Transforming a neural circuit to function without oxygen and glucose delivery

Abstract

Disruptions in the delivery of oxygen and glucose impair the function of neural circuits, with lethal consequences commonly observed in stroke and cardiac arrest. Intense focus has been placed on understanding how to overcome neuronal failure during energy stress. Important insights into neuroprotective strategies have come from studies of evolutionary adaptations for survival in hypoxic environments, such as those seen in turtles, naked mole-rats, and several other animals1. Amphibians are not usually numbered among 'champion' hypoxia-tolerant vertebrates, yet here we demonstrate a massive increase in the capacity of a neural circuit to produce activity following oxygen and glucose deprivation in adult bullfrogs. Rhythmic output from a brainstem circuit failed following minutes of severe hypoxia and simulated ischemia; however, after hibernation this network produced patterned activity for ∼3.5 hours during severe hypoxia and ∼2 hours in ischemia. This remarkable improvement was supported by a switch to brain glycogen to fuel anaerobic glycolysis, a pathway thought to support neuronal homeostasis for only a few minutes during ischemia2. These results reveal that circuit activity can exhibit dramatic metabolic plasticity that minimizes the need for ATP synthesis, and these findings represent the greatest range in hypoxia tolerance within a vertebrate neural network. Uncovering the rules that allow the brain to flexibly run only on endogenous fuel reserves will reveal new insights into brain energetics, circuit evolution, and neuroprotection.