An essential role for peptidergic signalling in the control of circadian rhythms in the suprachiasmatic nuclei

Two structurally related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP), colocalized with glutamate in neurones of the retinohypothalamic tract, and vasoactive intestinal peptide (VIP), present in light-responsive cells of the suprachiasmatic nuclei (SCN), appear to play distinct and important roles in the control of mammalian circadian rhythms. Mice deficient in the PACAP-selective PAC(1) receptor exhibit altered responsiveness of the SCN clock to light-induced phase-shifts, but display robust circadian patterns of wheel-running behaviour. By contrast, our studies of mice lacking the VPAC(2) receptor, which responds to both PACAP and VIP, indicate that this receptor plays a critical role in rhythm generation in the SCN. The predominant factor determining wheel-running activity in VPAC(2) receptor null (Vipr2(-/-)) mice is 'masking' by light. Mutant animals re-entrain immediately to advances or delays in the light/dark cycle and do not exhibit robust circadian rhythms of behaviour when in constant darkness. The mice do not exhibit circadian expression of core clock genes (mPer1 , mPer2 , mCry1), or of the clock-controlled gene arginine vasopressin (AVP), in the SCN. We propose that VIP signalling between SCN neurones provides a paracrine reinforcing signal that is essential for sustained rhythm generation. The presence of VIP signalling in the SCN may explain why SCN neurones are capable of generating long-lasting self-sustained oscillations, whereas rhythmic clock gene expression in other tissues is dependent on periodic reinforcement by neural or hormonal signals.