These actions of timed arousal are accompanied by restoration of 24 h behavioral rhythms, despite the absence of a key SCN-synchronizing intercellular signal. This indicates that, in the Vipr2 −/− SCN, SVE downregulates the coupling opposing actions of GABA without alleviating its suppression of neuronal activity. A reduction in inhibitory GABA signaling is typically associated with increased firing rate, but unexpectedly, spiking in both VPAC 2-deficient and intact SCN is reduced following SVE. In contrast, neuronal activity suppressive actions of GABA are reduced in neurochemically intact SCN but remain largely unchanged in the Vipr2 −/− SCN.
In the neuropeptide signaling-deficient SCN, clock cell rhythmicity and synchrony are enhanced by this arousal cue but unaltered in the SCN of neurochemically intact mice. Here we show that, following timed physical exercise, inhibitory and cell-coupling opposition actions of GABA signaling are differentially altered in the mouse SCN. Further, evidence indicates that blockade of GABA–GABA A receptor signaling in the SCN can synchronize molecular clock rhythms in the SCN of Vip −/− mice 10, but whether GABA signaling is altered in the SCN as a consequence of SVE is unresolved. However, it is unknown whether SVE boosts SCN molecular clock rhythms and neuronal activity in neuropeptide signaling-deficient mice. Intriguingly, sustained 24 h rhythms in behavior can be restored in Vip −/− and Vipr2 −/− animals by the arousal-related cue of daily scheduled voluntary exercise (SVE) 21. Mice lacking VIP or VPAC 2 receptor do not express endogenous 24 h rhythms in behavior 13, 19, 20, while targeted deficiency in SCN VGAT expression attenuates mouse locomotor rhythms without altering their ~24 h period 16.
In adult mice lacking VIP ( Vip −/−) or VPAC 2 receptor ( Vipr2 −/−), SCN molecular clock and neuronal rhythms are blunted and temporally disorganized 7, 13, 14, 15, while knockout of the vesicular GABA transporter ( VGAT −/−) alters burst spiking of SCN neurons but does not affect molecular clock rhythms 16.Įnvironmental light and internal arousal are key cues (or Zeitgebers) that synchronize the SCN with the 24 h external world 17, 18. Two key SCN neurochemicals are the neuropeptide vasoactive intestinal polypeptide (VIP), acting via its cognate VPAC 2 receptor 7, 8, and GABA signaling via the GABA A receptor 9, 10, 11, 12. This daily rhythm in neuronal activity facilitates intercellular signaling and synchrony among autonomous SCN cellular oscillators, which is paramount for optimal circadian function 5, 6. In SCN neurons, the molecular clock drives 24 h rhythms in electrical activity, with higher frequencies of spike firing during the day than the night 3, 4. The molecular clock within these cells enables them to function as autonomous oscillators, each with its own circadian period 2. These findings illustrate the potential utility of regular exercise as a long-lasting and effective non-invasive intervention in the elderly or mentally ill where circadian rhythms can be blunted and poorly aligned to the external world.ĭaily rhythms in physiology and behavior are controlled by coordinated activity of clock cells in the brain’s suprachiasmatic nuclei (SCN) 1.
Interestingly, in both intact and neuropeptide signaling deficient animals, SVE reduces SCN neural activity and alters GABAergic signaling. We show that in mice with disrupted neuropeptide signaling, SVE promotes SCN clock cell synchrony and robust 24 h rhythms in behavior. Utilizing mouse models in which SCN intercellular neuropeptide signaling is impaired as well as those with intact SCN neurochemical signaling, we examined how daily scheduled voluntary exercise (SVE) influenced behavioral rhythms and SCN molecular and neuronal activities.
To date, the long-lasting effects of regular physical exercise on SCN clock cell coordination and communication remain unresolved. Molecular clock cells in the brain’s suprachiasmatic nuclei (SCN) use electrical and chemical signals to orchestrate their activity and convey time of day information to the rest of the brain and body. An underexplored and intriguing property of exercise is its actions on the body’s 24 h or circadian rhythms. Regular exercise is important for physical and mental health.