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2014 ; 20
(18
): 2955-65
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Brain circadian oscillators and redox regulation in mammals
#MMPMID24111727
Gillette MU
; Wang TA
Antioxid Redox Signal
2014[Jun]; 20
(18
): 2955-65
PMID24111727
show ga
SIGNIFICANCE: Functional states of organisms vary rhythmically with a period of
about a day (i.e., circadian). This endogenous dynamic is shaped by day-night
alternations in light and energy. Mammalian circadian rhythms are orchestrated by
the hypothalamic suprachiasmatic nucleus (SCN), a brain region specialized for
timekeeping. These autonomous ~24-h oscillations are cell-based, requiring
transcription-translation-based regulation. SCN circadian oscillations include
the maintenance of intrinsic rhythms, sensitivities to input signals, and
generation of output signals. These change predictably as time proceeds from dawn
to day, dusk, and through the night. SCN neuronal excitability, a highly
energy-demanding process, also oscillates over ~24 h. The nature of the
relationship of cellular metabolism and excitability had been unknown. RECENT
ADVANCES: Global SCN redox state was found to undergo an autonomous circadian
rhythm. Redox state is relatively reduced in daytime, when neuronal activity is
high, and oxidized during nighttime, when neurons are relatively inactive. Redox
modulates neuronal excitability via tight coupling: imposed reducing or oxidizing
shifts immediately alter membrane excitability. Whereas an intact
transcription-translation oscillator is necessary for the redox oscillation,
metabolic modulation of excitability is too rapid to be under clockwork control.
CRITICAL ISSUES: Our observations lead to the hypothesis that redox state and
neuronal activity are coupled nontranscriptional circadian oscillators in SCN
neurons. Critical issues include discovering molecular and cellular substrates
and functional consequences of this redox oscillator. FUTURE DIRECTIONS:
Understanding interdependencies between cellular energy metabolism, neuronal
activity, and circadian rhythms is critical to developing therapeutic strategies
for treating neurodegenerative diseases and brain metabolic syndromes.
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