Intracellular ATP levels in mouse cortical excitatory neurons varies with sleep–wake states

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.

Global waves synchronize the brain’s functional systems with fluctuating arousal

“…The relevant biology is wide-ranging and likely includes many metabolic and nonneuronal process that slowly modulate neuronal excitability [see ( 8 , 28 ) and references therein]. Although reference limits preclude proper treatment of this literature, we note likely essential roles for redox metabolism ( 90 , 91 ), ion fluxes ( 3 , 92 ), and glial physiology [including upstream of the neurovascular cascade ( 4 , 93 )]. These interrelated factors are each influenced by neuromodulators that track behavioral state over infra-slow time scales ( 4 , 37 , 94 ).…”

Diurnal variation in neuronal chloride levels and seizure susceptibility, in neocortex, reflecting changes in activity of chloride-cation-cotransporters

“…Our data add to the growing list of diurnal fluctuations in neuronal function, including changes in firing rates [35][36][37] , in the number, strength and structure of synapses [38][39][40][41] , metabolic state 42 , gene expression and protein phosphorylation 43,44 . Given the direct coupling of the changes in [Cl -]i to the biochemical state of neurons, and the well-established role of synaptic inhibition in shaping all manner of neuronal activity [45][46][47][48][49][50][51] , we suggest that the changes we describe here, are among the root determinants of the distinct neuronal activity patterns that constitute the cycle of brain states through the day.…”

“…These fluctuations in [Cl - ] i are also associated with large changes in the excitability of the network at different times of the day, consistent with the well-recognized clinical phenomenon of circadian clustering of seizures 30–33 . These data add to the growing list of diurnal fluctuations in neuronal function, including changes in firing rates 34–36 , in the number, strength and structure of synapses 37–40 , metabolic state 41 , gene expression and protein phosphorylation 42,43 . Given the direct coupling of the changes in [Cl - ] i to the biochemical state of neurons, and the well-established role of synaptic inhibition in shaping all manner of neuronal activity 44–50 , we suggest that the changes we describe here, are among the root determinants of the distinct neuronal activity patterns that constitute the cycle of brain states through the day.…”

Dual imaging of dendritic spines and mitochondria in vivo reveals hotspots of plasticity and metabolic adaptation to stress

“…Neurons can elevate their own glycolysis in response to stimulation ( Dıaz-Garcıa et al, 2017 ); yet they depend on dendritic mitochondria to fuel protein synthesis in specific synapses, indicating the crucial importance of local mitochondrial ATP synthesis ( Rangaraju et al, 2019 ). The balance of glycolysis and oxidative phosphorylation in neurons is not understood and could vary between topography, states of rest and experience ( Yellen, 2018 ) as do intracellular ATP levels between sleep-wake states ( Natsubori et al, 2020 ). Neurons might temporarily use glycolysis over oxidative phosphorylation at specific synapses because it provides faster resupply of energy and lesser oxidative stress ( Yellen, 2018 ).…”

“…A majority of recent in vivo studies focused on pre-synaptic mitochondria in terminal experiments ( Lee et al, 2018 ). The currently known mechanisms regulating post-synaptic mitochondria structure and function are based on ex vivo and in vitro experiments that do not reproduce local and global brain energy homeostasis ( Natsubori et al, 2020 ).…”