早年社会不稳定应激会导致持久的认知能力下降以及海马体中与应激相关的基因表达升高。
Early life social instability stress causes lasting cognitive decrement and elevated hippocampal stress-related gene expression.
作者信息
Featherstone Robert E, Gifford Raymond L, Crown Lindsey M, Amirfathi Felix, Alaniz Jon P, Yi Janice, Tran AiVi, Adomian Derrick, Schwenk Andrew, Melnychenko Olya, Duval Christina, Parekh Krishna, Lee Darrin J, Siegel Steven J
机构信息
Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, United States of America.
Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, United States of America; Department of Neurosurgery, Keck School of Medicine, University of Southern California, 1200 North State St., Suite 3300, Los Angeles, CA 90033, United States of America.
出版信息
Exp Neurol. 2022 Aug;354:114099. doi: 10.1016/j.expneurol.2022.114099. Epub 2022 Apr 29.
BACKGROUND
Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents.
METHODS
The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4).
RESULTS
Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort.
CONCLUSIONS
Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.
背景
早年生活压力可能对大脑健康产生深远影响，导致短期和长期的认知或精神障碍。啮齿动物的早年社会不稳定应激（SIS）已被用于模拟早期慢性人类应激的影响。虽然许多研究评估了对这种应激源的急性和短期反应，但对啮齿动物早年生活压力的持久影响关注较少。
方法
本研究利用幼鼠的SIS来评估早年逆境对整个生命周期的影响。在成年期（18至66周龄）评估小鼠与焦虑、情感、社交性、攻击性、动机和识别记忆相关的行为变化。此外，在一部分暴露于应激后在人类中显示出改变的基因（CRHR1、CRHR2、FKBP5、SLC6A4）中评估小鼠的糖皮质激素水平和海马mRNA表达的变化。
结果
与未应激的小鼠相比，暴露于早期SIS的小鼠表现出记忆障碍，海马中FKBP5、CRHR2和SLC6A4 mRNA的表达增加。重要的是，FKBP5和CRHR2的增加与识别记忆的降低之间存在显著关联。此外，暴露于SIS的小鼠在渐进性强化比率时间表上的反应增加，表明记忆表现的降低不是由努力减少介导的。
结论
小鼠中与生态相关的社会应激会导致识别记忆的长期下降，可能由应激级联调节因子的持续变化介导。此外，暴露于早年生活压力的动物对奖励的动机增加，这可能导致一生中一系列享乐性寻求行为。这些数据表明，SIS可用于评估治疗干预措施，以减轻或逆转早年逆境的持久影响。
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