Elsevier

Physiology & Behavior

Volume 136, September 2014, Pages 179-184
Physiology & Behavior

Channeling satiation: A primer on the role of TRP channels in the control of glutamate release from vagal afferent neurons

https://doi.org/10.1016/j.physbeh.2014.09.003Get rights and content

Highlights

  • Vagal afferents initiate homeostatic reflexes via strong glutamatergic synapses.

  • Vagal afferents release glutamate via multiple pathways.

  • Central thermosensitive TRP channels control quantal forms of glutamate release.

  • TRP channels and multiple release pathways allow for robust but plastic signaling.

Abstract

Obesity results from the chronic imbalance between food intake and energy expenditure. To maintain homeostasis, the brainstem nucleus of the solitary tract (NTS) integrates peripheral information from visceral organs and initiates reflex pathways that control food intake and other autonomic functions. This peripheral-to-central neural communication occurs through activation of vagal afferent neurons which converge to form the solitary tract (ST) and synapse with strong glutamatergic contacts onto NTS neurons. Vagal afferents release glutamate containing vesicles via three distinct pathways (synchronous, asynchronous, and spontaneous) providing multiple levels of control through fast synaptic neurotransmission at ST–NTS synapses. While temperature at the NTS is relatively constant, vagal afferent neurons express an array of thermosensitive ion channels named transient receptor potential (TRP) channels. Here we review the evidence that TRP channels pre-synaptically control quantal glutamate release and examine the potential roles of TRP channels in vagally mediated satiety signaling. We summarize the current literature that TRP channels contribute to asynchronous and spontaneous release of glutamate which can distinctly influence the transfer of information across the ST–NTS synapse. In other words, multiple glutamate vesicle release pathways, guided by afferent TRP channels, provide for robust while adaptive neurotransmission and expand our understanding of vagal afferent signaling.

Introduction

Primary vagal afferent neurons provide a direct neural pathway through which the status of peripheral organ systems (including the heart, lungs, and gastrointestinal tract) and satiety signals are relayed to the brain [1], [2], [3]. Vagal afferent neurons convey a broad range of stimuli which vary by information types, time-frames, and relative physiological urgencies. As a result, information transfer must be at once reliable and precise while maintaining plasticity to match autonomic function to the physiological state. To control information transfer, vagal afferents release the fast excitatory neurotransmitter glutamate via three distinct pathways: synchronous, asynchronous, and spontaneous (Fig. 1) [4]. The interplay between these multiple complementary vesicle release pathways allows for robust and precise information transfer which is also adaptable and plastic to changing physiological states.

Vagal afferent neurons are broadly divided into myelinated A-fibers, lightly myelinated Aδ-fibers, and unmyelinated C-fibers based off conduction velocity and histological analysis. C-fibers compose the majority of neurons in the vagus and robustly express the transient receptor potential vanilloid type 1 (TRPV1) ion channel thus conveying their sensitivity to capsaicin lesion [5]. Centrally vagal afferents converge with the facial (VII) and glossopharyngeal (IX) nerves to form the solitary tract (ST) bundle and innervate second-order NTS neurons [2]. Afferent innervation onto second-order NTS neurons is limited relative to central synapses; with as few as 1–5 discrete primary afferent inputs converging [6]. Further, convergent inputs are completely segregated based on their expression of TRPV1 or not [7]. This organizational schema allowed for the observation that the presence of TRPV1 in the central terminals predicts facilitated forms of quantal glutamate release; including higher frequencies of spontaneous and asynchronous quantal release compared to afferents lacking TRPV1 [4]. This activity-dependent asynchronous glutamate release prolongs the period of action potential driven release (from milliseconds to seconds) and extends the postsynaptic excitatory period despite frequency dependent depression (FDD) of synchronous glutamate release [4]. Furthermore, TRPV1, and likely other thermosensitive TRP channels, provide temperature sensitive calcium conductances which largely determine the rate of spontaneous vesicle fusion [8], [9]. We speculate that these additional vesicle release pathways contribute to the relative strength of C-fibers in activating autonomic reflex pathways, including those that control food intake and energy balance.

Here, we discuss the plasticity of vagal afferent signaling within the context of food intake and energy balance. We will discuss the different forms of glutamate release which define the adaptive nature of vagal afferent signaling and summarize evidence that thermosensitive TRP channels guide glutamate release pathways. Consideration of peripheral and central peptides and their effects on satiation through these glutamate release pathways will be given. In short, complementary vesicle release pathways, segregated innervation of vagal afferents, and presence of highly adaptable temperature sensitive TRP ion channels allow vagal afferent signaling to be predictive and reactive in order to efficiently maintain energy homeostasis. By elucidating the cellular mechanisms that enable the adaptive nature of vagal afferent, we hope to gain a better understanding of vagal afferent control of food intake and energy balance.

Section snippets

Spontaneous vesicle fusion and release

Spontaneous vesicle fusion is a stochastic but regulated process of neurotransmitter release which occurs independently of action-potential depolarization of the terminal (Fig. 1B, top panel) [10]. Individual vesicles fuse and are released probabilistically over time from pre-synaptic active zones. The average peak current amplitude generated by the glutamate released from single vesicles acting at the postsynaptic receptors represents the fundamental unit or quantum (q) of neurotransmission.

Vagal afferent ‘TRP’ channel expression

In this review, we present evidence to suggest that the presence of thermosensitive TRP channels in vagal afferents contributes to the neurocircuitry of feeding by maintaining adaptable synaptic transmission at the ST–NTS synapse. TRPV1 is expressed at the terminals of vagal afferent terminals specifically in C-type fibers and provides a unique form of asynchronous vesicular release as well as temperature sensitive spontaneous vesicular release [4], [9], [25]. Recent findings that involve

Synaptic plasticity and satiety signaling

Vagal afferents to NTS glutamatergic synaptic transmission maintains homeostasis of many physiological processes, including those that control food intake and energy balance. To maintain energy homeostasis, the neuronal circuits that convey peripheral information are matched with hormonal, nutrient, and neuronal signals of the organism. This neurocircuitry is robust and precise in its ability to transmit signals, yet the fidelity of these signals must change from moment to moment in order to

Conclusions and future directions

To maintain homeostasis of energy stores, vagal afferents carry satiety information to the central nervous system. To do so efficiently, it undergoes continuous change. Vagal afferent to NTS neurotransmission is at once robust and reliable while maintaining the ability to adapt to changing internal environments and physiological states. This balance of traits is a result of the segregation of primary afferent innervation, presence of temperatures sensitive TRP channels, and multiple forms of

Acknowledgments

This manuscript is based on work presented during the 2013 Annual Meeting of the Society for the Study of Ingestive Behavior, July 30–August 3, 2013.

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    Supported by a grant from the National Institutes of Health, DK092651.

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