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1 Department of Psychiatry and Biobehavioral Sciences, University of California - Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: ccolwell{at}mednet.ucla.edu.
Previous studies indicate that light information reaches the suprachiasmatic nucleus (SCN)through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase activating peptide (PACAP). While the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors are only beginning to be understood. In order to investigate the functions of PACAP in vivo, we developed a mouse model in which the gene coding for PACAP was disrupted by targeted homologous recombination. Radioimmunoassay was used to confirm a lack of detectable PACAP protein in these mice. PACAP-deficient mice exhibited significant impairment in the magnitude of the response to brief light exposures with both light-induced phase delays and advances of the circadian system impacted. This mutation equally impacted phase shifts induced by bright and dim light exposure. Despite these effects on phase shifting, the loss of PACAP had only limited effects on the generation of circadian oscillations as measured by rhythms in wheel-running activity. Unlike melanopsin-deficient mice, the mice lacking PACAP exhibited no loss of function in the direct lightinduced inhibition of locomotor activity i.e. masking. Finally, the PACAP-deficient mice exhibited normal phase shifts in response to exposure to discrete dark treatments. The results reported here show that the loss of PACAP produced selective deficits in the light response of the circadian system.
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