Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

Abstract

Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious.

10-Week Hatha Yoga Increases Right Hippocampal Density Compared to Active and Passive Control Groups: A Controlled Structural cMRI Study

“…The consequent hypocapnia leads to a constriction of vessels in the brain, leading to a short-term relative hypoxia. This fits very well with the results of Bousama et al [108] who postulated in their work intermittent hypoxia as the key factor for neurogenesis modulation in the hippocampus. They hypothesized that activation of neurogenesis is a reaction to hypoxia-induced neuronal loss, thereby contributing relative hypoxia as a neuroprotective mechanism [109][110][111].…”

Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach

“…At the cerebral level, we know that apnea of prematurity (AOP) is a risk factor for neurodevelopment disorders in children37 and newborn rodents 38. A recent study showed that exposure to moderate IH (8% O 2 ) with 20 hypoxic events/hour for 6 hours/day offers neuroprotection against brain lesion and cognitive dysfunction related to AOP, a model that may be beneficial in newborns with moderate AOP 39. Similar data were described in patients with stroke in whom previous transient cerebral ischemic attacks protected them from the severity of stroke outcomes 40.…”

Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia

“…Mild motor deficits and white matter injury, but very few long‐term cognitive abnormalities were found in these models (Cai et al, 2012; Juliano et al, 2015; Darnall et al, 2017). Moreover, several studies utilizing mild neonatal IH report neuroprotection from excitotoxic injury and improvement of long‐term cognitive abilities in adulthood (Bouslama et al, 2015; Martin et al, 2012; Zhang et al, 2005). It appears that the IH insult must be relatively severe to result in cognitive deficits in rodent models.…”