Behaviors, such as sleeping, foraging, and learning, are controlled by different regions of the rat brain, yet they occur rhythmically over the course of day and night. They are aligned adaptively with the day‐night cycle by an endogenous circadian clock in the suprachiasmatic nucleus (SCN), but local mechanisms of rhythmic control are not established. The SCN expresses a ~24‐hr oscillation in reduction‐oxidation that modulates its own neuronal excitability. Could circadian redox oscillations control neuronal excitability elsewhere in the brain? We focused on the CA1 region of the rat hippocampus, which is known for integrating information as memories and where clock gene expression undergoes a circadian oscillation that is in anti‐phase to the SCN. Evaluating long‐term imaging of endogenous redox couples and biochemical determination of glutathiolation levels, we observed oscillations with a ~24 hr period that is 180° out‐of‐phase to the SCN. Excitability of CA1 pyramidal neurons, primary hippocampal projection neurons, also exhibits a rhythm in resting membrane potential that is circadian time‐dependent and opposite from that of the SCN. The reducing reagent glutathione rapidly and reversibly depolarized the resting membrane potential of CA1 neurons; the magnitude is time‐of‐day‐dependent and, again, opposite from the SCN. These findings extend circadian redox regulation of neuronal excitability from the SCN to the hippocampus. Insights into this system contribute to understanding hippocampal circadian processes, such as learning and memory, seizure susceptibility, and memory loss with aging.

Oxidation-reduction reactions are essential to life as the core mechanisms of energy transfer. A large body of evidence in recent years presents an extensive and complex network of interactions between the circadian and cellular redox systems. Recent advances show that cellular redox state undergoes a ~24-h (circadian) oscillation in most tissues and is conserved across the domains of life. In nucleated cells, the metabolic oscillation is dependent upon the circadian transcription-translation machinery and, vice versa, redox-active proteins and cofactors feed back into the molecular oscillator. In the suprachiasmatic nucleus (SCN), a hypothalamic region of the brain specialized for circadian timekeeping, redox oscillation was found to modulate neuronal membrane excitability. The SCN redox environment is relatively reduced in daytime when neuronal activity is highest and relatively oxidized in nighttime when activity is at its lowest. There is evidence that the redox environment directly modulates SCN K channels, tightly coupling metabolic rhythms to neuronal activity. Application of reducing or oxidizing agents produces rapid changes in membrane excitability in a time-of-day-dependent manner. We propose that this reciprocal interaction may not be unique to the SCN. In this review, we consider the evidence for circadian redox oscillation and its interdependencies with established circadian timekeeping mechanisms. Furthermore, we will investigate the effects of redox on ion-channel gating dynamics and membrane excitability. The susceptibility of many different ion channels to modulation by changes in the redox environment suggests that circadian redox rhythms may play a role in the regulation of all excitable cells.

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