Age-related changes in neuroinflammation and prepulse inhibition in offspring of rats treated with Poly I:C in early gestation
Age-related changes in neuroinflammation and prepulse inhibition in offspring of rats treated with Poly I:C in early gestation
复制标题
妊娠早期接受 Poly I:C 治疗的大鼠后代神经炎症和前脉冲抑制的年龄相关变化
DOI：
10.1186/s12993-019-0154-2
复制
发表时间：
2019-03-05
影响因子：
5.1
通讯作者：
Lv, Luxian
中科院分区：
文献类型：
--
作者：
Ding, Shuang;Hu, Yunqing;Lv, Luxian
背景：妊娠期母体免疫激活（MIA）可增加成年后代患精神分裂症的风险。神经炎症被认为是这一过程的基础。死后的大脑研究发现，精神分裂症患者的神经免疫系统发生了变化。然而，在疾病过程中，人们对大脑炎症和行为的动态变化知之甚少。方法：在妊娠第9天，对青春期大鼠和成年大鼠进行脉冲前抑制（PPI）试验，确定早期暴露于Poly I:C引发的行为轨迹。在两个年龄段分别测定前额叶皮质（PFC）和海马体（HC）的脑免疫变化。免疫组化染色检测小胶质细胞和星形胶质细胞的状态。采用酶联免疫吸附法测定两脑区的IL-6、IL-1β和TNF-α水平。结果：PPI紊乱是精神分裂症的核心表型，仅在成年期出现。青春期和成年期的行为改变都伴随着小胶质细胞（PFC和HC）的激活。星形胶质细胞仅在PN60激活。在Poly I: c暴露的母亲的后代中，促炎细胞因子（IL-1β， IL-6和TNF-α）的水平随大脑区域和时间的不同而不同，青春期周围细胞因子的升高高于成年期。结论：我们的研究结果表明，免疫激活在MIA大鼠后代出现症状之前就出现了。我们得出结论，早期产前Poly I:C挑战可导致与年龄相关的行为和神经炎症变化。这些数据为精神分裂症发展背后的神经炎症和神经病理机制提供了新的见解。他们还认为，在预防和治疗精神分裂症方面，青春期周围可能比成年期更重要。
Background:Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Neuroinflammation is believed to underlie this process. Postmortem brain studies have found changes in the neuroimmune systems of patients with schizophrenia. However, little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease.Methods:Here, the prepulse inhibition (PPI) test was conducted in adolescent and adult Sprague-Dawley rats prenatally challenged with polyriboinosinic-polyribocytidylic acid (Poly I:C) on gestational day 9 to determine the behavioral trajectory triggered by early exposure to Poly I:C. Brain immune changes were determined in the prefrontal cortex (PFC) and hippocampus (HC) at both ages. The status of the microglia and astrocytes was determined with immunohistochemical staining. The levels of IL-6, IL-1β, and TNF-α in both brain regions were evaluated with enzyme-linked immunosorbent assays.Results:Disrupted PPI, the core phenotype of schizophrenia, only emerged in adulthood. Behavioral changes during puberty and adulthood were both accompanied by the activation of microglia (PFC and HC). Astrocytes were only activated at PN60. The levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the offspring of the Poly I:C-exposed mothers differed with brain region and time, with more cytokines elevated during periadolescence than during adulthood.Conclusions:Our findings indicate that immune activation emerged before symptom manifestation in the offspring of MIA rats. We conclude that early prenatal Poly I:C challenge can lead to age-related behavioral and neuroinflammatory changes. These data provide new insight into the neuroinflammatory and neuropathological mechanisms underlying the development of schizophrenia. They also suggest that periadolescence could be more important than adulthood in the prevention and treatment of schizophrenia.