Department of Basic Sciences, Faculty of Nursing, School of Health Sciences, National and Kapodistrian University of Athens, Greece.
Faculty of Dentistry, School of Health Sciences, National and Kapodistrian University of Athens, Greece.
Physiol Behav. 2020 Mar 1;215:112791. doi: 10.1016/j.physbeh.2019.112791. Epub 2019 Dec 21.
Exposure to early life stress affects the development and function of the brain and when followed by adversities in adulthood, the negative effects of stress are enhanced. Microglia has been proposed as a potential mediator of this phenomenon. In the present study, we investigated the long-term effects of mild early life stress, the consequences of a stressor in adulthood as well as their interaction on microglial and cytokine (PPARγ, IL-1β and TNFα) levels in the brain of adult male rats. As an early life stress we used a model of maternal neglect, in which the dam is present but non-accessible to the pup for 15 min during postnatal days 10-13; as a stressor in adulthood we exposed animals to chronic social defeat (CSD) for 3 weeks. We determined in the hippocampus, prefrontal cortex and amygdala, the number of Iba-1+ microglial cells, the number of PPARγ+ cells as well as the relative expression of PPARγ, IL-1β and TNFα mRNA by qPCR. Following exposure to CSD, the number of Iba-1+ cells was increased in the hippocampus and the prefrontal cortex of adult animals exposed to mild early life stress, while in the absence of CSD no such difference was observed. Moreover, following CSD PPARγ levels were increased in the hippocampus of adult males exposed as neonates to "maternal neglect". Our findings support the notion that early life stress, even a mild one, primes microglia and enhances its reactivity to a second stressful event, later in life, in accord with the "two-hit" hypothesis.
早期生活应激暴露会影响大脑的发育和功能，而成年后如果再遇到逆境，应激的负面影响会增强。小胶质细胞被认为是这一现象的潜在介导者。在本研究中，我们研究了轻度早期生活应激的长期影响、成年期应激源的后果以及它们对成年雄性大鼠大脑中小胶质细胞和细胞因子（PPARγ、IL-1β 和 TNFα）水平的相互作用。作为早期生活应激，我们使用了一种母体忽视模型，即母鼠在产后第 10-13 天期间存在但不可接近幼崽 15 分钟；作为成年期应激源，我们让动物经历慢性社会挫败（CSD）3 周。我们在海马体、前额叶皮层和杏仁核中确定了 Iba-1+小胶质细胞的数量、PPARγ+细胞的数量以及 qPCR 测定的 PPARγ、IL-1β 和 TNFα mRNA 的相对表达。在经历 CSD 后，暴露于轻度早期生活应激的成年动物的海马体和前额叶皮层中的 Iba-1+细胞数量增加，而在没有 CSD 的情况下则没有观察到这种差异。此外，在 CSD 后，新生时暴露于“母体忽视”的成年雄性大鼠的海马体中 PPARγ 水平增加。我们的发现支持了这样一种观点，即早期生活应激，即使是轻度应激，也会使小胶质细胞致敏，并增强其对生命后期第二次应激事件的反应性，这与“双打击”假说一致。
