[C03] Neurobiology and Brain & Physiology and Biorhythms

[C03-03] An inhibitory synaptic interaction causes the hysteresis of the mammalian circadian clock

*Kazuto Yamazaki¹, Kouichiro Uriu¹ (1. Institute of Science Tokyo (Japan))

Keywords:

circadian clock,coupled oscillators,limit cycle,dynamical systems

The circadian clock regulates 24-hour behavioral and physiological rhythms in organisms. In mammals, the central pacemaker of the circadian clock is located in the suprachiasmatic nucleus (SCN) in the brain. Autonomous circadian firing activities of the SCN neurons are generated by the transcription-translation feedback loops (TTFL) of clock genes Period (Per) and Cryptochrome. These SCN neurons interact with each other with various neurotransmitters, including vasoactive intestinal peptide (VIP). The VIP neurons reside in the ventral core region of the SCN and receive light inputs from the retina. The light information is then transferred to the dorsal shell region via VIP. Furthermore, most SCN neurons produce gamma-aminobutyric acid (GABA) which inhibits firing activities of post-synaptic neurons. Although these neuronal interactions have been considered to regulate the synchronization of circadian rhythms in the SCN, the interplay between VIP and GABA signaling is not fully understood. Here we develop a mathematical model that describes the interactions between core and shell neurons in the SCN with these neurotransmitters. We describe the TTFL of Per and firing rates of the SCN neurons by using differential equations. Firing activity of neurons increases the calcium levels, which induce the transcription of Per through the activation of a transcription factor CREB. We assume that PER protein decreases the firing rate by activating ion channels for hyperpolarization. VIP activates CREB thereby induces Per transcription, while GABA decreases the firing rate, repressing Per transcription. We optimize the parameters so that the SCN neurons maintain rhythms with nearly 24-hour period, light stimulation induces the phase shifts of the clock, and oscillation is damped in the presence of an inhibitor of neuronal activity as in previous experiments. We find that the interaction via VIP causes in-phase synchronization between the core and shell neurons. As the strength of GABA signaling increases, the phase relationship between them changes from in-phase to anti-phase. Furthermore, we find the coexistence of two stable synchronized states with different periods near the boundary where the phase relationship changes. These results suggest that GABA contributes to a hysteresis known as the after effect, a phenomenon in which the SCN retains the period of a previously experienced light-dark cycle in the subsequent constant darkness for a long time.