Beat to beat regulation of the cardiovascular system depends on an intact baroreflex. This reflex arc first synapses in the nucleus tractus solitarius (NTS) where glutamate is released. Baroreflex function is compromised in common life threatening disease states: hypertension, shock, and heart failure. Work in large, accessible CNS terminals suggests that the presynaptic control of glutamate release involves ion channels and 2nd messenger systems that regulate vesicle exocytosis. Glutamate regulation differs across neurons, but the mechanisms are poorly understood. Reflex pathways regulating the cardiovascular and respiratory systems depend on brainstem neurons and these reflexes are initiated by cranial nerve primary afferents acting within the nucleus tractus solitarius (NTS). Little is known about how primary afferents behave centrally. The small size of these terminals has made direct investigation difficult. We have developed methods to permit patch clamp recording from single nerve terminals in NTS. Our Research Plan will use these methods to address our driving hypothesis that important mechanisms of regulation in NTS depend on the identity of the afferent neuron. Our Preliminary Work demonstrates that NTS neurons offer a unique opportunity because: 1. we can directly visualize, identify, stimulate and electrophysiologically record from single nerve terminals, 2. NTS receives pharmacologically distinguishable afferent terminals that form subclasses known to arise from molecularly distinct peripheral neurons, 3. Subsets of these terminals can be labeled to provide links to functionally distinct afferents. Our Plan encompasses the efforts of two labs with complementary expertise suited to this problem. We will use direct patch recording and stimulation of single terminals, as well as imaging, to study the mechanism of frequency dependent synaptic depression and peptide modulation of glutamate release. The work capitalizes on using markers of primary afferent terminals to distinguish the various sub classes (TRPV1 and P2X3; C- and A-type afferent terminals, respectively).
Specific Aims concern differential sodium, potassium and calcium channel expression across A- and C-type cranial afferent synaptic terminals plus the presence of new presynaptic mechanisms regulating synaptic cleft calcium. The different sub classes of afferent nerve terminal will be also be compared in terms of their control of glutamate release and modulation by peptides. ? ?
|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|
|Smith, Stephen M; Chen, Wenyan; Vyleta, Nicholas P et al. (2012) Calcium regulation of spontaneous and asynchronous neurotransmitter release. Cell Calcium 52:226-33|
|Jin, Y-H; Andresen, M C (2011) GABA(B) restrains release from singly-evoked GABA terminals. Neuroscience 193:54-62|
|Vyleta, Nicholas P; Smith, Stephen M (2011) Spontaneous glutamate release is independent of calcium influx and tonically activated by the calcium-sensing receptor. J Neurosci 31:4593-606|
|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|
|Andresen, Michael C; Peters, James H (2010) TRPV1, hypertension, and cardiovascular regulation. Cell Metab 12:421; author reply 422|
|Shoudai, Kiyomitsu; Peters, James H; McDougall, Stuart J et al. (2010) Thermally active TRPV1 tonically drives central spontaneous glutamate release. J Neurosci 30:14470-5|
|Jin, Y-H; Cahill, E A; Fernandes, L G et al. (2010) Optical tracking of phenotypically diverse individual synapses on solitary tract nucleus neurons. Brain Res 1312:54-66|
|Peters, James H; McDougall, Stuart J; Fawley, Jessica A et al. (2010) Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons. Neuron 65:657-69|
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