Loss of Estrogen‐Related Receptor Alpha (ESRRA) Impairs Neuronal Mitochondrial Function and Results in Disturbed Sleep and Neural Oscillatory Patterns

Abstract

ESRRA is an orphan nuclear receptor enriched in metabolically active tissues and has been known to affect the transcription of a set of genes that regulate mitochondrial bioenergetics in peripheral organs. Of note, ESRRA is also abundantly expressed in the brain, but the functional role of brain ESRRA remains poorly understood. To test the role of ESRRA on energy metabolism in neurons, we performed the Seahorse assay in mouse primary cortical neurons with or without ESRRA expression and found that neurons lacking ESRRA have significantly reduced cellular respiration compared to control neurons, indicating that loss of ESRRA decreases mitochondrial oxidative capacity and thus neuronal energy production. We have previously reported that global ESRRA null (KO) displayed markedly reduced locomotor activity (home cage vibration plate p<0.05, wheel running p<0.001), suggesting that these mice do display an energy deficit as a result of this manipulation. Based on the commonly appreciated role of sleep in the replenishment of energy stores for normal brain function, we hypothesized that reduced brain energy levels caused by genetic loss of ESRRA would lead to hypersomnia and diminished neural oscillations, which may underlie hypolocomotion seen in ESRRA KO mice. To test this hypothesis, wireless electroencephalography/electromyography (EEG/EMG) devices were implanted in a cohort of ESRRA KO and wildtype (WT) mice and 24hr sleep state was recorded and scored. Sleep architecture analysis from 24‐hour wireless EEG/EMG recording revealed that ESRRA KO mice exhibit significantly increased non‐rapid eye movement (NREM) (p<0.05) sleep as well as disrupted circadian pattern of rapid eye movement (REM) (p<0.01) sleep compared to WT littermates. Power spectral analysis further revealed that high range gamma (40‐100Hz) (p<0.001) and alpha (9‐13Hz) (p<0.05) oscillations are significantly decreased while low range gamma (25‐40Hz) (p<0.05) and beta (13‐25Hz) (p<0.05) oscillations are increased in ESRRA KO mice. Our findings not only reveal a previously unappreciated role of ESRRA in regulating neuronal mitochondrial function, sleep‐wake cycle, and neural oscillations, but also support a novel concept that a single molecular cause of diminished brain energy levels can prolong sleep duration and results in aberrant REM sleep pattern.