Mandyam Chitra D, Crawford Elena F, Eisch Amelia J, Rivier Catherine L, Richardson Heather N
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, USA.
Dev Neurobiol. 2008 Apr;68(5):575-89. doi: 10.1002/dneu.20600.
Hippocampal function and plasticity differ with gender, but the regulatory mechanisms underlying sex differences remain elusive and may be established early in life. The present study sought to elucidate sex differences in hippocampal plasticity under normal developmental conditions and in response to repetitive, predictable versus varied, unpredictable prenatal stress (PS). Adult male and diestrous female offspring of pregnant rats exposed to no stress (control), repetitive stress (PS-restraint), or a randomized sequence of varied stressors (PS-random) during the last week of pregnancy were examined for hippocampal proliferation, neurogenesis, cell death, and local microenvironment using endogenous markers. Regional volume was also estimated by stereology. Control animals had comparable proliferation and regional volume regardless of sex, but females had lower neurogenesis compared to males. Increased cell death and differential hippocampal precursor kinetics both appear to contribute to reduced neurogenesis in females. Reduced local interleukin-1beta (IL-1beta) immunoreactivity (IR) in females argues for a mechanistic role for the anti-apoptotic cytokine in driving sex differences in cell death. Prenatal stress significantly impacted the hippocampus, with both stress paradigms causing robust decreases in actively proliferating cells in males and females. Several other hippocampal measures were feminized in males such as precursor kinetics, IL-1beta-IR density, and cell death, reducing or abolishing some sex differences. The findings expand our understanding of the mechanisms underlying sex differences and highlight the critical role early stress can play on the balance between proliferation, neurogenesis, cell death, and hippocampal microenvironment in adulthood.
海马体的功能和可塑性存在性别差异，但其性别差异背后的调控机制仍不清楚，且可能在生命早期就已确立。本研究旨在阐明在正常发育条件下以及对重复性、可预测性与多样化、不可预测性产前应激（PS）的反应中，海马体可塑性的性别差异。使用内源性标记物，对在怀孕最后一周暴露于无应激（对照）、重复性应激（PS-束缚）或随机应激源序列（PS-随机）的怀孕大鼠的成年雄性和动情间期雌性后代进行海马体增殖、神经发生、细胞死亡和局部微环境的检测。还通过体视学估计区域体积。对照动物无论性别，增殖和区域体积都相当，但与雄性相比，雌性的神经发生较低。细胞死亡增加和海马体前体细胞动力学差异似乎都导致了雌性神经发生减少。雌性中局部白细胞介素-1β（IL-1β）免疫反应性（IR）降低，表明抗凋亡细胞因子在驱动细胞死亡的性别差异中起机制性作用。产前应激对海马体有显著影响，两种应激模式都导致雄性和雌性中活跃增殖细胞显著减少。雄性的其他几项海马体指标呈现出雌性化，如前体细胞动力学、IL-1β-IR密度和细胞死亡，减少或消除了一些性别差异。这些发现扩展了我们对性别差异潜在机制的理解，并突出了早期应激在成年期增殖、神经发生、细胞死亡和海马体微环境平衡中可能发挥的关键作用。
