Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, N.Y., USA.
Dev Neurosci. 2010 Jul;32(2):139-48. doi: 10.1159/000293989. Epub 2010 May 5.
Early life stress can elicit profound changes in adult gene expression and behavior. One consequence of early life stress is a decreased expression of glucocorticoid receptors (GRs) in the frontal cortex and hippocampus. However, neither the time of onset nor the mechanism(s) leading to decreased GR expression during postnatal development are known. The present study used two inbred strains of mice that differ in their behavioral responsiveness to stress (Balb/c and C57Bl/6), exposed them to an established paradigm of early life stress (infant maternal separation), and measured their expression of frontal cortical and hippocampal GRs and the putative transcriptional activator of the GR gene, early growth response gene (egr)-1, at defined stages of postnatal development. In both strains, real-time RT-PCR experiments revealed that decreased expression of GR in adolescence and adulthood is, in fact, preceded by increased GR expression during early life stress exposure. Thus, the early life stress-induced disruption of the normal stress-hyporesponsive period during infancy is accompanied by increased GR expression. Moreover, chronic treatment with the antidepressant drug fluoxetine during adolescence or adulthood reversed the effect of early life stress on adult GR mRNA expression. In contrast to the strain-independent effect of early life stress on GR expression, however, changes in egr-1 expression occurred only in Balb/c mice, and unlike the biphasic developmental changes in GR mRNA expression, egr-1 mRNA was decreased throughout postnatal development. Moreover, there was no consistent overlap of anatomic regions affected by decreased GR and egr-1 protein expression. Thus, in Balb/c mice, changes in GR and egr-1 expression can independently contribute to the phenotypes resulting from early life stress exposure. These findings illustrate that the impact of early life stress on gene expression changes is modulated by the genetic background and that the persistent changes in GR and egr-1 expression that arise early during postnatal developmental are reversible by chronic fluoxetine treatment during adolescence and adulthood.
早期生活压力会导致成年后基因表达和行为发生深刻变化。早期生活压力的一个后果是，前额皮质和海马体中的糖皮质激素受体 (GR) 表达减少。然而，目前尚不清楚导致产后发育过程中 GR 表达减少的起始时间或机制。本研究使用了两种在应激行为反应上存在差异的近交系小鼠（Balb/c 和 C57Bl/6），将它们暴露于早期生活压力的既定范式（婴儿期母婴分离）下，并在特定的产后发育阶段测量它们的前额皮质和海马体 GR 表达以及 GR 基因的潜在转录激活子早期生长反应基因 (egr)-1 的表达。在这两种品系中，实时 RT-PCR 实验表明，青春期和成年期 GR 表达减少实际上是在早期生活压力暴露期间 GR 表达增加之前发生的。因此，早期生活压力引起的婴儿期正常应激反应期的破坏伴随着 GR 表达的增加。此外，在青春期或成年期用抗抑郁药氟西汀进行慢性治疗可逆转早期生活压力对成年 GR mRNA 表达的影响。然而，与早期生活压力对 GR 表达的无品系效应相反，egr-1 表达的变化仅发生在 Balb/c 小鼠中，与 GR mRNA 表达的双相发育变化不同，egr-1 mRNA 整个产后发育过程中都减少了。此外，受 GR 和 egr-1 蛋白表达减少影响的解剖区域没有一致的重叠。因此，在 Balb/c 小鼠中，GR 和 egr-1 表达的变化可以独立导致早期生活压力暴露产生的表型。这些发现表明，早期生活压力对基因表达变化的影响受到遗传背景的调节，并且在产后发育早期出现的 GR 和 egr-1 表达的持续变化可以通过青春期和成年期的慢性氟西汀治疗来逆转。
