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The Roles of the Respiratory Oscillators: Effects of Optogenetics and Cholinergic Perturbations on the Respiratory Functions Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Alsahafi, Zaki
Supervisor and department
Silvia Pagliardini (Department of Physiology)
Examining committee member and department
John Greer (Physiology department)
Greg Funk (Physiology department)
Kelvin Jones (Physical Education and Recreation)
Department of Physiology

Date accepted
Graduation date
2017-06:Spring 2017
Master of Science
Degree level
Previous data have revealed the important and fundamental role in respiratory control of two groups of brainstem neurons: the preBötzinger Complex (preBötC) and the retrotrapezoid / parafacial respiratory group (RTN/pFRG). The preBötC which functions as the inspiratory oscillator, essential for inspiratory bursts initiation and pattern generation and the RTN/pFRG which functions as the active expiratory oscillator and central chemoreception region. This research thesis utilized various optogenetic and pharmacological tools to further examine the behaviour of the two respiratory oscillators. Specifically we aimed to investigate how a highly controlled excitation of the preBötC neurons affects ongoing breathing and we aimed to investigate the respiratory effects of cholinergic neurotransmission on the RTN/pFRG region. In the first chapter we investigated the effects of brief laser pulses stimulation in rats infected with an adeno associated virus that expresses a light sensitive protein (Channelrhodopsin) along with a fluorescent marker in the preBötC neurons. Previous work has revealed the importance of excitation within the preBötC network, nevertheless the effects of a highly temporally controlled excitation to the preBötC neurons was yet to be described. We tested the hypothesis that brief excitation of the preBötC neurons will drive the inspiratory activity and reset the respiratory rhythms. Precise laser pulse stimulation to the preBötC neurons increased the respiratory frequency, induced a respiratory reset, entrained respiratory frequency and reinstated breathing in absence of ongoing activity. These results provide further evidence for an essential role of excitation in respiratory rhythmogenesis within the preBötC network and support the fundamental role of preBötC as the main inspiratory oscillator. In the second chapter we investigated pharmacological properties of the expiratory oscillator RTN/pFRG. Previous work from our lab demonstrated the recruitment of abdominal muscles during periods of REM sleep or REM-like sleep under urethane anesthesia. Because acetylcholine is released during period of REM sleep, we hypothesized that cholinergic innervation contributes to the pFRG level of excitation and the subsequent occurrence of active expiration. We demonstrated that cholinergic innervation contributes to pFRG activation which leads to the recruitment of abdominal muscles activity and active expiration. We examined the presence of cholinergic fibers and terminals within the pFRG region, tested the pFRG response to various cholinergic modulators, and investigated the respiratory responses evoked by stimulating either medial or lateral para facial regions (RTN and pFRG). Our results demonstrate that cholinergic innervation is present within the region of the pFRG and local application of different cholinergic agonists and antagonists into the pFRG evoked various respiratory responses, which suggest that cholinergic innervation contributes to the process of the pFRG activation and abdominal muscles recruitment.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Alsahafi, Z., Dickson, C. T. and Pagliardini, S. (2015), Optogenetic excitation of preBötzinger complex neurons potently drives inspiratory activity in vivo. J Physiol, 593: 3673–3692. doi:10.1113/JP270471. Boutin, R. C.T., Alsahafi, Z. and Pagliardini, S. (2016), Cholinergic modulation of the paraFacial respiratory group. J Physiol. Accepted Author Manuscript. doi:10.1113/JP273012

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