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

这项发现计划将采取研究耐缺氧哺乳动物大脑的新方法，以了解自然进化的细胞策略，保护脑细胞免受低氧应激（即，缺氧）。特别是，我们对缺氧耐受的神经元机制感兴趣，因为神经元是体内对缺氧最敏感的细胞，因此对低氧应激的保护机制在大脑中最为明显。在细胞水平上，脊椎动物依靠持续的氧气输送来促进有氧能量的产生。然而，氧气的可用性往往受到环境因素的限制，这反过来又会最终损害能源生产和生存。无论是在全身还是在大脑中，耐受缺氧的关键是使代谢需求与能量供应相匹配。脊椎动物已经进化出一系列有助于这种平衡的适应策略。这些策略可以分为两类：i）增加向组织的氧气输送，以及ii）通过代谢率降低来减少全身能量需求。在哺乳动物中，第二种机制通常是通过进入麻木状态来实现的;然而，我在耐缺氧裸鼹鼠中的初步研究表明，这种物种在缺氧中经历了强烈的代谢抑制，但仍然保持清醒，温暖和活跃。这是一个重要的区别，因为在缺氧期间避免麻木允许裸鼹鼠在其天然缺氧环境中觅食，交配和防御捕食者。这些不同的策略表明从根本上不同的适应缺氧，特别是，表明裸鼹鼠可能已经进化出独特的细胞和神经元机制的局部代谢抑制，使这种动物，以避免麻木。然而，尽管氧稳态的关键性质，我们没有一个完整的理解的细胞机制，保护耐缺氧物种在低氧环境中。特别是对这种耐受性物种在缺氧期间保护脑细胞的机制知之甚少。这项研究计划旨在通过确定1）突触功能如何促进耐缺氧大脑中的代谢抑制和神经保护，以及2）细胞能量学如何在耐缺氧物种中改变来解决这一差距。这项研究将从根本上推动该领域的发展，揭示自然进化的机制，这些机制有益地调节突触活动和细胞能量学，以实现代谢稳态和缺氧中神经元的生存。我们将回答重要的基础研究问题的发展背景下的缺氧耐受大脑的进化。我们还将告知生物医学领域的重要翻译研究，重点是在缺氧中实现神经保护（例如，新生儿癫痫、心脏病发作/中风、在高海拔地区逗留/运动等）。

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.).