Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

The rhythm generator underlying breathing is located in the preBotzinger Complex (preBotC) of the brainstem. The activity of this network of neurons is controlled via reflexes to maintain blood oxygen and carbon dioxide levels. ATP (adenosine triphosphate) plays an important role as a signaling molecule in these reflexes. During periods of low oxygen, an initial increase in breathing is followed by a secondary depression. In the preBotC, low oxygen causes a delayed release of ATP, which, acting through purinergic receptors weakens the secondary depression. Glial cells in the brain are important for providing metabolic support to neurons. Recently, however, it has become recognized that glial cells are also important participants in brain signaling. Past work strongly suggests that this ATP excitation is mediated by glial cells in the brain. I will explore the role of glial cells and the process by which they release transmitters to influence neuron activity with respect to breathing. To do this, I will implement 'optogenetics', which will allow us to use light to specifically stimulate glial cells, and electrophysiological methods to determine effects on breathing. My research will also examine the importance of ectonucleotidases, a diverse family of enzymes that degrade ATP in the preBotC. The distribution of these enzymes is critical because they have different endproducts. Some enzymes degrade ATP into ADP (adenosine diphosphate), which is excitatory like ATP. Others degrade ATP to ADO (adenosine) which inhibits breathing. I hope to advance understanding of mechanisms by which astrocytes use ATP to modulate inspiratory network activity, and the importance of ectonucleotidases in determining ATP responses. Given the diversity of ATP receptors and ectonucleotidases in the brain and the emerging role of glial cells in signaling, defining these basic mechanisms will provide insight into the role of the ATP signaling system and glial cells in modulating breathing.