Date of Completion

5-24-2016

Embargo Period

5-18-2026

Major Advisor

Dr. Anastasios V. Tzingounis

Associate Advisor

Dr. Daniel K. Mulkey

Associate Advisor

Dr. Joseph J. LoTurco

Field of Study

Physiology and Neurobiology

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Central chemoreception is the physiological process by which the brain regulates breathing due to changes in CO2 /H+ within the tissue. One of the major regions for respiratory control, located in the brainstem, is the retrotrapezoid nucleus (RTN). Severe hypoventilation and the lack of arousal to hypercapnia during sleep links genetic dysfunction of RTN chemoreceptors to several respiratory pathologies, including central congenital hypoventilation syndrome (CCHS). RTN chemoreceptive neurons are sensitive to neuromodulatory inputs from multiple respiratory centers; they serve as a key nexus of respiratory control. The RTN receives extensive serotonergic projections that increase the activity of RTN chemoreceptors and enhance respiratory output. Substantial evidence supports the RTN as a site for central chemoreception. The mechanisms that regulate chemoreceptor function are just becoming unraveled, mainly, repetitive firing behavior and transmitter modulation.

Voltage-gated KCNQ channels and hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are susceptible to neuromodulation. These voltage-gated K+ channels are widely distributed throughout the nervous system and shape neuronal excitability. Suppression of these channels by serotonin and other G-coupled proteins receptors enhances membrane excitability through tonic cellular firing.

Both KCNQ and HCN channels are active at resting membrane potentials and therefore, can modulate the repetitive firing behavior of most neurons. Recent discovers implement numerous mutations in Kcnq genes to some forms of pediatric epilepsy, including Benign Familial Neonatal Epilepsy and Ohtahara syndrome. Similarly, recent evidence has shown alterations in HCN channel function can lead to epilepsy and neuropathic pain.

Although KCNQ and HCN channels have vast expression throughout the brain, little is known about their specific subunit expression, function, and modulation within brainstem respiratory centers. We hypothesize that these channels contribute to RTN chemoreceptor activity and serve as downstream effectors of serotonergic modulation which in turn can modulate respiratory output. This thesis aims to: 1.) determine the role of KCNQ and HCN channel modulation of RTN chemoreceptor basal activity and 2.) respiratory drive. 3.) Moreover, to identify the means of serotonergic modulation of RTN chemoreceptors.

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Available for download on Monday, May 18, 2026

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