funded projects
2011 October
Awardee: Jimmy Frainge
Research Team: Jimmy Frainge, John Peever, Junchal Kim
Project Title: Optogenetic dissection of hypothalamic circuits: Shining new light on narcolepsy
Project description: Approximately three million people worldwide suffer from the sleep disorder narcolepsy. Cataplexy, a defining symptom of this disorder, is characterized by involuntary and unwanted loss of skeletal muscle tone during wakefulness. There is strong evidence that dysregulation of the dopamine system contributes to narcolepsy. Previously, we identified a novel dopamine circuit that functions to support muscle tone during waking, but prevent it during sleep. Using optogenetic tools, we will investigate the function of this dopaminergic pathway in controlling loss of muscle tone during cataplexy in a mouse model of narcolepsy.
Awardee: Manuel Gil-Lozano
Research Team: Manuel Gil-Lozano, Erli Mingomataj, Robert Casper, Patricia L. Brubaker
Project Title: Circadian variations in GLP-1 responses.
Project Description: The metabolic clock appears to be implicated in insulin secretion, since disruption of the clock genes leads to a defective insulin response. It is also known that there is a marked circadian pattern in insulin secretion in response to feeding whereas the circadian pattern in response to an intravenous stimulus is less pronounced. This indicates that the intestinal hormone, glucagon-like peptide-1, which stimulates insulin secretion following a meal, may play a role in this process. We already have shown that there is a circadian variation in GLP-1 secretion in response to different stimuli in vitro. Hence, we are now determining whether the metabolic clock is regulating this process and if there is also a circadian variation in the GLP-1 response to nutrient ingestion in vivo.
Awardee: Joshua Krupps
Research Team: Joshua Krupp, Henry Krause, Joel Levine
Project Title: Characterization of the Drosophila nuclear receptor E75, a heme receptor hypothesized to coordinate circadian rhythms in behaviour and metabolism.
Project Description: The circadian system plays an integral role in coordinating rhythms in physiology and behaviour, such as metabolic and sleep/wake cycles, with anticipated daily environmental changes. It has been proposed that the heme-bound nuclear receptor REV-ERB alpha, a core component of the mammalian molecular timing mechanism, may act to link the circadian and metabolic regulatory networks. Here we propose to examine the function of the Drosophila nuclear receptor E75, the homolog of mammalian REV-ERB alpha. We hypothesize that the modulation of E75 activity through the redox state of its bound heme group by oxidative metabolism or nitric oxide production, may serve to homeostatically regulate circadian and metabolic processes.
Awardee: Lia Mesbah-Oskui
Research Team: Lia Mesbah-Oskui, Richard Horner, Beverley Orser
Project Title:: Thalamic Mechanisms Mediating the Sedating Effects of General Anesthetics
General anesthesia is a drug-induced state characterized by reversible loss of consciousness. Although the receptor and ion channel targets of the major classes of anesthetics are well characterized, the critical brain cells and pathways mediating the effects of general anesthetics in-vivo are not well understood. Recent studies suggest that the neural circuits and receptors involved in generating and maintaining natural sleep are similar to the circuits and receptors affected by common anesthetics. Our research will identify the brain cells and pathways mediating the sedating effects of general anesthetics in-vivo, with a particular focus on the major channels and receptors mediating tonic inhibition in the ventral basal complex of the thalamus.
Awardee: Azadeh Yadollahi
Research Team: Azadeh Yadollahi, Douglas Bradley, Geoff Fernie, John Floras
Project Title: Consequences of fluid redistribution on the pathogenesis of sleep apnea
Lay abstract: We proposed a new unifying paradigm for the pathogenesis of obstructive and central sleep apnea (OSA and CSA, respectively). The fluid which is accumulated in the legs during day moves towards the head when lay down to sleep and the consequent fluid accumulation in the neck or lung could be a major contributor to the development of OSA and CSA, respectively. To test these possibilities, we aim to determine whether: 1) intravenous fluid infusion during sleep will cause fluid accumulation in the neck and induce OSA; 2) the relative degree of fluid shift into the neck and lungs at night is associated with OSA and CSA, respectively; 3) the respiratory sounds recorded from lungs and neck can be used to estimate the amount of nocturnal fluid accumulated in the lungs and neck, respectively.
If so, a new approach for the therapy of sleep apnea would be to use respiratory sounds analysis for monitoring fluid accumulation in the lungs and neck and to prevent the nocturnal fluid shift towards head.
2011 February
Awardee: Bojana Gladanac
Research Team: Bojana Gladanac, Robert Casper, Martin Ralph, Shadab Rahman, Patricia Brubaker
Project Title: Effects of filtering short wavelengths from nocturnal lighting on circadian rhythms
Project Description: As the most potent environmental cue, light directly affects the master biological clock located in the anterior hypothalamus. This endogenous near-24-hour oscillator is entrained to light-dark cycles and thus exposure to light at night has the ability to disrupt various physiological rhythms altering gene expression, hormone secretion, and overall behaviour and activity. We have previously shown that these disruptive effects can be prevented by filtering short wavelengths from nocturnal light exposure in the range of 450 – 480nm. Currently, we are extending our findings and exploring the effects of selectively filtered nocturnal light on metabolic changes and circadian phase responses in rats using behavioural and physiological measures at the Centre for Biological Timing and Cognition facility.
Awardee: James Greco
Research Team: James Greco, Denise Belsham, Donald Pfaff
Project Title: The orexin/orexin receptor system in the hypothalamus: The dIrect connection between arousal and energy homoestatis
Project Description: Orexins, also known as hypocretins, are neuropeptides involved in both metabolism and sleep regulation. The orexin receptors are highly expressed in regions of the brain associated with energy homeostasis. This finding, in addition to others, suggests that orexin neurons monitor the body's nutritional status. Moreover, this property of orexin neurons may indicate that these neurons play a role in the adaptive changes of arousal in response to fasting and feeding. The overall goal for this project is to define how peripheral nutrient signals directly control orexin neurons. Currently, no in vitro model exists, thus our first aim is to develop a novel orexin-GFP cell model.
Awardee: Efrosini Papaconstantinou
Research Team: Efosini Papconstantinou, Robym Stremler, Ellen Hodnett, Mary-Jane Esplen
Project Title: The RELAX TO SLEEP Study: A pilot randomized controlled trial
Project Description: The primary purpose of this study is to examine the feasibility of the RELAX TO SLEEP program on hospitalized children. The RELAX TO SLEEP program consists of parental education and relaxation breathing for children. Hospitalized children meeting eligibility criteria will be randomized to either the intervention group or the usual care group. Both groups will wear actigraphs, a small device the size of a wristwatch, which objectively measures periods of sleep and wakefulness. Although this is a pilot study, comparisons will be made to examine sleep outcomes between both groups. Other comparisons include anxiety levels and the development of post-hospital maladaptive behaviours.
Awardee: Antonello Penna
Research Team: Antonello Penna, Beverley Orser, Richard Horner
Project Title: The role of extrasynaptic GABA-A receptors in postoperative memory and sleep disorders
Project Description: The anesthesia and surgery induce memory loss and sleep disorders, conditions that last for weeks to months. The aim of this project is to identify the molecular mechanisms, particularly the role of extrasynaptic GABA-A receptor in postoperative memory loss and the disruption of normal sleep/wake cycles. We expect that this knowledge will promote the development of new therapies that diminish postoperative cognitive deficits and sleep dysfunction and thereby enhance patient care.
Awardee: Blake Richards
Research Team: Blake Richards, Paul Frankland, Miguel Cortez
Project Title: How does the brain's clockwork help it to reorganize old memories while we sleep?
Project Description: When we sleep, the brain replays patterns of electrical activity related to recently formed memories in order to consolidate and reorganize them. To reactivate these patterns the brain must synchronize its different regions using oscillatory "rhythms" in electrical activity. These rhythms are generated by a genetic subclass of cells known as parvalbumin positive inhibitory interneurons, which are thought to provide the "clockwork" of the brain. Using genetically engineered mice whose clockwork neurons can be selectively ablated, my research will explore how these neurons and the rhythms that they generate contribute to memory processing during sleep.
Awardee: William To
Research Team: William To, Beverley Orser, Michael Salter
Project Title: Inflammation enhances alpha-5GABAAR activity to disrupt circadian rhythm
Project Description: The disruption of the circadian rhythm is a proposed mechanism in the development of post-operative cognitive dysfunction. Following surgical trauma, it is suspected that a rise in pro-inflammatory cytokines modulates the suprachiasmatic nucleus (SCN), the master regulator of circadian rhythms. It remains unknown whether the specific population of alpha-5 subunit containing ?-aminobutyric acid type A receptor (alpha-5GABAAR) in the SCN regulates circadian rhythms. Our preliminary data shows that the pro-inflammatory cytokine IL-1? increases the inhibitory activity of alpha-5GABAARs. We will investigate whether inflammation enhances alpha-5GABAAR activity in the SCN to disrupt normal circadian rhythm.
Awardee: Chen Yan
Research Team: Chen Yan, Sheena Josselyn, Junchul Kim
Project Title: Activity of fear memory neurons during sleep phase
Project Description: The overall goal of the Josselyn lab is to understand how the brain encodes memories, specifically fear memories. This lab previously used in situ hybridization for the activity-dependent gene arc to visualize specific neurons in the lateral amygdala (a region known to be important in fear) that are activated (or engaged) in a specific fear memory. Using this technique, the Josselyn lab established that neurons with higher levels of the transcription factor CREB are more likely than their neighbouring neurons to be recruited into a fear memory trace as indicated by arc transcription (Han et al., Science, 2007, 2009). In these experiments, fear memory was tested 24 hours after training (during which time the mice presumably slept). However, the possible role that sleep may play in consolidating this sort of fear memory was not assessed. Chen will now examine the role of sleep-induced reactivation of these specific neurons in fear memory consolidation