Author:

Keywords:

preterm birth, apnea of prematurity

Abstract:

Preterm birth, affecting roughly 10% of all infants, is an important health problem that puts children at risk for long-term morbidity and developmental disabilities. We will focus on one aspect of preterm infants’ complex pathology, namely respiratory instability. Respiratory instability, characterized by frequent apneas, and resultant intermittent hypoxia (IH) that can persist for weeks to months, is a common problem in preterm infants. Epidemiological studies suggest that it is related to poor developmental outcome. However, pinpointing causal relationships between respiratory instability and developmental outcome is difficult in infants because of numerous confounding comorbidities and ethical considerations that render clinical studies in this population difficult. Newborn animal models are necessary for this purpose. In this dissertation we have integrated physiological and behavioral techniques in newborn mice to tackle research questions about respiratory instability related to preterm birth and its consequences on neurobehavioral development.First, to be able to assess cognitive performance early in development, we developed a new conditioning procedure suitable for neonatal mouse pups, using artificial odors as conditioned stimuli and ambient temperature as the unconditioned stimulus. Second, we investigated the short- and long-term behavioral consequences of frequent apneas during the postnatal period in two mouse models, using an experimental and a genetic approach. In adult mice postnatally exposed to IH, we found evidence for hyperactivity in a novel environment. In male mice, we observed working memory impairment and alterations in social behavior. Phox2b+/- mice were studied as an alternative to IH. This genetic mouse model shows spontaneous apneas specifically during the postnatal period. We found evidence for emotional alterations in Phox2b+/-mice. These results indicate that newborns' ability to adequately respond to hypoxia is a key factor for developmental outcome. We consequently focused on the repertoire of defense reactions a newborn mouse exhibits to cope with hypoxia. We studied a broad range of both physiological and behavioral defense reactions to hypoxia in both a thermoneutral and a cold environment. The latter increases metabolic rate and aggravates hypoxic stress. We showed that newborn mice cope with hypoxia using a context-dependent strategy. Furthermore, based on conditioning studies using odors as conditioned stimuli and hypoxia as the unconditioned stimulus, we found that the defense response to hypoxia in newborn mice may be shaped by past experience. Finally, we investigated whether the group III metabotropic glutamate receptors mGluR4, mGluR7 and mGluR8, which are differentially implicated in anxiety and stress, are also involved in the defense response to hypoxia. This was done using genetic knockout (KO) mouse models. We observed a blunted ventilatory response to cold and hypoxia in mGluR7 KO mouse pups, while mGluR8 KO pups exhibited an enhanced response. This suggests that these receptors are differentially involved in the defense response to hypoxic stress.