The diving reflex is the most powerful autonomic reflex. Stimulation of the diving reflex evokes a pronounced bradycardia with heart rate decreasing up to 51% upon a single facial submersion. The diving reflex is highly beneficial by preventing invasion of water into the lungs and evoking a bradycardia that reduces myocardial oxygen consumption. However an exaggerated diving reflex has been implicated in sudden infant death syndrome (SIDS). Despite the strength and clinical importance of the diving reflex nearly all previous neurobiological studies have been anatomical rather than functional. The long-term goal of the present proposal is to provide a comprehensive functional blueprint of the neurobiology and receptors that mediate the diving reflex in the brainstem. To accomplish these goals we will utilize a novel brainstem preparation that allows us to stimulate trigeminal sensory afferent fibers and simultaneously characterize spontaneous rhythmic respiratory activity and evoked synaptic responses in cardiac vagal neurons. Specifically we will test the hypothesis that stimulation of trigeminal sensory afferent fibers evokes a central apnea and recruits an excitatory pathway to parasympathetic cardiac vagal neurons. The electrophysiological properties of this pathway will be characterized, receptors involved will be identified, and the location of the synapses within this brainstem pathway will be mapped. We will also determine whether inspiratory evoked GABAergic and glycinergic neurotransmission to cardiac vagal neurons is inhibited by evoking the dive reflex, and identify the neurotransmitters responsible. Recent work has shown serotonergic neurons and serotonin (5-hydroxytryptamine, 5-HT) receptors in the brainstem play an essential role in central respiratory function and abnormalities in brainstem 5-HT function are also strongly associated with SIDS. However the mechanisms by which 5-HT receptors alter cardiorespiratory interactions in the brainstem and increase the risk of SIDS is unknown.
In AIM 3 we will test the hypothesis that the brainstem pathways of the dive reflex are endogenously and differentially modulated by different 5-HT receptors.

Public Health Relevance

The work described in this proposal will not only address hypotheses fundamental to understanding the basis and mechanisms of the diving reflex within the brainstem, but will also test whether and which serotonin (5- hydroxytryptamine, 5-HT) receptors modulate the diving reflex and how enhanced 5-HT activity in the brainstem increase the risk of cardiorespiratory diseases such as Sudden Infant Death Syndrome (SIDS).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059895-15
Application #
8387000
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Wang, Lan-Hsiang
Project Start
1998-04-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
15
Fiscal Year
2013
Total Cost
$368,745
Indirect Cost
$133,125
Name
George Washington University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Wengrowski, Anastasia M; Wang, Xin; Tapa, Srinivas et al. (2015) Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function. Cardiovasc Res 105:143-50
Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi et al. (2015) Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure. Am J Physiol Heart Circ Physiol 309:H1281-7
Wang, Xin; Piñol, Ramón A; Byrne, Peter et al. (2014) Optogenetic stimulation of locus ceruleus neurons augments inhibitory transmission to parasympathetic cardiac vagal neurons via activation of brainstem α1 and β1 receptors. J Neurosci 34:6182-9
Dyavanapalli, Jhansi; Jameson, Heather; Dergacheva, Olga et al. (2014) Chronic intermittent hypoxia-hypercapnia blunts heart rate responses and alters neurotransmission to cardiac vagal neurons. J Physiol 592:2799-811
Dergacheva, Olga; Weigand, Letitia A; Dyavanapalli, Jhansi et al. (2014) Function and modulation of premotor brainstem parasympathetic cardiac neurons that control heart rate by hypoxia-, sleep-, and sleep-related diseases including obstructive sleep apnea. Prog Brain Res 212:39-58
Piñol, Ramón A; Jameson, Heather; Popratiloff, Anastas et al. (2014) Visualization of oxytocin release that mediates paired pulse facilitation in hypothalamic pathways to brainstem autonomic neurons. PLoS One 9:e112138
Dergacheva, Olga; Dyavanapalli, Jhansi; Piñol, Ramón A et al. (2014) Chronic intermittent hypoxia and hypercapnia inhibit the hypothalamic paraventricular nucleus neurotransmission to parasympathetic cardiac neurons in the brain stem. Hypertension 64:597-603
Sharp, Douglas B; Wang, Xin; Mendelowitz, David (2014) Dexmedetomidine decreases inhibitory but not excitatory neurotransmission to cardiac vagal neurons in the nucleus ambiguus. Brain Res 1574:1-5
Wan, Ruiqian; Weigand, Letitia A; Bateman, Ryan et al. (2014) Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability. J Neurochem 129:573-80
Dyavanapalli, J; Byrne, P; Mendelowitz, D (2013) Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus. Neuroscience 247:213-26

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