Zanni Giulia, van Dijk Milenna T, Cagliostro Martha Caffrey, Sepulveda Pradyumna, Pini Nicolò, Rose Ariel L, Kesin Alexander L, Lugo-Candelas Claudia, Goncalves Priscila Dib, MacKay Alexandra S, Iigaya Kiyohito, Kulkarni Praveen, Ferris Craig F, Weissman Myrna M, Talati Ardesheer, Ansorge Mark S, Gingrich Jay A
Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
Nat Commun. 2025 May 6;16(1):4002. doi: 10.1038/s41467-025-58785-4.
Before assuming its role in the mature brain, serotonin modulates early brain development across phylogenetically diverse species. In mice and humans, early-life SSRI exposure alters the offspring's brain structure and is associated with anxiety and depression-related behaviors beginning in puberty. However, the impact of early-life SSRI exposure on brain circuit function is unknown. To address this question, we examined how developmental SSRI exposure changes fear-related brain activation and behavior in mice and humans. SSRI-exposed mice showed increased defense responses to a predator odor, and stronger fMRI amygdala and extended fear-circuit activation. Likewise, adolescents exposed to SSRIs in utero exhibited higher anxiety and depression symptoms than unexposed adolescents and also had greater activation of the amygdala and other limbic structures when processing fearful faces. These findings demonstrate that increases in anxiety and fear-related behaviors as well as brain circuit activation following developmental SSRI exposure are conserved between mice and humans. These findings have potential implications for the clinical use of SSRIs during human pregnancy and for designing interventions that protect fetal brain development.
在血清素在成熟大脑中发挥作用之前，它会调节系统发育上不同物种的早期大脑发育。在小鼠和人类中，生命早期接触选择性5-羟色胺再摄取抑制剂（SSRI）会改变后代的大脑结构，并与青春期开始出现的焦虑和抑郁相关行为有关。然而，生命早期接触SSRI对脑回路功能的影响尚不清楚。为了解决这个问题，我们研究了发育过程中接触SSRI如何改变小鼠和人类与恐惧相关的大脑激活和行为。接触SSRI的小鼠对捕食者气味的防御反应增强，功能磁共振成像（fMRI）显示杏仁核和扩展恐惧回路的激活更强。同样，子宫内接触SSRI的青少年比未接触的青少年表现出更高的焦虑和抑郁症状，并且在处理恐惧面孔时杏仁核和其他边缘结构的激活也更强。这些发现表明，发育过程中接触SSRI后焦虑和恐惧相关行为以及脑回路激活的增加在小鼠和人类之间是保守的。这些发现对人类孕期SSRI的临床使用以及设计保护胎儿大脑发育的干预措施具有潜在意义。
