Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Child Youth and Emerging Adult Programme, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Sci Adv. 2023 Oct 6;9(40):eadi8750. doi: 10.1126/sciadv.adi8750. Epub 2023 Oct 4.
Early-life adversities are associated with altered defensive responses. Here, we demonstrate that the repeated cross-fostering (RCF) paradigm of early maternal separation is associated with enhancements of distinct homeostatic reactions: hyperventilation in response to hypercapnia and nociceptive sensitivity, among the first generation of RCF-exposed animals, as well as among two successive generations of their normally reared offspring, through matrilineal transmission. Parallel enhancements of acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 messenger RNA transcripts were detected transgenerationally in central neurons, in the medulla oblongata, and in periaqueductal gray matter of RCF-lineage animals. A single, nebulized dose of the ASIC-antagonist amiloride renormalized respiratory and nociceptive responsiveness across the entire RCF lineage. These findings reveal how, following an early-life adversity, a biological memory reducible to a molecular sensor unfolds, shaping adaptation mechanisms over three generations. Our findings are entwined with multiple correlates of human anxiety and pain conditions and suggest nebulized amiloride as a therapeutic avenue.
早期生活逆境与防御反应的改变有关。在这里，我们证明了早期母婴分离的反复交叉寄养 (RCF) 范式与特定的体内平衡反应增强有关：第一代 RCF 暴露动物以及随后两代正常饲养的后代对高碳酸血症的过度通气和疼痛敏感性增强，通过母系遗传传递。在 RCF 系动物的延髓中央神经元、延髓和导水管周围灰质中，可检测到酸感应离子通道 1 (ASIC1)、ASIC2 和 ASIC3 信使 RNA 转录物的跨代增强。单次雾化给予 ASIC 拮抗剂阿米洛利可使整个 RCF 系动物的呼吸和疼痛反应恢复正常。这些发现揭示了在经历早期生活逆境后，一种可简化为分子传感器的生物记忆是如何展开的，从而在三代动物中形成适应机制。我们的发现与人类焦虑和疼痛状况的多种相关性交织在一起，并表明雾化阿米洛利是一种治疗途径。
