Quantification of early gait development: Expanding the application of Catwalk technology to an infant rhesus macaque model.

BACKGROUND: Understanding gait development is essential for identifying motor impairments in neurodevelopmental disorders. Defining typical gait development in a rhesus macaque model is critical prior to characterizing abnormal gait. The goal of this study was to 1) explore the feasibility of using the Noldus Catwalk to assess gait in infant rhesus macaques and 2) provide preliminary normative data of gait development during the first month of life. NEW METHOD: The Noldus Catwalk was used to assess gait speed, dynamic and static paw measurements, and interlimb coordination in twelve infant rhesus macaques at 14, 21, and 28 days of age. All macaque runs were labeled as a diagonal or non-diagonal walking pattern. RESULTS: Infant rhesus macaques primarily used a diagonal (mature) walking pattern as early as 14 days of life. Ten infant rhesus macaques (83.3%) were able to successfully walk across the Noldus Catwalk at 28 days of life. Limited differences in gait parameters were observed between timepoints because of the variability within the group at 14, 21, and 28 days. COMPARISON WITH EXISTING METHODS: No prior gait analysis system has been used to provide objective quantification of gait parameters for infant macaques. CONCLUSIONS: The Catwalk system can be utilized to quantify gait in infant rhesus macaques less than 28 days old. Future applications to infant rhesus macaques could provide a better understanding of gait development and early differences within various neurodevelopmental disorders.

Neonatal Development in Prenatally Zika Virus-Exposed Infant Macaques with Dengue Immunity.

Infants exposed to Zika virus (ZIKV) prenatally may develop birth defects, developmental deficits, or remain asymptomatic. It is unclear why some infants are more affected than others, although enhancement of maternal ZIKV infection via immunity to an antigenically similar virus, dengue virus (DENV), may play a role. We hypothesized that DENV immunity may worsen prenatal ZIKV infection and developmental deficits in offspring. We utilized a translational macaque model to examine how maternal DENV immunity influences ZIKV-exposed infant macaque neurodevelopment in the first month of life. We inoculated eight macaques with prior DENV infection with ZIKV, five macaques with ZIKV, and four macaques with saline. DENV/ZIKV-exposed infants had significantly worse visual orientation skills than ZIKV-exposed infants whose mothers were DENV-naive, with no differences in motor, sensory or state control development. ZIKV infection characteristics and pregnancy outcomes did not individually differ between dams with and without DENV immunity, but when multiple factors were combined in a multivariate model, maternal DENV immunity combined with ZIKV infection characteristics and pregnancy parameters predicted select developmental outcomes. We demonstrate that maternal DENV immunity exacerbates visual orientation and tracking deficits in ZIKV-exposed infant macaques, suggesting that human studies should evaluate how maternal DENV immunity impacts long-term neurodevelopment.

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.