Roles of Suprachiasmatic Nucleus VIP Cells in the Control of Physiological Rhythms

UoM administered thesis: Phd

Abstract

All mammals possess an internal timing system, a biological clock, to allow them to respond to the predictable daily changes in the global environment arising from the earth’s rotation relative to the sun. In mammals the central clock is located in the suprachiasmatic nucleus of the hypothalamus (SCN); receiving input from the eyes to provide a daily timing signal, and communicating this information to a multitude of physiological systems. The precise mechanisms by which the SCN transmits this timing information downstream to multiple different timing systems are incompletely understood. Modern technological advances allow for the precise opto- or chemogenetic manipulation of different SCN cell types, based on characteristics such as their neuropeptide content, to establish the roles they play in circadian control of physiology. This thesis will focus on the role of SCN VIP cells, a principle neuropeptide population within the SCN, and their involvement in the control of physiology. Initially I assessed the electrophysiological impact of optogenetic SCN VIP cell activation on downstream neurons to establish what, if any, influence they exert over downstream neuronal populations. It was found that optogenetically identified neurons in the SPZ, PVN and ventral thalamus, key output areas of the SCN, show circadian variability in their firing patterns, with a relative absence of firing when SCN VIP neurons are most active. From this we established that SCN VIP neurons shape the firing profile of downstream neuronal populations. Following on from this I looked at the role of SCN VIP cells in the control of physiological systems that exert circadian variability; namely, corticosterone, heart rate, body temperature and locomotor activity. Chemogenetic manipulations in vivo resulted in time dependant changes to physiology. Principally, when SCN VIP neurons are inhibited during their peak activity phase, there was an increase in circulating corticosterone, implicating SCN VIP cells in the suppression of corticosterone prior to the daily rise. Additionally, these experiments revealed a role of SCN VIP cells in the control of heart rate. Finally I assessed the efficacy of genetically encoded optical reporters, specifically the calcium indicator GCaMP6, to measure circadian changes in neural activity in acute ex vivo slices. Rhythms in intracellular calcium were successfully recorded in dorsal SCN neurons, but were substantially disrupted in ventral SCN neurons, eliminating this avenue as a suitable technique for recording circadian variation in populations of SCN neurons. This thesis adds to the growing body of work positing SCN VIP neurons as not only input mediators within the SCN network, but also a key transmitter of daily timing information to key physiological systems.

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Original languageEnglish
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Award date1 Aug 2021