Abstract
The two sister peptides, pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) and their receptors, the PAC1 –and the VPAC2 receptors, are involved in regulation of the circadian timing system. PACAP as a neurotransmitter in the retinohypothalamic tract (RHT) and VIP as a neurotransmitter, involved in synchronization of SCN neurons. Behavior and physiology in VPAC2 deficient mice are strongly regulated by light most likely as a result of masking. Consequently, we used VPAC2 and PAC1/VPAC2 double mutant mice in comparison with PAC1 receptor deficient mice to further elucidate the role of PACAP in the light mediated regulation of behavior and physiology of the circadian system. We compared circadian rhythms in mice equipped with running wheels or implanted radio-transmitter measuring core body temperature kept in a full photoperiod ((FPP)(12:12 h light dark-cycles (LD)) and skeleton photo periods (SPP) at high and low light intensity. Furthermore, we examined the expression of PAC1- and VPAC2 receptors in the SCN of the different genotypes in combination with visualization of PACAP and VIP and determined whether compensatory changes in peptide and/or receptor expression in the reciprocal knockouts (KO) (PAC1 and VPAC2) had occurred. Our data demonstrate that in although being closely related at both ligand and receptor structure/sequence, PACAP/PAC1 receptor signaling are independent of VIP/VPAC2 receptor signaling and vice versa. Furthermore, lack of either of the receptors does not result in compensatory changes at neither the physiological or anatomical level. PACAP/PAC1 signaling is important for light regulated behavior, VIP/VPAC2signaling for stable clock function and both signaling pathways may play a role in shaping diurnality versus nocturnality.
Highlights
In mammals, the brain’s biological clock located in the suprachiasmatic nucleus (SCN) [1] generates circadian rhythms in physiology and behavior of approximately 24 h. 10–20.000 neurons constitute the neuronal network of the SCN, and the individual neurons express a molecular clockwork based on positive–and negative feedback loops of so-called clock proteins and their respective genes [2]
The ventral SCN receives retinal input via the retinohypothalamic tract (RHT) which daily entrains the clock to light [12, 13], and VIPergic neurons located in this part of the SCN project both within and outside the nucleus [6]
During a full photoperiod of 12:12 h LD at 300 lux followed by a period of constant darkness (DD) we confirmed that PAC1 deficient mice entrained to the LD cycle and showed stable nocturnal activity during DD
Summary
The brain’s biological clock located in the suprachiasmatic nucleus (SCN) [1] generates circadian rhythms in physiology and behavior of approximately 24 h. 10–20.000 neurons constitute the neuronal network of the SCN, and the individual neurons express a molecular clockwork based on positive–and negative feedback loops of so-called clock proteins and their respective genes [2]. The brain’s biological clock located in the suprachiasmatic nucleus (SCN) [1] generates circadian rhythms in physiology and behavior of approximately 24 h. PAC1- and VPAC2 receptors in light regulated behavior in the SCN need to be synchronized. Mice lacking either VIP or VPAC2 receptors have similar phenotype. Both strains of mice become arrhythmic in constant darkness but show stable nocturnal activity during normal light-dark photoperiods. The ventral SCN receives retinal input via the retinohypothalamic tract (RHT) which daily entrains the clock to light [12, 13], and VIPergic neurons located in this part of the SCN project both within and outside the nucleus [6]. The VIPergic neurons are hypothesized to be important for relaying photic information in light regulated behavior [14]
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