Dos Santos Adriana Souza, da Costa Meirylanne Gomes, de Almeida Wellington, de Aguiar Gabrielle Batista, Bohn Anna Luísa Lothhammer, Martini Ana Paula Rodrigues, Carvalho Andrey Vinicios Soares, Smaniotto Thiago Ângelo, Rieder Alessandra Schmitt, Varelad Ana Paula Muterle, Teixeirad Thais Fumaco, Roehe Paulo Michel, Wyse Angela Terezinha de Souza, Dalmaz Carla, Netto Carlos Alexandre, Pereira Lenir Orlandi
Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Brain Res. 2025 Mar 1;1850:149421. doi: 10.1016/j.brainres.2024.149421. Epub 2024 Dec 20.
Congenital Zika Syndrome (CZS) is a condition that arises when a neonate presents with abnormalities resulting from Zika virus infection during gestation. While microcephaly is a prominent feature of the syndrome, other forms of brain damage are also observed, often accompanied by significant neurological complications. It is therefore essential to investigate the long-term effects of CZS, with special attention to sex differences, particularly concerning hippocampal function, given its vulnerability to viral infections. The aim of this study was to evaluate the long-term impacts on cognitive and memory functions, as well as neuroinflammatory and glial alterations in the hippocampus, in offspring of both sexes exposed to a model of congenital Zika virus infection. Pregnant rats were subcutaneously inoculated with ZIKV-BR at a dose of 1 × 10^7 plaque-forming units (PFU mL^-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). From postnatal day 70, the animals underwent behavioral tests. On postnatal day 80, the animals were euthanized, and hippocampal samples were collected for biochemical and histological analyses. In the open field test, females displayed more exploratory behavior and less grooming, while no significant differences in locomotion were observed between the sexes. Additionally, ZIKV-exposed females showed a reduction in grooming behavior compared to ZIKV-exposed males. In the memory test, males in the ZIKV group exhibited greater memory impairment, spending more time to locate the correct quadrant, while females showed relatively better performance. Neuroinflammatory markers, such as TNF-α, were significantly elevated in the hippocampus of ZIKV-exposed animals, regardless of sex. However, microglial and astrocytic responses, indicated by higher IBA1 and GFAP density, were only observed in male ZIKV rats. In conclusion, our findings suggest that congenital ZIKV exposure leads to sex-specific behavioral and neuroinflammatory alterations. While both males and females exhibited some behavioral changes, males were more significantly impacted in memory performance. Additionally, increased neuroinflammatory markers and glial activation were observed in the hippocampus of ZIKV-exposed animals, with a pronounced response in males. These results highlight the long-term impact of ZIKV infection on neurodevelopment, emphasizing the importance of considering sex differences in studies of congenital ZIKV syndrome.
先天性寨卡综合征（CZS）是指新生儿因孕期感染寨卡病毒而出现异常情况。小头畸形是该综合征的一个突出特征，但也观察到其他形式的脑损伤，常伴有严重的神经并发症。因此，研究CZS的长期影响至关重要，尤其要关注性别差异，鉴于海马体易受病毒感染，特别要关注其功能方面的性别差异。本研究的目的是评估先天性寨卡病毒感染模型对后代认知和记忆功能以及海马体神经炎症和神经胶质细胞改变的长期影响。在妊娠第18天（G18），给怀孕大鼠皮下接种1×10^7个巴西分离的寨卡病毒（ZIKV-BR）的噬斑形成单位（PFU mL^-1）。从出生后第70天开始，对动物进行行为测试。在出生后第80天，对动物实施安乐死，并采集海马体样本进行生化和组织学分析。在旷场试验中，雌性表现出更多的探索行为且梳理行为较少，而两性之间在运动方面未观察到显著差异。此外，与寨卡病毒暴露的雄性相比雌性的梳理行为减少。在记忆测试中，寨卡病毒组的雄性表现出更严重的记忆障碍，找到正确象限花费的时间更多，而雌性表现相对较好。无论性别，寨卡病毒暴露动物海马体中的神经炎症标志物如肿瘤坏死因子-α（TNF-α）均显著升高。然而，仅在雄性寨卡病毒大鼠中观察到由更高的离子钙结合衔接分子1（IBA1）和胶质纤维酸性蛋白（GFAP）密度所表明的小胶质细胞和星形胶质细胞反应。总之，我们的研究结果表明先天性寨卡病毒暴露会导致特定性别的行为和神经炎症改变。虽然雄性和雌性都表现出一些行为变化，但雄性在记忆表现方面受到的影响更大。此外，在寨卡病毒暴露动物的海马体中观察到神经炎症标志物增加和神经胶质细胞激活，雄性反应更为明显。这些结果凸显了寨卡病毒感染对神经发育的长期影响，强调了在先天性寨卡病毒综合征研究中考虑性别差异的重要性。
