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Abstract
The vagus nerve transmits interoceptive information from visceral organs to the nucleus of the solitary tract (NTS) to regulate autonomic reflexes, food intake and convey internal status to the brain. The primary afferent terminals of the vagus terminate within the NTS and transmit visceral signals through glutamate release. Glutamate, the most abundant excitatory neurotransmitter in the brain, is controlled by countless factors including, hormones, temperature, and circadian rhythms to modulate incoming signals. This thesis provides the principal investigation into the effects of circadian rhythms, glucocorticoids, and TRPM3 activation on vagal afferent signaling and synaptic transmission in the NTS. In Chapter 2, I investigate the role of circadian rhythms in controlling synaptic neurotransmission and cellular excitability. I determined that action potential dependent and independent glutamate neurotransmission onto NTS neurons showed circadian rhythmicity with peak release during the light phase. This oscillation in glutamate was sufficient to drive rhythmicity in postsynaptic action potential firing. In Chapter 3, I investigate the neurophysiological effect of corticosterone (CORT) within the NTS. I determined that CORT induced a rapid and sustained inhibition of glutamate neurotransmission indicating that glucocorticoids provide negative feedback of vagal afferent signals. This effect required activation of the glucocorticoid receptor, downstream signaling cascades involved in endocannabinoid synthesis, and activation of presynaptic CB1 receptors. In Chapter 4, I investigated the role of TRPM3 in regulating the activity vagal afferent neurons. I determined that TRPM3 mediates a calcium current induced by the neurosteroid pregnenolone sulphate in nodose ganglia neurons. At central afferent terminals, activation of TRPM3 enhanced spontaneous glutamate release, yet its presence was not required for the expression of asynchronous glutamate release. Finally, I found that blockade of TRPM3 inhibits spontaneous release and reduces the temperature sensitivity of vagal afferent glutamate release at physiologically relevant temperatures. Collectively, these findings demonstrate that endogenous signals have robust control over vagal afferent synaptic release and throughput indicating a potential role for circadian rhythms, glucocorticoids, and temperature in influencing incoming visceral signals and physiological output of the parasympathetic nervous system.
