Mechanisms underlying respiratory motor plasticity

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Context: The respiratory control system is not just reflexive - it is smart, it learns and in fact it has a working memory. The respiratory system listens to and carefully remembers how previous stimuli affect breathing. Respiratory memory is laid down by adjusting synaptic strength between respiratory neurons. Repeated respiratory stimuli (e.g. apnea) induce a form of memory that strengthens the ability of respiratory motoneurons to trigger contraction of breathing muscles. This type of respiratory motor plasticity is called long-term facilitation (LTF) and it may serve to deepen breathing and improve effective lung ventilation. Rationale: Although the physiological factors that trigger respiratory LTF are known (e.g., apneas), the actual brain circuitry and transmitter pathways that cause LTF remain largely unidentified. This grant will: 1) identify and map-out the neuro-circuits that induce LTF. 2) determine how these circuits communicate with the respiratory system to elicit LTF of breathing. Research Approach and Aims: Work from my previous NSERC Discovery Grant identified a novel type of respiratory LTF that is caused by repeated apneas (Tadjalli et al, J. Neuroscience, 30(50):16886-95, 2010). In anesthetized and spontaneously breathing rats, we found that repeated airway occlusions - similar to those in obstructive sleep apnea - caused LTF of respiratory activity in upper airway muscles, e.g., genioglossus. The physiological factor responsible for apnea-induced LTF activation was the lung afferent feedback caused by repeated airway obstructions. Importantly, activation of the noradrenergic system was required to elicit LTF. How this transmitter system initiates LTF is unknown. This grant proposal is a direct extension of our previous work. Its overall aim is to identify and define the noradrenergic mechanisms and pathways responsible for respiratory LTF.