Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques

Abstract

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

Hippocampal and Prefrontal Cortical Brain Tissue Levels of Irisin and GDF15 Receptor Subunits in Children

“…Zika virus causes devastating deformations (microcephaly) to the developing brain but the risk of CNS damage is considered greatest during pregnancy (i.e., injury to the fetal brain in utero) [ 46 , 47 ]. However, a 2020 report called into question the timing of the “susceptibility window” by demonstrating that inoculating 5-week-old infant macaques with Zika (equivalent to a 4-month-old human infant) resulted in enlarged ventricles, damage to multiple brain structures, and produced a variety of behavioral deficits [ 48 ]. Consistent with those findings, Pacheco and colleagues showed that 15% of patients, in a cohort of < 1-year-old infants postnatally infected with Zika, later developed long-term neurological abnormalities.…”

Neurological Development, Epilepsy, and the Pharmacotherapy Approach in Children with Congenital Zika Syndrome: Results from a Two-Year Follow-up Study

“…In our cohort, conversely, we observed that in the period between birth and the second year of life, most children showed greater retardation in the growth of the head circumference, showing a much lower Z-score (Z-score −8.84 to −4.80) in relation to that measured at birth (Z-score −4.53 to −1.12). In a study carried out with primates, Raper et al [ 38 ] reported that until the sixth month after the experimental postnatal infection, damage processes in the developing brain were still observed, even with the virus undetectable in the blood serum 7 days after the infection. This demonstrates that ZIKV infection causes a progressive damage process in the brain that can persist for months, causing structural and functional anomalies.…”

The Neurobiology of Zika Virus: New Models, New Challenges

“…Although the main effect of ZIKV occurs in the embryonic period, brain impairments are persistent and, importantly, they might be continuous extending to the postnatal period. Indeed, the brain is still vulnerable to significant structural and functional complications at later developmental stages including ZIKV, and even postnatally (Mavigner et al, 2018;Carvalho et al, 2019;Dudley et al, 2019;Raper et al, 2020).…”