Pre‐ and early postnatal enriched environmental experiences prevent neonatal hypoxia‐ischemia late neurodegeneration via metabolic and neuroplastic mechanisms

Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia‐ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult‐onset neurodegenerative diseases. However, the impact of non‐pharmacologic strategies to attenuate HI‐induced brain glucose dysfunction is still underexplored. This study investigated the long‐term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In‐vivo cerebral metabolism was assessed by means of [18F]‐FDG micro‐positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18F]‐FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down‐regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth‐associated protein 43 was up‐regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI‐induced impairments that may contribute to functional decline and progressive late neurodegeneration. The long‐term effects of early environmental enrichment in an experimental model of neonatal hypoxia‐ischemia (HI) were studied. HI caused prolonged metabolic dysregulations in [18F]‐FDG uptake, metabolic brain network, and glucose transporter levels. Moreover, it induced changes in amyloid precursor protein and growth‐associated protein 43 levels. Enrichment during prenatal and lactation period, revealed a significant attenuation of metabolic failures, reduction of disturbances in proteins related to axonal plasticity as well as increment in spatial memory, compared with HI rats exposed to standard conditions. These results