Brain Circadian Oscillators and Redox Regulation in Mammals

Abstract

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. Antioxid. Redox Signal. 20, 2955Signal. 20, -2965

Role of the Nrf2 signaling system in health and disease

“…In humans and other mammals, circadian biological oscillations -with a period of about 24 h -influence a variety of behavioral and physiological processes pertaining to sleep, metabolism, immune function, etc. (74)(75)(76)(77)(78). Recently, it has been found that redox-dependent processes participate in the circadian rhythms along with genetic timekeeping clock processes (75,76,78,79), which supports possible participation of the Nrf2 pathway as it pertains to response to cellular redox status (74,77,(80)(81)(82).…”

Circadian rhythm of redox state regulates membrane excitability in hippocampal CA1 neurons

“…An intrinsic, self‐sustained circadian oscillation in SCN redox couples was detected. That novel study also found that redox oscillation could regulate SCN neuronal excitability through non‐transcriptional modulation of K + channels (Gillette & Wang, ; Wang et al., ).…”

Circadian rhythm and sleep-wake systems share the dynamic extracellular synaptic milieu

“…Conversely, transplanting fetal SCN tissue back into the brain after SCN lesions can restore circadian rhythms (DeCoursey and Buggy, 1986, Lehman et al, 1986, Ralph, 1996). The SCN continues to generate 24 h rhythms in neuronal activity, neuropeptide secretion, and metabolism when isolated in vitro (Gillette and Reppert, 1987, Shibata and Moore, 1988, Prosser and Gillette, 1989, Herzog, 2007, Gillette and Wang, 2014). Together with many other lines of data, these results support the SCN’s role as the master circadian clock.…”