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.
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).
|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|
|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 ?1 and ?1 receptors. J Neurosci 34:6182-9|
|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|
|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|
|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; 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|
|Woerman, Amanda L; Mendelowitz, David (2013) Perinatal sulfur dioxide exposure alters brainstem parasympathetic control of heart rate. Cardiovasc Res 99:16-23|
|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|
|Woerman, Amanda L; Mendelowitz, David (2013) Postnatal sulfur dioxide exposure reversibly alters parasympathetic regulation of heart rate. Hypertension 62:274-80|
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