Understanding the Impact of Metabolic Alterations on Brain Development

Abstract

Evaluating the metabolic requirements of neural stem cells, including the balance between glucose and ketone body utilisation, is important in understanding their role in brain development and disease. This study examined how changes in metabolism affect brain development by testing the hypothesis that glucose is crucial for neural stem cell growth and survival, while ketone bodies act as an important energy source during glucose deprivation. Additionally, it was hypothesised that genomic analysis of glycolytic and ketolytic genes in neuroblastoma would reveal increased glycolytic expression linked to MYCN amplification and worse prognosis, while higher ketolytic expression would correlate with better outcomes. To address these hypotheses, the aims were to perform a literature review to clarify the roles of glucose and ketone bodies in brain development, disease, and therapeutic potential, to analyse glycolytic and ketolytic gene expression in neuroblastoma to understand their role in tumour progression and prognosis, with relevance to neural stem cell metabolism, and, to conduct in vitro experiments to evaluate how glucose deprivation and ketone body supplementation impacts neural stem cell density, metabolic viability, and cellular metabolism. Findings demonstrated that glucose, the primary energy source for neural stem cells, is critical for homeostasis, with deprivation significantly reducing cell density and viability, whereas ketone body supplementation elicited only minor effects. Genomic analysis of neuroblastoma revealed increased glycolytic gene expression in MYCN-amplified metastatic tumours, correlating with poor prognosis, and lower ketolytic gene expression associated with better survival outcomes. These results demonstrate the essential role of metabolic pathways in neural stem cell behaviour and brain development, highlighting potential metabolic targets for therapeutic interventions and prognosis prediction in neurological and oncological conditions. These studies therefore contribute to a better understanding of neural stem cell metabolism and its implications for development, disease, and treatment.