A hVIPR transgene as a novel tool for the analysis of circadian function in the mouse suprachiasmatic nucleus.

Feb 27, 2003The European journal of neuroscience

Using a new genetic tool to study daily rhythm control in the mouse brain’s clock center

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Abstract

23.6% of arrhythmic SCN lesioned mice showed restored circadian activity rhythms after receiving hVIPR transgenic SCN grafts.

Neurons expressing the human VPAC2 receptor are distributed within the hypothalamic suprachiasmatic nuclei (SCN) and show circadian rhythmicity.
These neurons synchronize rhythmic expression of mPERIOD proteins, indicating their role in circadian function.
Nocturnal light exposure triggers specific mPER protein expression patterns in the SCN, suggesting photic responsiveness.
Transplanted prenatal SCN tissue from hVIPR transgenic mice survived and maintained expression of key markers in adult hosts.
The hVIPR transgene enables functional and anatomical identification of SCN neurons, aiding in circadian research.

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A mouse bearing a novel transgene encoding the human VPAC2 receptor (hVIPR; Shen et al. (2000) PNAS, 97, 11575-11580) was used to investigate circadian function in the hypothalamic suprachiasmatic nuclei (SCN). Neurons expressing hVPAC2R, detected by a beta-galactosidase (beta-GAL) tag, have a distinct distribution within the SCN, closely matching that of neurophysin (NP) neurons and extending into the region of peptide histidine isoleucine (PHI) cells. In common with NP and PHI cells, neurons expressing hVPAC2R are circadian in nature, as revealed by synchronous rhythmic expression of mPERIOD (mPER) proteins. A population of SCN cells not expressing PHI, NP or hVPAC2R exhibited circadian PER expression antiphasic with the rest of the SCN. Nocturnal light exposure induced mPER1 in the ventral SCN and mPER2 widely across the nucleus. Induction of nuclear mPER2 in hVPAC2R cells confirmed their photic responsiveness. Having established their circadian properties, we tested the utility of SCN neurons expressing the hVIPR transgene as functionally and anatomically explicit markers for SCN tissue grafts. Prenatal SCN tissue from hVIPR transgenic pups survived transplantation into adult CD1 mice, and expressed beta-GAL, PER and PHI. Over a series of studies, hVIPR transgenic SCN grafts restored circadian activity rhythms to 17 of 72 arrhythmic SCN lesioned recipients (23.6%). By using heterozygous hVIPR transgenic grafts on a heterozygous Clock mutant background we confirmed that restored activity rhythms were conferred by the donor tissue. We conclude that the hVIPR transgene is a powerful and flexible tool for examination of circadian function in the mouse SCN.

A hVIPR transgene as a novel tool for the analysis of circadian function in the mouse suprachiasmatic nucleus.

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