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 PAC₁ 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 VPAC₂ 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 VPAC₂ 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.