Early-life stress(ES)leads to cognitive dysfunction in female adolescents,but the underlying neural mechanisms remain elusive.Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role i...Early-life stress(ES)leads to cognitive dysfunction in female adolescents,but the underlying neural mechanisms remain elusive.Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents.In this study,we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents.Applying the well-established limited bedding and nesting material paradigm,we found that ES impairs recognition memory,suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression,and upregulates corticotropin-releasing hormone(Crh)and its receptor 1(Crhr1)mRNA levels in the hippocampus of adolescent female mice.Genetic experiments revealed that the reduction of dorsal CA1(dCA1)NECTIN3 mediates ES-induced object recognition memory deficits,as knocking down dCA1 NECTIN3 impaired animals’performance in the novel object recognition task,while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits.Notably,prefrontal NECTIN1 knockdown did not result in significant cognitive impairments.Furthermore,acute systemic administration of antalarmin,a CRHR1 antagonist,upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice.Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice,highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.展开更多
基金supported by the National Natural Science Foundation of China(82271569,82001418,82371530,82171529,and 82071528)the Beijing Natural Science Foundation(7222236)the Capital Medical Development Research Fund(2022-1-4111)。
文摘Early-life stress(ES)leads to cognitive dysfunction in female adolescents,but the underlying neural mechanisms remain elusive.Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents.In this study,we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents.Applying the well-established limited bedding and nesting material paradigm,we found that ES impairs recognition memory,suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression,and upregulates corticotropin-releasing hormone(Crh)and its receptor 1(Crhr1)mRNA levels in the hippocampus of adolescent female mice.Genetic experiments revealed that the reduction of dorsal CA1(dCA1)NECTIN3 mediates ES-induced object recognition memory deficits,as knocking down dCA1 NECTIN3 impaired animals’performance in the novel object recognition task,while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits.Notably,prefrontal NECTIN1 knockdown did not result in significant cognitive impairments.Furthermore,acute systemic administration of antalarmin,a CRHR1 antagonist,upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice.Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice,highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
