Objective: Sleep is necessary for brain maturation in infants. Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of chronic neurological disease in infants. Although the developmental changes of electroencephalogram (EEG) in human newborns have been described, little is known about the EEG normal maturation characteristics in rodents and the changes in sleep-awake states caused by hypoxia-ischemia (HI). This study aimed to investigate the pathological response of sleep-wake states in neonatal rats with HIE. Methods: We constructed HIE and sham models on postnatal day (P) 3 rats and continuously monitored them using electroencephalography and electromyography for up to P12. The distribution of sleep-wake states was analyzed to estimate the effects of HIE. Results: Compared with the sham group, the HI group showed lower rapid eye movement (REM) sleep percentage, but wake percentage and frequency was higher during P4-P12. The frequency of REM and non-rapid eye movement (NREM) sleep increased and the duration of REM and NREM sleep decreased after HI induction. However, it gradually returned to the normal level with an increase in daytime. Conclusion: HI damage alters the sleep-wake patterns during early neural development. The findings provide a comprehensive assessment of serial sleep-wake state recordings in neonatal rats from P4-P12.

Objective: Perinatal hypoxic–ischemic encephalopathy (HIE) is a major cause of epilepsy and chronic neurologic morbidity in premature infants. This study aimed to investigate the characteristics of acute seizures and the pattern of background activity on amplitude-integrated electroencephalography (aEEG) in neonatal rats with HIE.Methods: Hypoxia–ischemia (HI) was induced in postnatal day (P) 3 neonatal rats (n = 12) by ligation of the left carotid artery and exposure to airtight hypoxia for 2 h. Data regarding seizure type, frequency, and duration and those related to neurobehavioral development were collected, and the integrated power of background EEG was analyzed to evaluate the effect of HI.Results: All neonatal rats in the HI group experienced frequent seizures during hypoxia, and 83.3% of rats (10/12) experienced seizures immediately after hypoxia. Seizure frequency and duration gradually decreased with increasing age. The mortality rate of the HI group was 8.33% (1/12); 120 h after HI induction, only 27.3% (3/11) of pups had low-frequency and short-duration electrographic seizures, respectively. HI rats, which presented seizure activities 96 h after HI insult, exhibited an increase in righting reflex time and a decrease in forelimb grip reflex time. Background EEG was significantly inhibited during HI induction and immediately after hypoxia and gradually recovered 72 h after hypoxia.Conclusion: Seizures caused by HI brain damage in premature infants can be simulated in the P3 neonatal rat model.

Hypoxic-ischemic brain injury (HIBI) is a prevalent global health challenge, which is characterized by high disability and mortality rates. Despite extensive research, effective therapeutic interventions that can mitigate the influences of this disease and reduce associated disability and mortality rates remain elusive. Hypoxia-ischemia-induced energy deficiency in brain tissue not only impairs neurons but also disrupts the structural and functional integrity of mitochondria. This review focuses on mitochondrial reprogramming in hypoxia-ischemia brain injury and targeting mitochondrial reprogramming as a therapeutic goal to mitigate mitochondrial damage and restore neuronal energy supply. Mitochondrial reprogramming refers to a series of adaptive changes (including changes in size, fusion, fission, transport and anchoring) that mitochondria undergo in response to changes in cellular metabolism under physiological or pathological conditions. Our systematic summary of new therapeutic directions for mitochondrial reprogramming in hypoxic-ischemic brain injury models, particularly the mechanism of action of MitoQ, Ferrostatin-1analogue (UAMC-3203), to protect damaged neurons, points to a new therapeutic strategy for neonatal hypoxic-ischemic brain injury disorders.

Objective: Mitochondrial dysfunction and apoptosis are key pathological events in neonatal hypoxic-ischemic brain damage (HIBD). Oligodendrocyte transcription factor 2 (Olig2) is upregulated during the early phase of hypoxic-ischemic brain injury. This study aimed to investigate whether Olig2 downregulation modulates mitochondrial dynamics, apoptosis-related signaling, and early neurobehavioral outcomes in neonatal HIBD. Methods: In vivo, postnatal day 3 (P3) rats were subjected to hypoxic-ischemic injury using the Rice–Vannucci model and were intracerebroventricularly injected with adenoviral vectors carrying Olig2-targeting RNAi or a matched control sequence. Olig2 knockdown and neurobehavioral performance were evaluated at P6/P10. In vitro, HT22 cells were subjected to 3-h oxygen-glucose deprivation, followed by 24 h of reoxygenation (OGD/R). Olig2 was silenced using small interfering RNA; then, mitochondrial morphology, ATP levels, and mitochondrial and apoptosis-related proteins were assessed. Results: In vivo, Olig2 expression was upregulated following hypoxic-ischemic injury, and its knockdown partially improved early neurological deficits, including righting reflex and forelimb grasp at P6, as well as righting reflex, forelimb grip, and cliff avoidance at P10. In vitro, OGD/R-induced Olig2 upregulation, while Olig2 knockdown increased mitochondrial aspect ratio and partially restored ATP levels. OGD/R also elevated dynamin-related protein 1 (Drp1) expression and reduced B-cell lymphoma 2 and optic atrophy 1 levels compared with controls. Olig2 knockdown reversed these changes while decreasing Drp1 and mitofusin 1 (Mfn1), with mitofusin 2 (Mfn2) remaining unchanged. Conclusion: Downregulation of Olig2 was associated with improvements in early neurobehavioral outcomes and mitochondrial function, potentially mediated through suppression of apoptosis and modulation of mitochondrial dynamics.