Zhao Xin, Rondón-Ortiz Alejandro N, Lima Erika P, Puracchio Madeline, Roderick Ryland C, Kentner Amanda C
School of Arts & Sciences, Health Psychology Program, Massachusetts College of Pharmacy and Health Sciences, Boston Massachusetts, United States 02115.
Brain Behav Immun Health. 2020 Mar;3. doi: 10.1016/j.bbih.2020.100043. Epub 2020 Jan 30.
Maternal immune activation (MIA) has been identified as a significant risk factor for several neurodevelopmental disorders. We have previously demonstrated that postpubertal environmental enrichment (EE) rescues and promotes resiliency against MIA in male rats. Importantly, EE protocols have demonstrated clinical relevancy in human rehabilitation settings. Applying some of the elements of these EE protocols (e.g. social, physical, cognitive stimulation) to animal models of health and disease allows for the exploration of the mechanisms that underlie their success. Here, using a MIA model, we further investigate the rehabilitative potential of complex environments with a focus on female animals. Additionally, we expand upon some of our previous work by exploring genetic markers of synaptic plasticity and stress throughout several brain regions of both sexes. In the current study, standard housed female Sprague-Dawley rats were challenged with either the inflammatory endotoxin lipopolysaccharide (LPS; 100 μg/kg) or saline (equivolume) on gestational day 15. On postnatal day 50, male and female offspring were randomized into one of three conditions that differed in terms of cage size, number of cage mates (social stimulation) and enrichment materials. Spatial discrimination ability and social behavior were assessed six weeks later. Similar to our previously published work in males, our results revealed that a single LPS injection during mid gestation disrupted spatial discrimination ability in female rats. Postpubertal EE rescued this disruption. On the endocrine level, EE dampened elevations in plasma corticosterone that followed MIA, which may mediate EE's rehabilitative effects in female offspring. Within the prefrontal cortex, hippocampus, amygdala, and hypothalamus, MIA and EE altered the mRNA expression of several genes associated with resiliency and synaptic plasticity in both sexes. Overall, our findings provide further evidence that EE may serve as a therapeutic intervention for MIA-induced behavioral and cognitive deficits. Moreover, we identify some sexually dimorphic molecular mechanisms that may underlie these impairments and their rescue.
母体免疫激活（MIA）已被确定为几种神经发育障碍的重要风险因素。我们之前已经证明，青春期后环境富集（EE）可挽救并促进雄性大鼠对MIA的恢复力。重要的是，EE方案已在人类康复环境中显示出临床相关性。将这些EE方案的一些要素（例如社交、身体、认知刺激）应用于健康和疾病动物模型，有助于探索其成功背后的机制。在这里，我们使用MIA模型，进一步研究复杂环境对雌性动物的康复潜力，重点关注雌性动物。此外，我们通过探索两性多个脑区中突触可塑性和应激的遗传标记，扩展了我们之前的一些工作。在当前研究中，在妊娠第15天，将标准饲养的雌性Sprague-Dawley大鼠用炎性内毒素脂多糖（LPS；100μg/kg）或生理盐水（等体积）进行刺激。在出生后第50天，将雄性和雌性后代随机分为三种条件之一，这三种条件在笼子大小、笼伴数量（社交刺激）和富集材料方面有所不同。六周后评估空间辨别能力和社交行为。与我们之前发表的关于雄性大鼠的研究结果相似，我们的结果显示，妊娠中期单次注射LPS会破坏雌性大鼠的空间辨别能力。青春期后EE挽救了这种破坏。在内分泌水平上，EE抑制了MIA后血浆皮质酮的升高，这可能介导了EE对雌性后代的康复作用。在额叶前皮质、海马体、杏仁核和下丘脑内，MIA和EE改变了两性中与恢复力和突触可塑性相关的几个基因的mRNA表达。总体而言，我们的研究结果提供了进一步的证据，表明EE可能作为一种治疗干预措施，用于治疗MIA诱导的行为和认知缺陷。此外，我们确定了一些可能是这些损伤及其挽救基础的性别差异分子机制。
