The circadian system A regulatory feedback network of periphery and brain

The earth revolves around the sun while it rotates on its axis once every 24 hours, exposing all organisms on earth to alternating cycles of light and darkness. In mammals, a central autonomous pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) drives rhythmic behavioral, neuroendocrine and autonomic output, providing a daily organization to physiology. In this thesis we investigate the role of the SCN as part of a circadian network, integrating peripheral feedback in order to effectively regulate day-night fluctuations in physiological functions.
We first provide evidence that the SCN is incorporated in a neuronal feedback circuit arising from the nucleus tractus solitarius (NTS), modulating cardiovascular reactivity. We then demonstrate the SCN is key in mediating the early side effects of olanzapine, an antipsychotic drug, on cardiovascular function. Shifting our focus to metabolic feedback, we demonstrate the SCN does not depend exclusively on the Arcuate nucleus (ARC) or NTS to obtain information on the body’s metabolic status. The intergeniculate leaflet (IGL) can also transmit metabolic information it receives from the NTS and Nucleus Gracilis. Investigating reciprocal connections between the ARC and SCN, we show their interaction is essential for the expression of circadian physiological rhythms. Finally, we demonstrate the SCN may form part of a Kisspeptin feedback network to adequately time the reproductive cycle. We conclude that these multiple intertwined feedback loops of the circadian system make it robust and adaptable, capable of withstanding brief erroneous feedback. Long-term conflicting feedback or ill-timed behavior will increase an individuals’ susceptibility to disease.