Richard L. Horner

Richard L. Horner
University of Toronto | U of T · Department of Medicine, and Department of Physiology

PhD

About

142
Publications
9,895
Reads
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Introduction
BOOK AUTHOR: "The Universal Pastime: Sleep and Rest Explained"​. RESEARCH: Identifying cells and circuits underlying sleep, sedation and anesthesia, and their impact on vital functions such as breathing and brain network activity. TEACHING & TRAINING: Undergraduate and graduate teaching in sleep science. Lead two collaborative programs bringing together trainees, scientists and clinicians in sleep science and medicine. CONSULTING: Ad-hoc consultant to private sector (no conflict with research).
Additional affiliations
September 2011 - present
University of Toronto
Position
  • Course Director and Facilitator
Description
  • GRADUATE COURSE - PSL 1075: Biology in Time
July 2011 - present
University of Toronto
Position
  • Professor (Full)
October 2009 - October 2013
University of Toronto
Position
  • Lecturer
Description
  • UNDERGRADUATE COURSE: PSL 372: Mammalian Physiology Laboratory
Education
August 1986 - January 1991
University of London
Field of study
  • Physiology
October 1983 - June 1986
The University of Sheffield
Field of study
  • Physiology

Publications

Publications (142)
Book
Full-text available
The human brain is the most complex known machine in the universe, yet it shuts itself off from the outside world each and every day, for hours on end. Why? This book identifies why rest and sleep evolved in living things. The question of why we and other organisms sleep - long considered a scientific mystery - is simply resolved. The book identif...
Article
Full-text available
Initial theories of rapid eye movement (REM) sleep generation posited that induction of the state required activation of the pontine subceruleus (SubC) by cholinergic inputs. Although the capacity of cholinergic neurotransmission to contribute to REM sleep generation has been established, the role of cholinergic inputs in the generation of REM slee...
Article
Extrasynaptic δ-subunits containing GABAA receptors (δGABAARs) are sensitive targets for several commonly used hypnotic agents and mediate tonic neuronal inhibition. δGABAARs are highly expressed within the thalamus and their activation promotes a switch from tonic to burst firing in vitro. Here we test two hypotheses in vivo. (1) Activation of tha...
Article
Full-text available
Rationale: Inhibition of pharyngeal motoneurons accompanies REM sleep and is a cause of hypoventilation and obstructive sleep apnea in humans. One explanation posits that the neurotransmitters glycine and γ-aminobutyric acid are responsible for REM sleep motor inhibition. However, blockade of that mechanism at cranial motor nuclei increases motor...
Article
Obstructive sleep apnea (OSA) is a significant public health problem caused by repeated episodes of upper airway closure that occur only during sleep. Attempts to treat OSA pharmacologically have been unsuccessful because there has not been identification of a target operating at cranial motor nuclei, blockade of which can reactivate pharyngeal mus...
Article
Alterations in thalamic GABAergic signaling are implicated in mediating the rise in 12-30Hz electroencephalogram (EEG) activity that signals anesthetic-induced loss-of-consciousness with GABAA receptor-targeting general anesthetics. A number of modeling studies have identified that anesthetic-induced alterations in thalamocortico-corticothalamic si...
Article
Full-text available
Obstructive sleep apnea (OSA) occurs exclusively during sleep due to reduced tongue motor activity. Withdrawal of excitatory inputs to the hypoglossal motor nucleus (HMN) from wake to sleep contributes to this reduced activity. Several awake-active neurotransmitters with inputs to the HMN (e.g., serotonin, 5-HT) inhibit K+ leak mediated by TASK-1/3...
Article
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Thyrotropin-releasing hormone (TRH) is produced by the hypothalamus but most brain TRH is located elsewhere where it acts as a neuromodulator. TRH-positive neurons project to the hypoglossal motoneuron pool where TRH receptor RNA shows a high degree of differential expression compared to the rest of the brain. Strategies to modulate hypoglossal mot...
Article
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Motoneurons are the final output pathway for the brain’s influence on behavior. Here we identify properties of hypoglossal motor output to the tongue musculature. Tongue motor control is critical to the pathogenesis of obstructive sleep apnea, a common and serious sleep-related breathing disorder. Studies were performed on mice expressing a light s...
Article
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In addition to their analgesic properties, opioid drugs induce sedation and respiratory depression. Here, we aimed to reveal the link between the sedative properties and the respiratory depressant effects of opioids. We first characterized the behavioral and electrocortical changes associated with sedation by fentanyl. Fentanyl reduced motor activi...
Article
Appropriate levels of muscle tone are needed to support waking behaviors such as sitting or standing. However, it is unclear how the brain functions to couple muscle tone with waking behaviors. Cataplexy is a unique experiment of nature in which muscle paralysis involuntarily intrudes into otherwise normal periods of wakefulness. Cataplexy therefor...
Article
Study Objectives Previous research has suggested that general anesthetics can disturb postoperative sleep patterns by affecting the sleep-wake cycle. The objective was to identify the effects of general anesthetics on sleep quality and related behavioral changes in children. Methods This was a prospective, observational case-control study with chi...
Article
Full-text available
Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function...
Article
Purpose of review: This article outlines the fundamental brain mechanisms that control sleep-wake patterns and reviews how pathologic changes in these control mechanisms contribute to common sleep disorders. Recent findings: Discrete but interconnected clusters of cells located within the brainstem and hypothalamus comprise the circuits that gen...
Data
Appendix S1 This file contains the database of differentially expressed hypoglossal motor nucleus (HMN) and premotor HMN (PRE‐HMN) genes, drugs and drug targets. The database is separated into four parts on separate spreadsheets: (i) differentially expressed HMN genes; (ii) differentially expressed PRE‐HMN genes; (iii) Food and Drug Administration...
Article
Full-text available
There is currently no pharmacotherapy for obstructive sleep apnoea (OSA) but there is no principled a priori reason why there should not be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. T...
Article
Full-text available
Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to crani...
Article
Full-text available
Human studies demonstrate that sleep impairment is a concurrent comorbidity of autism spectrum disorders (ASD), but its etiology remains largely uncertain. One of the prominent theories of ASD suggests that an imbalance in synaptic excitation/inhibition may contribute to various aspects of ASD, including sleep impairments. Following the identificat...
Article
Cataplexy is a hallmark of narcolepsy characterized by the sudden uncontrollable onset of muscle weakness or paralysis during wakefulness. It can occur spontaneously, but is typically triggered by positive emotions such as laughter. Although cataplexy was identified over 130 years ago, its neural mechanism remains unclear. Here, we show that a newl...
Article
A reduction in the activity of GABAA receptors, particularly α5 subunit-containing GABAA receptors (α5GABAARs), has been implicated in the etiology of Autism Spectrum Disorders (ASD). Genetically modified mice that lack α5GABAARs (Gabra5(-/-)) exhibit autism-like behaviors and both enhanced and impaired learning and memory, depending on the behavio...
Article
Full-text available
Breathing is generated by a respiratory network in the brainstem. At its core, a population of neurons expressing neurokinin-1 receptors (NK1R) and the peptide somatostatin (SST) form the preBötzinger Complex (preBötC), a site essential for the generation of breathing. PreBötC interneurons generate rhythm and follower neurons shape motor outputs by...
Article
Background: Alterations in thalamic γ-aminobutyric acid-mediated signaling are thought to underlie the increased frontal α-β frequency electrocortical activity that signals anesthetic-induced loss of consciousness with γ-aminobutyric acid receptor type A (GABAAR)-targeting general anesthetics. The general anesthetic etomidate elicits phasic extras...
Article
Background: Opioid analgesia is an essential component of perioperative care, but effective analgesia can be limited by excessive sedation and respiratory depression. The cortical signatures associated with sedation by opioids and the relationship between changes in cortical activity and respiratory function are not well understood. The objectives...
Article
Background: Drugs acting on μ-opioid receptors (MORs) are widely used as analgesics but present side effects including life-threatening respiratory depression. MORs are G-protein-coupled receptors inhibiting neuronal activity through calcium channels, adenylyl cyclase, and/or G-protein-gated inwardly rectifying potassium (GIRK) channels. The pathw...
Article
How much would we sleep if we lived without the pressures and distractions associated with industrialized lifestyles? New research shows that hunter-gatherer societies sleep for 6-7 hours a night - a level similar to industrialized societies.
Article
Background: Critically ill patients with severe inflammation often exhibit heightened sensitivity to general anesthetics; however, the underlying mechanisms remain poorly understood. Inflammation increases the number of γ-aminobutyric acid type A (GABAA) receptors expressed on the surface of neurons, which supports the hypothesis that inflammation...
Article
Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic...
Article
Full-text available
Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system. Initial theories of rapid eye movement (REM) sleep generation posited that induction of the state required activation of the ‘pontine REM sleep generator’ by ch...
Article
Purpose of review: Our understanding of rapid eye movement (REM) sleep and how it is generated remains a topic of debate. Understanding REM sleep mechanisms is important because several sleep disorders result from disturbances in the neural circuits that control REM sleep and its characteristics. This review highlights recent work concerning how t...
Article
Drugs acting on μ-opioid receptors (MOR) are widely used as analgesics but present serious side-effects such as addiction and respiratory depression. The latter is critical considering its potential lethality and the current absence of treatments to prevent it. The development of therapies to reduce respiratory depression is limited because the cri...
Article
We agree with Lalley et al. (2014) that various brainstem sites may contribute to opioid-induced respiratory depression. Our focus here, however, is on respiratory rate depression by systemically administered drugs acting on μ-opioid receptors. Of all the potential neural sites where systemically administered μ-opioids could act, Lalley et al. sug...
Article
Full-text available
The root cause of the most common and serious of the sleep disorders is impairment of breathing, and a number of factors predispose a particular individual to hypoventilation during sleep. In turn, obstructive hypopneas and apneas are the most common of the sleep-related respiratory problems, and are caused by dysfunction of the upper airway as a c...
Article
How rhythms are generated by neuronal networks is fundamental to understand rhythmic behaviors such as respiration, locomotion, and mastication. Respiratory rhythm is generated by the preBötzinger complex (preBötC), an anatomically and functionally discrete population of brainstem neurons, central and necessary for respiratory rhythm. In specific i...
Article
The study is to observe the effect of nitric oxide (NO) donor and scavenger to the hypoglossal motor nucleus (HMN) activity and explore the underlying mechanism. Male adult anesthetized Wistar rats were anesthetized. The activity of genioglossus (GG), diaphragma, blood pressure (BP) and respiratory rate (RR) were recorded when constant microdialysi...
Article
Full-text available
Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct...
Article
The various neural mechanisms affecting the control of the upper airway muscles are discussed in this review, with particular emphasis on structure-function relationships and integrative physiological motor-control processes. Particular foci of attention include the respiratory function of the upper airway muscles, and the various reflex mechanisms...
Article
The neural networks controlling vital functions such as breathing are embedded in the brain, the neural and chemical environment of which changes with state, i.e., wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep, and with commonly administered drugs such as anaesthetics, sedatives and ethanol. One particular output from the state-...
Article
Full-text available
Nitric oxide (NO) is an important signaling molecule that regulates numerous physiological processes, including activity of respiratory motoneurons. However, molecular mechanism(s) underlying NO modulation of motoneurons remain obscure. Here, we used a combination of in vivo and in vitro recording techniques to examine NO modulation of motoneurons...
Article
Full-text available
The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of...
Article
Synaptic plasticity is an intrinsic and conserved feature of neuronal activity that has been most extensively studied in the context of learning and memory in Aplysia and the mammalian hippocampus. However, the intracellular mechanisms underlying plasticity at motor nuclei, influencing motor behaviour, are less well studied. In vitro experiments in...
Article
Obstructive sleep apnoea (OSA) is a common disease, recognized as an independent risk factor for a range of clinical conditions, such as hypertension, stroke, depression and diabetes. Despite extensive research over the past two decades, the mechanistic links between OSA and other associated clinical conditions, including metabolic disorders and ca...
Article
Full-text available
Neonatal maternal separation (NMS) disrupts development of cardiorespiratory regulation. Adult male rats previously subjected to NMS are hypertensive and show a hypoxic ventilatory response greater than that of controls. These results have been obtained in awake or anesthetised animals, and the consequences of NMS on respiratory control during norm...
Article
Full-text available
Ethanol, one of the most widely used drugs in Western society, worsens obstructive sleep apnea in humans. No studies, however, have distinguished between two primary mechanisms that could mediate suppression of genioglossus (GG) activity with ethanol. We test the hypothesis that ethanol suppresses GG activity by effects at the hypoglossal motor poo...
Article
Full-text available
Respiratory muscles with dual respiratory and non-respiratory functions (e.g. the pharyngeal and intercostal muscles) show greater suppression of activity in sleep than the diaphragm, a muscle almost entirely devoted to respiratory function. This sleep-related suppression of activity is most apparent in the tonic component of motor activity, which...
Article
Histamine neurons comprise a major component of the aminergic arousal system and significantly influence sleep-wake states, with antihistamines widely used as sedative hypnotics. Unlike the serotonergic and noradrenergic components of this arousal system, however, the role of histamine in the central control of respiratory motor activity has not be...
Article
Full-text available
Caffeine is commonly used clinically to treat apnoeas and unstable breathing associated with premature birth. Caffeine antagonizes adenosine receptors and acts as an efficient respiratory stimulant in neonates. Owing to its persistent effects on adenosine receptor expression in the brain, neonatal caffeine administration also has significant effect...
Article
I read with interest the recent article by Dr. Michael Levitzky on using the pathophysiology of obstructive sleep apnea (OSA) to teach cardiopulmonary integration ([2][1]). With 10 years of experience of teaching courses in both respiratory physiology and sleep at the University of Toronto, I also
Article
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compared the effects of chronic IH on hypersomnolence, oxida- tive injury, and proinflammatory responses in iNOS-deficient mice with those in wild-type control mice. For delivery of IH, ambient O2 was reduced from 21 to 10% for 5 s at 90-s intervals (causing arterial O2 saturations of about 85%), with the stimuli applied for 10 h/d for 6 wk. When m...
Article
Opioids can modulate breathing and predispose to respiratory depression by actions at various central nervous system sites, but the mechanisms operating at respiratory motor nuclei have not been studied. This study tests the hypotheses that (i) local delivery of the mu-opioid receptor agonist fentanyl into the hypoglossal motor nucleus (HMN) will s...
Article
Full-text available
The transmission of rhythmic drive to respiratory motoneurons in vitro is critically dependent on glutamate acting primarily on non-NMDA receptors. We determined whether both non-NMDA and NMDA receptors contribute to respiratory drive transmission at respiratory motoneurons in the intact organism, both in the state of anesthesia and in the same ani...
Article
Hypoglossal motoneurons are influenced by a variety of neuromodulators, some of which change dynamically across sleep-wake states to alter motoneuron excitability and responses to pharmacological manipulations. Determining the mechanisms underlying the modulation of hypoglossal motoneurons during sleep is relevant to understanding the increased upp...
Article
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with cognitive deficits and behavioral abnormalities, but this does not occur in all children and is not fully accounted for by OSA severity. Gozal and colleagues (3) hypothesized that C-reactive protein levels may identify children with OSA who have high susceptibility for cognitive abnormalities. In a community-based study of snoring and nonsnori...
Article
Full-text available
To determine if systemic administration of selected sedative-hypnotics that modulate the function of the y-amino-butyric acid-A (GABAA) receptor can: (i) delay arousal thereby allowing genioglossus (GG) activity to increase more in response to respiratory stimulation during sleep, (ii) also cause the robust increase in GG activity during undisturbe...
Article
Pharyngeal muscle tone decreases in sleep and this predisposes some individuals to obstructive sleep apnea. This review summarizes the control of the genioglossus muscle by sleep-state dependent neuromodulators at the hypoglossal motor nucleus, the source of motor output to the genioglossus muscle of the tongue. Knowledge of such mechanisms is rele...
Article
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Obese Zucker rats have a narrower and more collapsible upper airway compared with lean controls, similar to obstructive sleep apnea (OSA) patients. Genioglossus (GG) muscle activity is augmented in awake OSA patients to compensate for airway narrowing, but the neural control of GG activity in obese Zucker rats has not been investigated to determine...
Article
Full-text available
To determine whether certain sedatives may, by increasing arousal threshold, allow pharyngeal dilator muscle activity to increase more in response to chemical stimuli before arousal occurs. DESIGN, PARTICIPANTS AND INTERVENTIONS: Thirteen chronically instrumented rats were studied during sleep following injections of placebo or sedating doses of pe...
Article
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studies addressing the mechanisms underlying upper airway collapsibility during sleep are significant given the prevalence of obstructive sleep apnea (OSA) in the general population ([27][1]) and the serious public health impact of this disorder ([14][2]). A variety of factors predispose to OSA
Article
Full-text available
Sleep, especially rapid-eye-movement sleep, causes fundamental modifications of respiratory muscle activity and control mechanisms, modifications that can predispose individuals to sleep-related breathing disorders. One of the most common of these disorders is obstructive sleep apnea (OSA) that affects approximately 4% of adults. OSA is caused by r...
Article
Full-text available
The concept of a tonic drive activating respiratory muscle in wakefulness but not sleep has been an important and enduring notion in respiratory medicine, not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders such as obstructive sleep apnea. However, a neurotran...
Article
Brainstem respiratory neurons innervate the hypoglossal motor nucleus which in turn transmits this respiratory drive signal to the genioglossus muscle of the tongue. The mechanism of this transmission is important to help maintain an open airspace for effective breathing, and is thought to rely almost exclusively on non-N-methyl-d-aspartate (non-NM...
Article
This study tested the hypothesis that apnoea index would be greater during daytime sleep than nighttime sleep in the rat. Electroencephalogram and electromyogram were monitored via biotelemetry implant and respiration was measured using whole body plethysmography in six male rats in two separate 34h recording sessions per animal. Apnoeas were class...
Article
Full-text available
Although exogenous serotonin at the hypoglossal motor nucleus (HMN) activates the genioglossus muscle, endogenous serotonin plays a minimal role in modulating genioglossus activity in awake and sleeping rats (Sood S, Morrison JL, Liu H, and Horner RL. Am J Respir Crit Care Med 172: 1338-1347, 2005). This result therefore implies that medullary raph...