The suprachiasmatic nuclei (SCN) of the hypothalamus consists of about 20,000 neurons that function together to produce an innate biological clock in mammals. This clock is maintained by transcriptional and translational feedback loops of circadian gene expression including Period 1 (Per1). SCN rhythms are set by and synchronized with the external environment by light signaling pathways including vasoactive intestinal peptide (VIP), which upregulates the expression of Per1 upon stimulation by light. Dysfunction in the circadian clock has been linked to various forms of depression and sleep disorders in humans, and has been shown to have dramatic behavioral consequences in animal models. This proposal will attempt to answer the following specific questions regarding the role of VIP in the SCN: First, how is the SCN organized in VIP and Vipr2 (VIP's receptor) knockout mice, and how does this organization account for the behavioral output? Second, what influence does wheel-running have on the behavioral characteristics of these animals? The behavioral role of VIP will be investigated using wheel-running and infrared motion detection in VIP- and Vipr2-deficient mice. A mPer1::GFP (green fluorescent protein) transgenic reporter line will be used to perform real-time circadian gene expression analyses by confocal microscopy in the SCN of VIP- and Vipr2-deficient mice. These are novel and highly successful approaches used in our laboratory and in conjunction with collaborators. Circadian clock dysfunction can dramatically affect human health. Seasonal Affective Disorder (SAD), for example, occurs when the human clock gets less light input during the winter months and affects up to 3% of the United States population every year. The disease is treated with light therapy and selective serotonin reuptake inhibitors (SSRI)-two modulators of VIP in mammals. VIP's essential role in photic entrainment implicates the peptide as a genetic applicant that could contribute greatly to circadian dysfunction. The knockout mouse models are the most extreme evidence of what could happen if the VIP or Vipr2 genes are altered by mutation or polymorphism. This evidence suggests that VIP-ergic signaling is important to human health, and that the study of the mouse model can grant valuable insight into the human clock and its capacity for dysfunction in circadian-linked disease. ? ? ?
| Ciarleglio, Christopher M; Axley, John C; Strauss, Benjamin R et al. (2011) Perinatal photoperiod imprints the circadian clock. Nat Neurosci 14:25-7 |
| Ciarleglio, Christopher M; Gamble, Karen L; Axley, John C et al. (2009) Population encoding by circadian clock neurons organizes circadian behavior. J Neurosci 29:1670-6 |
| Gamble, Karen L; Ciarleglio, Christopher M (2009) Ryanodine receptors are regulated by the circadian clock and implicated in gating photic entrainment. J Neurosci 29:11717-9 |
