Depressed but still functional: exploring the interplay between cellular and systemic adaptations of hypoxia-tolerant vertebrates

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This Discovery Program will take the novel approach of studying the brains of hypoxia-tolerant mammals to understand naturally evolved cellular strategies that protect brain cells against low oxygen stress (i.e., hypoxia). In particular we are interested in neuronal mechanisms of hypoxia-tolerance because neurons are the most hypoxia-sensitive cells in the body and therefore protective mechanisms against low oxygen stress will be most apparent in brain. At the cellular level, vertebrates rely on continuous oxygen delivery to facilitate aerobic energy production. Oxygen availability, however, is often limited by environmental factors, which in turn can ultimately impair energy production and survival. The key to tolerating hypoxia, both systemically and in the brain, is matching metabolic demand to energy supply. Vertebrates have evolved a range of adaptive strategies that contribute to this balance. These strategies can be grouped into two categories: i) increasing oxygen delivery to tissues, and ii) reducing systemic energy demand via metabolic rate depression. In mammals, this second mechanism is typically achieved via entry into torpor; however, my pilot studies in the hypoxia-tolerant naked mole rat demonstrate that this species undergoes robust metabolic depression in hypoxia but remains conscious, warm, and active. This is an important distinction as avoidance of torpor during hypoxia permits naked mole rats to forage, mate, and defend against predators in their natural hypoxic environment. These divergent strategies suggest fundamentally different adaptations to hypoxia, and in particular, suggest that naked mole rats may have evolved unique cellular and neuronal mechanisms of localized metabolic suppression that permit this animal to avoid torpor. However, despite the critical nature of oxygen homeostasis, we do not have a complete understanding of the cellular mechanisms that protect hypoxia-tolerant species in low oxygen environments. Particularly poorly understood are the mechanisms that protect brain cells during hypoxia in such tolerant species. This research program is designed to address this gap by determining 1) how synaptic function promotes metabolic suppression and neuroprotection in the hypoxia-tolerant brain, and 2) how cellular energetics are altered in hypoxia-tolerant species. This research will fundamentally advance the field by revealing naturally evolved mechanisms that beneficially modulate synaptic activity and cellular energetics to achieve metabolic homeostasis and neuronal survival in hypoxia. We will answer important basic research questions about the evolution of the hypoxia-tolerant brain in a developmental context. We will also inform important translation studies in biomedical fields focused on achieving neuroprotection in hypoxia (e.g., neonatal seizures, heart attack/stroke, sojourn/exercise at altitude, etc.).**