Is there a role for NF-κB in the suprachiasmatic circadian clock?

Circadian rhythms are recurring patterns in behavioural, physiological, and other parameters that display periods of approximately every twenty four hours. The molecular basis of the circadian timekeeping involves clock genes which act as transcription factors in a serious of feedback loops. Disruption of clock genes in transgenic models leads to dysregulation of the temporal architecture of behaviour and physiology. The master circadian pacemaker is the suprachiasmatic nuclei (SCN) in the anterior hypothalamus. There are circadian oscillators in numerous brain areas and peripheral organs and tissues. NF-κB is composed of dimers of members of the Rel family, including p65 (RelA), p50, p52, c-Rel and Rel B. NF-κB transcription factors are required for regulating cell survival and differentiation and also are important for inflammatory and immune responses. Dysregulation of this transcription factor has been shown to lead to inflammatory and autoimmune diseases. NF-κB is expressed in neurons and glia throughout the brain. We hypothesised that the NF-κB pathway may play a role in the generation and perhaps the phase setting of the circadian rhythms in the master mammalian circadian pacemaker. Understanding the role NF-κB system may play in the free running circadian clock, may be of great importance in understanding the effects of ageing, neuroinflammation and neurodegeneration on circadian rhythms. We set out to examine whether there might be a role for the NF-κB system in the master suprachiasmatic clock. We have examined expression of constituents of the pathway across the circadian cycle in the SCN, we examined the effects of pharmacological inhibition of the pathway on circadian processes in vivo and in vitro and have examined whether there is evidence for circadian regulation of NF-kB-mediated transcription in the SCN. Furthermore, we examined whether the NF-κB pathway played a role in ageing. Overall, we found no evidence that the NF-kB pathway is involved in the basal functioning of the SCN clock or in photic resetting. We do find some evidence that the NF-kB pathway may have a role in transducing immune events in the SCN. This data suggest that while the NF-kB pathway may be involved in circadian function in peripheral clocks, it does not appear to play a major role in the SCN