Sexually Dimorphic Outcomes after Neonatal Stroke and Hypoxia-Ischemia

Charriaut‐Marlangue, Christiane; Besson, Valérie; Baud, Olivier

doi:10.3390/ijms19010061

Cited by 83 publications

(65 citation statements)

References 84 publications

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“…Since significant differences in memory tests were found only in males, sex differences become critical for understanding the significance of the LTP impairment to problems with learning and memory. Sexual dimorphism in behavioral outcome and extension of brain damage is now widely recognized in neonatal hypoxia ischemia (Charriaut‐Marlangue et al, 2017). This is a limitation of the study that needs be addressed in the future.…”

Section: Discussionmentioning

confidence: 99%

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

Goussakov

Synowiec

Yarnykh

et al. 2019

Intl J of Devlp Neuroscience

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Apnea of prematurity is a common clinical condition that occurs in premature infants and results in intermittent hypoxia (IH) to brain and other organs. While short episodes of apnea are considered of no clinical significance, prolonged apnea with bradycardia and large oxygen desaturation is associated with adverse neurological and cognitive outcome. The mechanisms of cognitive deficits in IH are poorly understood. We hypothesized that brief but multiple episodes of severe oxygen desaturation accompanied by bradycardia may affect early and late synaptic plasticity and produce long‐term cognitive deficits. C57BL/6 mouse pups were exposed to IH paradigm consisting of alternating cycles of 5% oxygen for 2.5 min and room air for 5–10 min, 2 h a day from P3 to P7. Long term potentiation (LTP) of synaptic strength in response to high frequency stimulation in hippocampal slices were examined 3 days and 6 weeks after IH. LTP was decreased in IH group relative to controls at both time points. That decrease was associated with deficits in spatial memory on Morris water maze and context fear conditioning test. Hypomyelination was observed in multiple gray and white matter areas on in vivo MRI using micromolecule proton fraction and ex vivo diffusion tensor imaging. No difference in caspase labeling was found between control and IH groups. We conclude that early changes in synaptic plasticity occurring during severe episodes of neonatal IH and persisting to adulthood may represent functional and structural substrate for long term cognitive deficits.

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Section: Discussionmentioning

confidence: 99%

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

Goussakov

Synowiec

Yarnykh

et al. 2019

Intl J of Devlp Neuroscience

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“…Clinically, sex differences have also been observed following traumatic brain injury, where females were more resistant to neurological deficits (Roof and Hall, 2000). The multiple mechanisms underlying the sex differences are still not clearly understood, as pointed by recent reviews (Charriaut‐Marlangue et al, 2017; Bilbo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Behavioral, cognitive and histological changes following neonatal anoxia: Male and female rats' differences at adolescent age

Kumar

Motta-Teixeira

Takada

et al. 2018

Intl J of Devlp Neuroscience

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Neonatal anoxia induces long‐term brain injury that may underlie neurobehavioral deficits at adolescence. Neonatal anoxia, induced by exposure of 30‐hour old pups to 100% nitrogen, represents a non‐invasive and global stimulus, which simulates clinical conditions of human pre‐term babies (around 6 gestational months). Previous studies showed that neonatal anoxia induced impairments of spatial memory and altered anxiety‐like behaviors in male rats tested at adult age. This study evaluated if neonatal anoxia induces similar behavioral effects in female rats, as compared to males, by testing the animals at adolescence, and also searched for possible cell losses in hippocampal subfields. Results in the Elevated Plus Maze test showed that anoxic females spent proportionally more time within the open arms as compared to anoxic males, suggesting a less anxious‐like behavior. In the Morris Water Maze Test, latencies and path lengths of the anoxic subjects were longer as compared to control subjects, thus indicating that anoxia disrupted the cognitive functions required for spatial mapping. In addition, results showed that anoxia‐induced disruption was greater in male rats as compared to female rats. Stereological analysis revealed that anoxic male rats exhibited significant cell losses in the dorsal hippocampus dentate gyrus and CA1 subfields, but not in CA3‐2 subfield. Similar results were observed in the ventral hippocampus, but now with cell loss in the male CA3‐2 subfield. There were also significant cell loss differences of anoxic male rats as compared to anoxic female rats. In conclusion, neonatal anoxia induces deleterious and long lasting behavioral and cognitive disruptions, and these effects were stronger in male rats as compared to female rats. These changes are congruent with the pattern of cell losses observed in hippocampal subfields. Together, these results emphasize the relevance of scientific research, aiming at clinical strategies and treatments, consider the sex differential patterns of response to neonatal injury.

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“…There is a growing body of evidence showing sexually dimorphic outcomes after hypoxic-ischemic insults in the neonatal brain [68][69][70]. However, we did not have sufficient numbers of fetal sheep with sex identification to detect sex-related differences in MMPs or TIMPs after brain ischemia in the fetal sheep brain.…”

Section: Discussionmentioning

confidence: 79%

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

Chen¹,

Patra²,

Sadowska³

et al. 2018

Dev Neurosci

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Hypoxic-ischemic brain injury is a leading cause of neurodevelopmental morbidities in preterm and full-term infants. Blood-brain barrier dysfunction represents an important component of perinatal hypoxic-ischemic brain injury. The extracellular matrix (ECM) is a vital component of the blood-brain barrier. Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are important ECM components. They contribute to brain development, blood-brain barrier maintenance, and to regenerative and repair processes after hypoxic-ischemic brain injury. We hypothesized that ischemia at different durations of reperfusion affects the ECM protein composition of MMPs and TIMPs in the cerebral cortex of fetal sheep. Cerebral cortical samples were snap-frozen from sham control fetuses at 127 days of gestation and from fetuses after exposure to 30-min carotid occlusion and 4-, 24-, and 48-h of reperfusion. Protein expression of MMP-2, -8, -9, and -13 and TIMP-1, -2, -3, and -4 was measured by Western immunoblotting along with the gelatinolytic activity of MMP-2 and MMP-9 by zymography. The expression of MMP-8 was increased (Kruskal-Wallis, p = 0.04) in fetuses 48 h after ischemia. In contrast, changes were not observed in the protein expression of MMP-2, -9, or -13. The gelatinolytic activity of pro-MMP-2 was increased (ANOVA, p = 0.02, Tukey HSD, p = 0.05) 24 h after ischemia. TIMP-1 and -3 expression levels were also higher (TIMP-1, ANOVA, p = 0.003, Tukey HSD, p = 0.01; TIMP-3, ANOVA, p = 0.006, Tukey HSD, p = 0.01) 24 h after ischemia compared with both the sham controls and with fetuses exposed to 4 h of reperfusion. The changes in the expression of TIMP-1, -2, and -3 correlated with the changes in the MMP-8 and -13 protein expression. We speculate that regulation of MMP-8, MMP-13, and TIMPs contributes to ECM remodeling after is chemic-reperfusion injury in the fetal brain.

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Sexually Dimorphic Outcomes after Neonatal Stroke and Hypoxia-Ischemia

Cited by 83 publications

References 84 publications

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

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

Behavioral, cognitive and histological changes following neonatal anoxia: Male and female rats' differences at adolescent age

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

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