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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.


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Improvements in memory in mice postnatally exposed to IH. Memory was assessed on P22 using the Object Recognition Task (ORT, A–C) and Object Location Task (OLT, D–F). IH, mice exposed to chronic intermittent hypoxia (n = 20); AIR, mice exposed to air (n = 20); UNT, untreated unmanipulated mice left with their dams (n = 19). ORT, (B,C) In the training phase, the three groups tended to equally explore the two objects. In the ORT test phase, the IH group had significantly higher preference (B) and discrimination (C) indices compared to the AIR group; with both values similar to those in the UNT group. OLT, (E,F) gave similar results. Values are group means ± SEM. ***p < 0.001; ****p < 0.0001.
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Figure 3: Improvements in memory in mice postnatally exposed to IH. Memory was assessed on P22 using the Object Recognition Task (ORT, A–C) and Object Location Task (OLT, D–F). IH, mice exposed to chronic intermittent hypoxia (n = 20); AIR, mice exposed to air (n = 20); UNT, untreated unmanipulated mice left with their dams (n = 19). ORT, (B,C) In the training phase, the three groups tended to equally explore the two objects. In the ORT test phase, the IH group had significantly higher preference (B) and discrimination (C) indices compared to the AIR group; with both values similar to those in the UNT group. OLT, (E,F) gave similar results. Values are group means ± SEM. ***p < 0.001; ****p < 0.0001.

Mentions: Recognition memory was first evaluated using the ORT (Figure 3A). In the ORT training phase, all groups spent roughly the same time exploring the two objects (Figures 3B,C). These data suggested similar locomotion, attention, motivation, and visual perception among the groups. The ORT test phase (conducted 30 min after training) revealed significant differences across groups (main effect for group, p < 0.0001; and group-by-phase interaction, p < 0.0001; for both preference and discrimination). The IH group performed significantly better than the AIR group and similarly to the UNT group (Figures 3B,C). The OLT (Figure 3D) then confirmed these differences across groups (Figures 3E,F). During the OLT training phase, preference and discrimination indices were closely similar in the three groups. The OLT test phase revealed large and significant differences across groups: the IH group performed significantly better than the AIR group and similarly to the UNT group (main effect for group, p < 0.0001; and group-by-phase interaction, p < 0.0001; for both preference and discrimination; Figures 3E,F). Thus, IH prevented the adverse effects of maternal separation on memory.


Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity
Improvements in memory in mice postnatally exposed to IH. Memory was assessed on P22 using the Object Recognition Task (ORT, A–C) and Object Location Task (OLT, D–F). IH, mice exposed to chronic intermittent hypoxia (n = 20); AIR, mice exposed to air (n = 20); UNT, untreated unmanipulated mice left with their dams (n = 19). ORT, (B,C) In the training phase, the three groups tended to equally explore the two objects. In the ORT test phase, the IH group had significantly higher preference (B) and discrimination (C) indices compared to the AIR group; with both values similar to those in the UNT group. OLT, (E,F) gave similar results. Values are group means ± SEM. ***p < 0.001; ****p < 0.0001.
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getmorefigures.php?uid=PMC4631942&req=5

Figure 3: Improvements in memory in mice postnatally exposed to IH. Memory was assessed on P22 using the Object Recognition Task (ORT, A–C) and Object Location Task (OLT, D–F). IH, mice exposed to chronic intermittent hypoxia (n = 20); AIR, mice exposed to air (n = 20); UNT, untreated unmanipulated mice left with their dams (n = 19). ORT, (B,C) In the training phase, the three groups tended to equally explore the two objects. In the ORT test phase, the IH group had significantly higher preference (B) and discrimination (C) indices compared to the AIR group; with both values similar to those in the UNT group. OLT, (E,F) gave similar results. Values are group means ± SEM. ***p < 0.001; ****p < 0.0001.
Mentions: Recognition memory was first evaluated using the ORT (Figure 3A). In the ORT training phase, all groups spent roughly the same time exploring the two objects (Figures 3B,C). These data suggested similar locomotion, attention, motivation, and visual perception among the groups. The ORT test phase (conducted 30 min after training) revealed significant differences across groups (main effect for group, p < 0.0001; and group-by-phase interaction, p < 0.0001; for both preference and discrimination). The IH group performed significantly better than the AIR group and similarly to the UNT group (Figures 3B,C). The OLT (Figure 3D) then confirmed these differences across groups (Figures 3E,F). During the OLT training phase, preference and discrimination indices were closely similar in the three groups. The OLT test phase revealed large and significant differences across groups: the IH group performed significantly better than the AIR group and similarly to the UNT group (main effect for group, p < 0.0001; and group-by-phase interaction, p < 0.0001; for both preference and discrimination; Figures 3E,F). Thus, IH prevented the adverse effects of maternal separation on memory.

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