The suprachiasmatic nucleus (SCN) in the hypothalamus has been identified as a primary timekeeper of mammalian circadian rhythms, exhibiting a neuronal firing rate pattern near 24 h in length in the animals in an aperiodic environment. The neuronal rhythms of the SCN can be phase delayed in response to a pulse of light given in the early night, which correlates to a similar phase delay in the activity rhythms of rodents. Despite its central role as a circadian clock, the emerging picture of the SCN is one of internal heterogeneity. Little is known of how subregions contribute to the function of the SCN as a whole. Interestingly, in hamsters, a subset of cells within the SCN immunoreactive for a calcium binding protein, calbindin-D28k (CaBP), correlates with rhythm generation and seems to be particularly responsive to light stimulation. However, rats lack this distinct CaBP subregion. An analogous region may, instead, be a distinct subregion containing cells immunoreactive for calretinin (CN). The SCN retains its clock properties in vitro, exhibiting similar phase delays in response to the neurochemical signal of light, glutamate (GLU), during the early night. Downstream communication includes GLU binding to NMDA receptor, Ca2+ influx, nitric oxide (NO) production, and activation of Ca2+(I) via the ryanodine receptor (RyR). Light or GLU stimulation in the early night also up-regulates two clock genes, Per1 and Per2. This proposal will investigate the signaling pathway involved in light-induced up-regulation of Per1 and Per2 in early night.
The specific aims are: 1) To test the hypothesis that the light-induced up-regulation in Per1 and Per2 is localized in specific subregions of the SCN, 2) To test the hypothesis that the GLU induced up-regulation of Per1 and Per2 in early night is signaled through the NMDA-NO-RyR pathway, 3) To test the hypothesis that the light/GLU-induced up-regulation of Per2 requires expression of Per in early night. This study will contribute to understanding the light signaling mechanisms in the context of the cellular organization of the SCN.
| Beaulé, Christian; Mitchell, Jennifer W; Lindberg, Peder T et al. (2009) Temporally restricted role of retinal PACAP: integration of the phase-advancing light signal to the SCN. J Biol Rhythms 24:126-34 |
