Intermittent hypoxia and cerebellar development

Data & R analysis code

Abstract

Background: Apnea of prematurity (AOP) is caused by respiratory control immaturity and affects nearly 50% of premature newborns. This pathology induces perinatal intermittent hypoxia (IH), which leads to neurodevelopmental disorders. The impact on the brain has been well investigated. However, despite its functional importance and immaturity at birth, the involvement of the cerebellum remains poorly understood. Therefore, this study aims to identify the effects of IH on cerebellar development using a mouse model of AOP consisting of repeated 2-min cycles of hypoxia and reoxygenation over 6 h and for 10 days starting on postnatal day 2 (P2).

Results: At P12, IH-mouse cerebella present higher oxidative stress associated with delayed maturation of the cerebellar cortex and decreased dendritic arborization of Purkinje cells. Moreover, mice present with growth retardation and motor disorders. In response to hypoxia, the developing cerebellum triggers compensatory mechanisms resulting in the unaltered organization of the cortical layers from P21 onwards. Nevertheless, some abnormalities remain in adult Purkinje cells, such as the dendritic densification, the increase in afferent innervation, and axon hypomyelination. Moreover, this compensation seems insufficient to allow locomotor recovery because adult mice still show motor impairment and significant disorders in spatial learning.

Conclusions: All these findings indicate that the cerebellum is a target of intermittent hypoxia through alterations of developmental mechanisms leading to long-term functional deficits. Thus, the cerebellum could contribute, like others brain structures, to explaining the pathophysiology of AOP.

Foreword

This website serves as documentation as well as to showcase the data and R analysis code for Leroux S., Rodriguez-Duboc A., Arabo A., Basille-Dugay M., Vaudry D., & Burel D., 2022:

Intermittent hypoxia in a mouse model of apnea of prematurity leads to a retardation of cerebellar development and long-term functional deficits

Structure of this website

Each of the files listed in the navigation bar (left side of the screen) contains multiple variables that we analyzed, grouped by thematic. Each file will contain a section for each of those variables. Each of those sections is further divided into three subsections:

1. Data Exploration: variable’s summary statistics, distribution, and evolution in time (if applicable).

2. Models & Diagnostics: quality of fit, diagnostics and predictions for each of the candidate models of that variable.

Each candidate model is split in its own tab.

Disclaimer on the presence of multiple models

We chose to (sometimes) display several candidate models for each variable of interest for the sake of exploration, and to asses the robustness of our inferences to model assumptions. However, the model we used for testing our hypotheses was picked mainly based on theoretical criteria, also taking into account the model’s quality of fit (evaluated through residual and predictive plots).

3. Effects Analysis: the chosen model’s coefficients, main effects (Wald \(\chi^2\) and Likelihood Ratio Test), and the marginal means and contrasts for each of its predictor. This subsection also includes the box plots showcased in the article.

Each predictor is split in its own tab.

Disclaimer on multiple testing

For the sake of exploration and transparency, we showcase the marginal means and contrasts for all the predictors (and interactions) of the chosen model. However, only a subset of those contrasts were of interest during the study (viz. mainly the impact of Condition, i.e. whether the mouse was submitted to Intermittent Hypoxia or not). Many of those contrasts were thus not included in the paper, not because they were not significant, but because they were not of interest to the authors.