Transient Receptor Potential Vanilloid Type 1 Receptors (TRPV1) contribute to detection of noxious heat (>420C) and tissue damage by spinal primary afferent nociceptors. This proposal will examine the mechanisms by which TRPV1 expression in cranial primary afferents within the solitary tract nucleus (NTS) control a newly discovered form of synaptic transmission - TRPV1 mediated asynchronous glutamate transmission. Our Preliminary Studies indicate that this TRPV1 mechanism is active at physiological temperatures and potentiates long-lasting glutamate release in an afferent activity-dependent fashion - the latter being a new form of synaptic plasticity. This new form of glutamate transmission is only present in transmission from capsaicin sensitive solitary tract afferents. The Research Plan proposes to establish the mechanisms of action of TRPV1 in ST afferent transmission with a focus on CNS function in cardiovascular control. Our global hypothesis proposes that TRPV1 localized to presynaptic cranial afferent terminals is a focal integrator of multiple signals in NTS. In this pivotal role, we postulate that TRPV1 serves as a gain rheostat - increasing or decreasing the impact of unmyelinated baroreceptor afferents. We will investigate the role of TRPV1 in NTS in combining signals related to temperature;G-protein coupled receptors, membrane derived lipid mediators and other signals. Preliminary work indicates that the asynchronous TRPV1 pool of excitatory glutamate vesicles is regulated independently from the synchronous glutamate vesicle pool responsible for excitatory postsynaptic currents triggered at low jitter latency by afferent action potentials - a synchronous release process that appears identical in all solitary tract afferents. My laboratory has extensive experience with TRPV1 mechanisms in peripheral baroreceptors, baroreceptor reflexes, and central ST transmission. Studies will rely on methods including electrophysiological, live cell imaging, dye tracing and reflex assays in a combination of rats, mice and transgenic mice.
Our Specific Aims i nclude evaluations of cannabinoid signaling in afferent activity-dependent generation of asynchronous glutamate release, protein kinase C requirements, G-protein coupled receptor contributions to sensitizing asynchronous release, and NTS TRPV1 impact on cardiovascular regulation. The proposed research will help us to fully understand the normal basis of these neural control mechanisms in order to identify pathophysiological changes and new therapeutic avenues in clinical syndromes that may include consequences of central nervous system inflammation, hypertension, stroke, metabolic syndrome, and heart failure - all of which display altered autonomic reflexes to detrimental effect.

Public Health Relevance

The brain contains networks of neurons that are essential to maintain normal bodily functions in a state compatible with life. These networks of neurons form reflexes that include regulation for an adequate blood pressure to support the systemic circulation as well as appropriate breathing rates. This proposal concerns a key part of the brain that is required for normal reflexes that produce unconscious adjustments in the heart, blood vessels and lungs that provide normal conditions throughout the body. These neurons sometimes function abnormally during disease states within the institute mission such as hypertension, hypoxia, metabolic syndrome, and heart failure, and this research is designed to understand the cellular mechanisms controlling function of these neurons and how they relate to cardiovascular regulation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Maric-Bilkan, Christine
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Oregon Health and Science University
Schools of Medicine
United States
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Hofmann, Mackenzie E; Andresen, Michael C (2017) Dynasore blocks evoked release while augmenting spontaneous synaptic transmission from primary visceral afferents. PLoS One 12:e0174915
McDougall, Stuart J; Guo, Haoyao; Andresen, Michael C (2017) Dedicated C-fibre viscerosensory pathways to central nucleus of the amygdala. J Physiol 595:901-917
Fawley, Jessica A; Hofmann, Mackenzie E; Andresen, Michael C (2016) Distinct Calcium Sources Support Multiple Modes of Synaptic Release from Cranial Sensory Afferents. J Neurosci 36:8957-66
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Hermes, Sam M; Andresen, Michael C; Aicher, Sue A (2016) Localization of TRPV1 and P2X3 in unmyelinated and myelinated vagal afferents in the rat. J Chem Neuroanat 72:1-7
Hofmann, Mackenzie E; Andresen, Michael C (2016) Vanilloids selectively sensitize thermal glutamate release from TRPV1 expressing solitary tract afferents. Neuropharmacology 101:401-11
Fawley, Jessica A; Hofmann, Mackenzie E; Largent-Milnes, Tally M et al. (2015) Temperature differentially facilitates spontaneous but not evoked glutamate release from cranial visceral primary afferents. PLoS One 10:e0127764
Hofmann, Mackenzie E; Largent-Milnes, Tally M; Fawley, Jessica A et al. (2014) External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1. J Neurophysiol 112:2697-706
Largent-Milnes, Tally M; Hegarty, Deborah M; Aicher, Sue A et al. (2014) Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons. J Neurophysiol 111:2222-31
Fawley, Jessica A; Hofmann, Mackenzie E; Andresen, Michael C (2014) Cannabinoid 1 and transient receptor potential vanilloid 1 receptors discretely modulate evoked glutamate separately from spontaneous glutamate transmission. J Neurosci 34:8324-32

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