The selfish yet forgetful brain: Stable cerebral oxygen metabolism during hypoglycemia but impaired memory consolidation

Abstract

The continuous supply of glucose and oxygen is essential for healthy brain function. Accordingly, the Selfish Brain Theory proposes that the human brain prioritizes its own energy demands, making it less vulnerable to fluctuations in systemic energy availability. Although studies have reported decreases in cerebral glucose metabolism, alternative energy sources other than glucose might be oxidized for ATP production. However, cerebral oxygen metabolism (CMRO2) has never been quantified across the human brain. In this study, we investigated the influence of insulin-induced hypoglycemia on CMRO2 in healthy male participants. Additionally, we explored the prolonged effects of hypoglycemia on cognitive function following the restoration of euglycemia. We found that CMRO2 remained stable under hypoglycemia, even at blood glucose levels below 49 mg/dL. Interestingly, we detected a significant increase in cerebral blood flow (CBF) of up to 11%, particularly in regions involved in higher cognitive processing. Despite stable rates of oxygen metabolism, we identified a selective impairment in memory consolidation following hypoglycemia, even after normal glucose levels were restored, with no effects observed in memory encoding or attention. In favor of the Selfish Brain Theory, the stability in CMRO2 suggests that the brain efficiently shifts to alternate energy pathways under hypoglycemia, potentially using astrocytic glycogen. Despite this metabolic flexibility, our results indicate that prior hypoglycemia imposes long-lasting effects on memory consolidation, possibly linked to glycogen depletion and impaired glutamate synthesis. In summary, our study suggests that clinical states of hypoglycemia pose a critical impact on patient brain health and functioning.