基因的表达增加是与尼古丁对辨别学习和认知灵活性的认知影响的性别差异相关的可能分子机制。我们的结果表明，尼古丁通过改变内侧前额叶皮质中特定基因集的表达以性别依赖的方式调节认知功能。
