Investigation of the role of neuronal glycolysis in the regulation of mammalian sleep

• Applicant: Professor Dr. Henrik Bringmann
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565312448

Sleep is a fundamental physiological state in all animals that possess a nervous system. Sleep is essential and disorders of sleep are widespread in modern societies posing an unmet medical and economical problem. Despite its importance, non-REM sleep, characterized by cortical neuronal slow oscillations, remains poorly understood at the biochemical and molecular levels. This project seeks to explore the influence of neuronal glycolysis on sleep regulation, building upon preliminary findings in C. elegans. Our previous work in C. elegans revealed an inhibition of neuronal glycolysis as a hallmark of sleep. Genetic manipulation of glycolysis indicates that downregulation of neuronal glycolysis promotes sleep, while upregulation of glycolysis is associated with decreased sleep, identifying PFKFB as a positive regulator of neuronal glycolysis and a negative regulator of sleep and FBPase as a negative regulator of glycolysis and a positive regulator of sleep. Our objective of this proposal is to translate these findings to mammals, by using mice, to investigate the impact of manipulating neuronal glycolysis on both non-REM and REM sleep. Conditional mutants with floxed alleles of glycolysis genes will be created using Cre recombinase to selectively delete genes in glutamatergic neurons, that are crucial for slow oscillations during sleep. We will test the hypotheses that PKM and PFKFB in glutamatergic neurons play an inhibitory role in sleep, and that FBP in glutamatergic neurons promotes sleep. Our aims hence involve generating conditional knockdowns for each gene and evaluating sleep behavior and EEG during baseline and recovery sleep after sleep deprivation. This research aims to identify crucial factors regulating neuronal glycolysis and their implications for sleep, contributing to a deeper biochemical understanding of sleep regulation mechanisms. The comprehensive approach, utilizing both behavioral tests and EEG, ensures a thorough investigation into the complex relationship between neuronal glycolysis and sleep in mammals, addressing a critical gap in our understanding of sleep biology. The study may offer insights into potential therapeutic strategies for sleep disorders by targeting neuronal glycolysis.

• DFG Programme: Research Grants