Abstract
This study was designed in a rat model to determine the hallmarks of possible permanent behavioral and structural brain alterations after a single moderate hypoxic insult. Eighty-two Wistar Han (RccHan: WIST) rats were randomly subjected to hypoxia (pO2 73 mmHg/2 h) or normoxia at the first postnatal day. The substantially increased blood lactate, a significantly decreased cytochrome-C-oxygenase expression in the brain, and depleted subventricular zone suggested a high vulnerability of subset of cell populations to oxidative stress and consequent tissue response even after a single, moderate, hypoxic event. The results of behavioral tests (open-field, hole-board, social-choice, and T-maze) applied at the 30–45th and 70–85th postnatal days revealed significant hyperactivity and a slower pace of learning in rats subjected to perinatal hypoxia. At 3.5 months after hypoxic insult, the histochemical examination demonstrated a significantly increased number of specific extracellular matrix—perineuronal nets and increased parvalbumin expression in a subpopulation of interneurons in the medial and retrosplenial cingulate cortex of these animals. Conclusively, moderate perinatal hypoxia in rats causes a long-lasting reorganization of the connectivity in the cingulate cortex and consequent alterations of related behavioral and cognitive abilities. This non-invasive hypoxia model in the rat successfully and complementarily models the moderate perinatal hypoxic injury in fetuses and prematurely born human babies and may enhance future research into new diagnostic and therapeutic strategies for perinatal medicine.
Highlights
Perinatal cerebral hypoxia-ischemia and preterm birth are the most common causes of neurological disorders or impaired brain function of developmental origin (Volpe, 2012; Vohr, 2014; Laptook, 2016; Vanes et al, 2021)
We aim to investigate the effect of moderate hypoxia on early neonatal development in a rat model (P1, which corresponds to the mid-fetal and early premature period in humans), in the acute phase at the molecular and cellular levels and in the chronic time frame, examining the subsequent structural reorganization level
Even though pups showed restlessness, shortness of breath, convulsive twitching of the whole body, and general cyanosis during the hypoxia, the pH blood values were maintained within the physiological range (Figure 1B), and shortly after the hypoxia, pups looked seemingly healthy and behaved ageappropriately
Summary
Perinatal cerebral hypoxia-ischemia and preterm birth are the most common causes of neurological disorders or impaired brain function of developmental origin (Volpe, 2012; Vohr, 2014; Laptook, 2016; Vanes et al, 2021). Perinatal Hypoxia Signature on Brain and Behavior or later in life (Johnson, 2011; Franz et al, 2018). Despite the multifactorial and combinatorial etiology (genetic, trophic, infectious, inflammatory, ante- or postnatally), the most frequently found periventricular white matter injury, commonly results from hypoxic-ischemic reperfusion failure (Liu et al, 2013; Clowry et al, 2014; Millar et al, 2017). The highest vulnerability of the human brain to hypoxic injuries is between 22- and 34 weeks of gestation, at the stage of intensive cell migration, glial cell proliferation, axon guidance, synaptogenesis, and dendrite and connectivity elements differentiation. The time frame from postnatal day (P) 1 to P3 is approximately equivalent to the period of 22–32 weeks of gestation (wg) for human brain development, based on morphogenetic processes, such as proliferation and migration, while P7-10 approximately correspond to 32–40 wg according to vasculogenesis and time of six-layered cortex formation. P40 approximately corresponds to the maturation of interneurons and approximately P60, corresponds to early adulthood cortex (Semple et al, 2013)
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