The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N = 568 and N = 319) and in two samples of traumatized individuals (N = 350 and N = 463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued memory impairment, suggesting a conserved role of NCAM1 for memory. In parallel, DNA methylation of the NCAM1 promoter in two independent healthy Swiss cohorts was associated with memory performance. In two independent Sub-Saharan populations of conflict zone survivors who had faced severe trauma, DNA methylation at an alternative promoter of the NCAM1 gene was associated with traumatic memories. Our results support a role of NCAM1 in associative memory in nematodes and humans, and might, ultimately, be helpful in elucidating diagnostic markers or suggest novel therapy targets for memory-related disorders, like PTSD.

神经细胞粘附分子 1 (NCAM-1) 与几个大脑相关的生物学过程有关，包括神经元迁移、轴突分支、束状和突触发生，在突触可塑性中起关键作用。在这里，我们研究了 NCAM-1 在学习和记忆中的进化保守作用。首先，我们使用分子遗传学方法研究了秀丽隐杆线虫厌恶性嗅觉调节后 ncam-1 表达的持续变化。此外，我们在两个健康个体样本（N  = 568 和N  = 319）和两个受创伤个体样本（N  = 350 和N = 463）。我们发现，秀丽隐杆线虫中的嗅觉调节诱导了 ncam-1 表达，并且 ncam-1 功能的丧失选择性地损害了联想长期记忆，而不会导致采集、感觉或短期记忆缺陷。重新引入秀丽隐杆线虫或人类 NCAM1 完全挽救了记忆障碍，表明 NCAM1 对记忆的保护作用。同时，两个独立的健康瑞士队列中 NCAM1 启动子的 DNA 甲基化与记忆力有关。在面临严重创伤的两个独立的撒哈拉以南冲突地区幸存者群体中，NCAM1 基因替代启动子的 DNA 甲基化与创伤记忆有关。我们的研究结果支持 NCAM1 在线虫和人类联想记忆中的作用，并最终可能有助于阐明诊断标志物或为记忆相关疾病（如 PTSD）提出新的治疗目标。