The control and functions of spontaneous glutamate release from vagal afferent neurons

Rachel A. Arnold

doi:10.7273/000007886

The vagus nerve, or tenth cranial nerve, is the most widely branching nerve in the body; it innervates the visceral organs, controlling vital functions such as food intake and gastrointestinal reflexes, among others. Vagal afferent neurons provide the major sensory input from the visceral organs to the nucleus of the solitary tract (NTS) in the brainstem. The central and peripheral terminals of vagal afferent neurons express various receptors and ion channels to sense signals from the gastrointestinal tract and circulating hormones. Vagal afferents form strong synaptic contacts onto second-order NTS neurons via activity-dependent evoked and activity-independent spontaneous glutamate release. Spontaneous release from vagal afferent neurons is uniquely controlled by the ion channel TRPV1 (transient receptor potential vanilloid type 1), which is expressed in a majority of vagal afferent fibers. Spontaneous release is also controlled by circulating satiety hormones such as cholecystokinin, as well as endogenous circadian rhythms. The goal of my dissertation was to examine the points of control and the importance of spontaneous glutamate release from vagal afferent neurons, which I have achieved in the three following chapters. In Chapter 2, I examined the functional overlap between vesicles used for evoked versus spontaneous glutamate release. Despite the clear functional differences between spontaneous and evoked release processes, there exists a common pool of presynaptic vesicles and postsynaptic NDMA receptors that serves both forms of release from vagal afferent neurons. In Chapter 3, I explored the cellular mechanisms that mediate the effects of CCK receptor activation on neuronal activity and spontaneous glutamate release. I pharmacologically dissected the interaction between the CCK1R and TRPV1, showing that TRPV1 enhances the effect of CCK on vagal afferent signaling and information transfer to the NTS in the low affinity state of the CCK1R that couples to TRPV1 via a non-vanilloid binding site. Finally, in Chapter 4 I examined the influence of the time of day on vagal afferent responses to CCK. Despite previous findings that food intake, CCK-mediated satiety, and vagal to NTS neurotransmission are coordinated by circadian rhythms, I found that the vagal afferent neurons exhibit constant responsiveness to CCK regardless of the time of day. Collectively, these findings demonstrate how vagal afferent neurons integrate various signal types to control spontaneous glutamate release, as well as how different forms of release are organized within the synapse to serve parallel pathways for information transfer. Overall, spontaneous glutamate release provides a strong and scalable signal that conveys a wide range of information to the NTS to ultimately shape NTS signal integration, thereby controlling vagally-mediated reflexes that are critical for health and survival.

The control and functions of spontaneous glutamate release from vagal afferent neurons

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