Dr. Joseph Santin (Biology) received new funding from the National Institute of Neurological Disorders and Stroke for the project “Acquiring resistance to anoxia in neural circuit function.”
The goal of this project is to understand how to prevent neurological dysfunction caused by oxygen deprivation in the brain. Impaired delivery of oxygen to the brain occurs during leading causes of neurological disability such as stroke and traumatic brain injury. It is well established that hypoxia damages the brain in these conditions, killing patients or severely decreasing their quality of life. The medical and financial burden of brain hypoxia will likely increase over the next 40 years because the most susceptible part of our population, the aging, is expected to rise by about 60%. The ultimate goal for patients is “prime” their brains to work better without oxygen, so when an insult occurs, damage is minimized.
To gain fundamental insight needed to reach this goal, we will exploit a circuit that can prime itself to work without oxygen beyond that of most other neural systems- a central pattern generating circuit found in the brainstem of frogs. Like neural circuits of most vertebrates, this network needs oxygen to function. After minutes without oxygen, the network falls silent. In striking contrast, the PI found that this circuit transforms and continues to produce rhythmic activity when deprived of oxygen a day after these animals come out of hibernation. Such a dramatic improvement in circuit function during anoxia -from no activity to normal activity- has yet to be shown in any other model circuit.
We assert that fundamental concepts needed to eventually achieve anoxia resistance in patients’ brains will be easier to reveal in our system compared to other models where such a high degree of functional improvement is not yet possible.
The central hypothesis of this application is that changes supporting the energetic stress of activity and preserving neuronal firing lead to anoxia resistance of circuit function. This hypothesis will be tested by three mechanistic aims: (1) identify shifts in metabolic processes that maintain energy status of the network during anoxia, (2) assess the extent to which reducing inhibitory ion pumps promotes neuronal firing during anoxia, and (3) determine changes in ion channel expression profiles in single anoxia-resistant neurons.
These aims will afford diverse training opportunities to undergraduate and graduate students in single-cell molecular biology, patch clamp electrophysiology, fluorescence imaging microscopy, and extracellular nerve recording. Overall, this work will provide insight into how to make a neural circuit work properly without oxygen and will inform clinical investigations that must achieve this same outcome before patients’ lives can be improved when they encounter life-threatening hypoxia.