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

View Article: PubMed Central

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.

No MeSH data available.


Related in: MedlinePlus

Graphical representation of the IH protocol. (A) Each session lasted 2 h with a frequency of 20 events/h. For each hypoxic event, after 90 s of normoxia, pure N2 was injected into the chamber for 30 s, which decreased FIO2 from 20.9 to 8%. FIO2 was maintained at 8% for 60 s. (B) The pups were exposed to IH during three 2-h sessions per day. During rest periods, the pups were returned to their dam for 1 h. After completion of the third session, all pups were returned to their dam until the following day. (C) The pups were exposed to IH over 5 consecutive days, from P6 to P10; hist: histology.
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Figure 1: Graphical representation of the IH protocol. (A) Each session lasted 2 h with a frequency of 20 events/h. For each hypoxic event, after 90 s of normoxia, pure N2 was injected into the chamber for 30 s, which decreased FIO2 from 20.9 to 8%. FIO2 was maintained at 8% for 60 s. (B) The pups were exposed to IH during three 2-h sessions per day. During rest periods, the pups were returned to their dam for 1 h. After completion of the third session, all pups were returned to their dam until the following day. (C) The pups were exposed to IH over 5 consecutive days, from P6 to P10; hist: histology.

Mentions: Figure 1 describes the IH protocol. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH and maternal separation (IH group), a group exposed to normoxia and maternal separation (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning under standard housing conditions (UNT group). The UNT group controlled for the effects of maternal separation on development.


Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity
Graphical representation of the IH protocol. (A) Each session lasted 2 h with a frequency of 20 events/h. For each hypoxic event, after 90 s of normoxia, pure N2 was injected into the chamber for 30 s, which decreased FIO2 from 20.9 to 8%. FIO2 was maintained at 8% for 60 s. (B) The pups were exposed to IH during three 2-h sessions per day. During rest periods, the pups were returned to their dam for 1 h. After completion of the third session, all pups were returned to their dam until the following day. (C) The pups were exposed to IH over 5 consecutive days, from P6 to P10; hist: histology.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631942&req=5

Figure 1: Graphical representation of the IH protocol. (A) Each session lasted 2 h with a frequency of 20 events/h. For each hypoxic event, after 90 s of normoxia, pure N2 was injected into the chamber for 30 s, which decreased FIO2 from 20.9 to 8%. FIO2 was maintained at 8% for 60 s. (B) The pups were exposed to IH during three 2-h sessions per day. During rest periods, the pups were returned to their dam for 1 h. After completion of the third session, all pups were returned to their dam until the following day. (C) The pups were exposed to IH over 5 consecutive days, from P6 to P10; hist: histology.
Mentions: Figure 1 describes the IH protocol. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH and maternal separation (IH group), a group exposed to normoxia and maternal separation (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning under standard housing conditions (UNT group). The UNT group controlled for the effects of maternal separation on development.

View Article: PubMed Central

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.

No MeSH data available.


Related in: MedlinePlus