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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105703-02
Application #
8213417
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2011-01-15
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$385,000
Indirect Cost
$135,000
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
McDougall, Stuart J; Andresen, Michael C (2013) Independent transmission of convergent visceral primary afferents in the solitary tract nucleus. J Neurophysiol 109:507-17
Peters, James H; McDougall, Stuart J; Fawley, Jessica A et al. (2011) TRPV1 marks synaptic segregation of multiple convergent afferents at the rat medial solitary tract nucleus. PLoS One 6:e25015
Fawley, Jessica A; Peters, James H; Andresen, Michael C (2011) GABA(B)-mediated inhibition of multiple modes of glutamate release in the nucleus of the solitary tract. J Neurophysiol 106:1833-40
Jin, Y-H; Andresen, M C (2011) GABA(B) restrains release from singly-evoked GABA terminals. Neuroscience 193:54-62
Fernandes, L G; Jin, Y-H; Andresen, M C (2011) Heterosynaptic crosstalk: GABA-glutamate metabotropic receptors interactively control glutamate release in solitary tract nucleus. Neuroscience 174:1-9