Grant: Project Grant

The mammalian brain depends on a constant supply of oxygen to meet its energy needs. If this supply fails for even a few minutes permanent brain damage or death can result. A host of adaptive responses have evolved to protect brain oxygen. Prominent among these is the biphasic hypoxic ventilatory response (HVR) in which a fall in blood oxygen (hypoxia) supplying the brain triggers an initial increase in breathing. If this increase does not restore oxygen levels, breathing falls in what is called the secondary hypoxic respiratory depression. Release of the excitatory neurochemical ATP in breathing centers of the brain helps maintain the increased breathing. However, this ATP is degraded to adenosine; brain hypoxia also causes widespread release of adenosine. Adenosine causes widespread depression of neuronal activity. This depression is highly adaptive in most brain regions because it reduces metabolic demand and hypoxic brain injury. However, depression of breathing is highly maladaptive because it is only through increases in breathing that oxygen levels can be restored. The net result is that the initial hypoxia-induced increase in breathing is followed by a secondary depression that is potentially fatal in premature infants who suffer from apnea of prematurity; it is also problematic in adults with sleep-disordered breathing where repeated, cyclic falls in oxygen exacerbate cardiovascular disease. Thus, there is great clinical interest in understanding the mechanisms underlying the HVR. The interaction between ATP excitation and adenosine inhibition of breathing is emerging as key in determining the magnitude of the hypoxic depression. The aim of this proposal is to use rodent models to determine the factors that control the balance between the excitatory actions of ATP and inhibitory actions of adenosine during hypoxia and develop strategies to shift the balance in favor of excitation to counteract the life-threatening hypoxic respiratory depression.