Effects of birth asphyxia on neonatal hippocampal structure and function in the spiny mouse

Abstract

Studies of human neonates, and in animal experiments, suggest that birth asphyxia results in functional compromise of the hippocampus, even when structural damage is not observable or resolves in early postnatal life. The aim of this study was to determine if changes in hippocampal function occur in a model of birth asphyxia in the precocial spiny mouse where it is reported there is no major lesion or infarct. Further, to assess if, as in human infants, this functional deficit has a sex-dependent component. At 37 days gestation (term=39 days) spiny mice fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5min of in utero asphyxia causing systemic acidosis and hypoxia. At 5 days of age hippocampal function was assessed ex vivo in brain slices, or brains were collected for examination of structure or protein expression. This model of birth asphyxia did not cause infarct or cystic lesion in the postnatal day 5 (P5) hippocampus, and the number of proliferating or pyknotic cells in the hippocampus was unchanged, although neuronal density in the CA1 and CA3 was increased. Protein expression of synaptophysin, brain-derived neurotrophic factor (BDNF), and the inositol trisphosphate receptor 1 (IP(3)R1) were all significantly increased after birth asphyxia, while long-term potentiation (LTP), paired pulse facilitation (PPF), and post-tetanic potentiation (PTP) were all reduced at P5 by birth asphyxia. In control P5 pups, PPF and synaptic fatigue were greater in female compared to male pups, and after birth asphyxia PPF and synaptic fatigue were reduced to a greater extent in female vs. male pups. In contrast, the asphyxia-induced increase in synaptophysin expression and neuronal density were greater in male pups. Thus, birth asphyxia in this precocial species causes functional deficits without major structural damage, and there is a sex-dependent effect on the hippocampus. This may be a clinically relevant model for assessing treatments delivered either before or after birth to protect this vulnerable region of the developing brain.

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

“…A decrease of LTP has been shown in hippocampal slices obtained 3 and 7 days after IH in adult rats (Payne et al, 2004) and LTP was proportionally lower in adult mice IH after 3 and 14 days of 10% oxygen 90 s cycle IH (Xie et al, 2010) that could be rescued by exogenous BDNF. There is a paucity of data in LTP changes after neonatal IH and neonatal hypoxia‐ischemia, but a decrease of LTP had been found postnatally in spiny mice 5 days after near term acute fetal asphyxia (Fleiss et al, 2011) in the model associated with postnatal behavioral abnormalities (Ireland et al, 2010). Of interest, there was no structural injury observed in this model, but neuronal density and synaptophysin expression and BDNF were increased in hippocampus in male P5 pups, suggesting that the behavioral changes were likely due to changes in synaptic plasticity.…”

“…White matter injury is a consistent finding in perinatal brain hypoxia and ischemia injury of different types (Cai et al, 2012; Juliano et al, 2015; Darnall et al, 2017; Oorschot et al, 2013) and may also be a determinant of later cognitive abnormalities. Impairments in LTP have been examined in models of single acute hypoxic event during prenatal period (Fleiss et al, 2011), but have not been studied in neonatal IH, especially in relation to cognitive outcome. We hypothesize that brief but multiple episodes of severe desaturation accompanied by bradycardia will affect synaptic plasticity and be sufficient to produce long‐term cognitive deficits.…”

Amnesia and Pain Relief after Cardiopulmonary Resuscitation in a Cancer Pain Patient: A Case Report

“…Many cognitive impairments and memory losses occur by hypoxic brain injury after cardiac arrest, but the precise mechanism of this phenomenon is not yet clearly proven (6). Fleiss et al (7) reported that hypoxic brain injury in an animal model of birth asphyxia produced significant functional deficits in the hippocampus, and caused a reduction of long-term potentiation (LTP), paired pulse facilitation (PRF), and post-tetanic potentiation (PTP). This occurred in the absence of gross cellular damage.…”

Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy

“…Analysis was made for glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1), myelin basic protein (MBP), and microtubule-associated protein 2 (MAP2) using densitometric analysis, as previously described [31,32] using Image J (NIH, USA). Counts were made of CD68, CD45, Ki67, Olig2, NeuN, Calbindin and BrdU.…”

“…Figure 2 demonstrates brain regions evaluated with IHC staining. Analyses were made in 3 fields of view (FOV) per brain region for densitometric analysis and 2 FOV per brain region for counts as previously described [31,32]. IHC data across fields of view were averaged and the mean used in statistical analyses in Graphpad prism (version 5 for Mac).…”