Abstract
Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.
Highlights
IntroductionIt is necessary to utilize animal models that best mirror the symptoms, transmission, and outcomes associated with this virus in order to understand the long-term neurological consequences of prenatal Zika virus (ZIKV) infection in all affected offspring
Male breeders were removed from the breeding cage, and females were moved to a Biosafety Level 2 (BSL 2) animal isolation facility where they were individually housed in clean cages prior to infection on embryonic day 18 (E18)
At postnatal day 2 (P2), we found a significant effect of inoculation on WB volume in the automated segmentation method (F2,48 = 11.24, p < 0.001; Figure 2A), and post-hoc tests revealed that the inactivated ZIKV (iZIKV)-inoculated rats had significantly reduced WB volume when compared to the mock and Zika virus (ZIKV) cohorts (p ≤ 0.001; Figure 2A)
Summary
It is necessary to utilize animal models that best mirror the symptoms, transmission, and outcomes associated with this virus in order to understand the long-term neurological consequences of prenatal ZIKV infection in all affected offspring. This approach will allow clinicians to identify very early on which individuals may be at risk for developmental delays and neurocognitive deficits later in life, even in infants that were asymptomatic at birth, so that these individuals can be recommended for occupational, physical, and cognitive therapeutic interventions that could hopefully rescue or mitigate the long-term consequences of the prenatal ZIKV infection. We utilize a longitudinal in vivo MRI technique and employ a dual approach of automated segmentation and manual segmentation for subsequent analyses to explore the long-term neurological sequelae of prenatal ZIKV infection in rat offspring
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