Metabolic Regulation of Clock Neurons in the Rat Suprachiasmatic Nucleus

The circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) is mostly entrained by photic input to synchronize daily rhythms of physiological, endocrine, metabolic, and behavioral activities in mammals. The SCN can also be entrained by non-photic cues, such as behavioral activity and social interaction. Recent developments also indicate that metabolic signals such as the availability of glucose can act on the SCN to modulate the circadian phase and response to light. While evidence suggests an indirect action of glucose on the circadian clock, we have recently demonstrated that the SCN neurons are sensitive to metabolic regulation. In particular, energy supply from both glycolysis and oxidative phosphorylation is needed to fuel the Na/K pump to regulate excitability and [Na+]i homeostasis. Importantly, while mitochondrial inhibition blocks Na/K pumps to increase [Na+]i in all SCN neurons, it also activates a K+ conductance in a subset of SCN neurons to inhibit their firing rates, suggesting two different metabolic phenotypes in the SCN neurons.. Indeed, the rat SCN can be distinguished into two independent oscillators, the AVP-containing neurons in the dorsomedial SCN (dmSCN) and the VIP-containing neurons in the ventrolateral SCN (SCN). Studies from forced desynchronized rats indicate that the vlSCN and dmSCN oscillators may become dissociated from each other to drive distinct rhythms such as locomotor activity, melatonin release, core body temperature, and sleep rhythms. As such, misalignment of vlSCN and dmSCN at the time of light stimulation may impair the ability of light to phase shift the locomotor activity. Our preliminary results suggest that the two different metabolic phenotypes in the SCN neurons correspond to the dmSCN and vlSCN oscillators. We hypothesize that metabolic effects on the circadian clock in the SCN may be due to the misalignment of dmSCN and vlSCN oscillators as a result of differential responses to metabolic stress. With this hypothesis in mind, this three years project aims to investigate metabolic regulation of SCN neurons, with special efforts to characterize metabolic phenotype between dmSCN and vlSCN neurons. In the first year, we will investigate the role of glycolysis metabolism in the regulation of excitability and [Na+]i and [Ca2+]i homeostasis in the SCN neurons. In the second and third years, we will determine the effects of glucose on the SCN neurons, and investigate the role of KATP channels (as well as Na/K pumps) in mediating differential metabolic responses to metabolic stress such as mitochondrial inhibition and glucoprivation.

Project ID:PC10308-0674
External Project ID:MOST103-2320-B182-007