Abstract
Whilst the brain is assumed to exert homeostatic functions to keep the cellular energy status constant under physiological conditions, this has not been experimentally proven. Here, we conducted in vivo optical recordings of intracellular concentration of adenosine 5’-triphosphate (ATP), the major cellular energy metabolite, using a genetically encoded sensor in the mouse brain. We demonstrate that intracellular ATP levels in cortical excitatory neurons fluctuate in a cortex-wide manner depending on the sleep-wake states, correlating with arousal. Interestingly, ATP levels profoundly decreased during rapid eye movement sleep, suggesting a negative energy balance in neurons despite a simultaneous increase in cerebral hemodynamics for energy supply. The reduction in intracellular ATP was also observed in response to local electrical stimulation for neuronal activation, whereas the hemodynamics were simultaneously enhanced. These observations indicate that cerebral energy metabolism may not always meet neuronal energy demands, consequently resulting in physiological fluctuations of intracellular ATP levels in neurons.
Highlights
Whilst the brain is assumed to exert homeostatic functions to keep the cellular energy status constant under physiological conditions, this has not been experimentally proven
We observed that in vivo intracellular adenosine 5’-triphosphate (ATP) levels in cortical neurons decreased under local electrical stimulation, which was compatible with the results of a previous ex vivo report[11], whereas hemodynamic responses were induced in terms of local brain energy homeostatic functions
Fiber photometric recordings and wide-field microscopic imaging revealed that global fluctuations in intracellular ATP levels of cortical neurons depend on the sleep-wake states of animals, presumably affected by local and global brain energy homeostatic mechanisms
Summary
Whilst the brain is assumed to exert homeostatic functions to keep the cellular energy status constant under physiological conditions, this has not been experimentally proven. Energy homeostasis is crucial for enabling vital cellular activities In the brain, such homeostatic mechanisms are often described as “neurometabolic coupling” (NMC) between high-frequency neuronal oscillations that are involved in energy expenditure and hemodynamics or glucose metabolism[1,2,3,4]. These global parallel dynamics of energy producing and consuming activities across the sleep-wake states could be brought about by the brain monoaminergic systems[5,9] Under these local and global brain energy homeostatic mechanisms, it is hypothesized that the cellular energy status in the brain could be maintained constant across the sleep-wake states of animals and cellular energy depletion could be prevented in all physiological conditions. Fiber photometric recordings and wide-field microscopic imaging revealed that global fluctuations in intracellular ATP levels of cortical neurons depend on the sleep-wake states of animals, presumably affected by local and global brain energy homeostatic mechanisms. Simultaneous in vivo recording of neuronal activity and cerebral hemodynamics could help us understand the unique characteristics of intracellular ATP dynamics in neurons and mechanisms of brain energy homeostasis as a whole
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