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

这一发现计划将采用研究耐低氧哺乳动物大脑的新方法，以了解保护脑细胞免受低氧应激(即低氧)的自然进化的细胞策略。我们尤其对神经元耐缺氧机制感兴趣，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将在大脑中最为明显。在细胞水平上，脊椎动物依赖持续的氧气输送来促进有氧能量的产生。然而，氧气的可获得性往往受到环境因素的限制，这反过来最终可能会损害能源生产和生存。无论是从系统还是在大脑中，耐受低氧的关键是将代谢需求与能量供应相匹配。脊椎动物进化出了一系列有助于实现这种平衡的适应策略。这些策略可以归类为两类：i)增加组织的氧气输送，ii)通过降低代谢率来减少全身能量需求。在哺乳动物中，这种第二种代谢机制通常是通过进入麻木状态实现的；然而，我在耐缺氧的裸鼠身上进行的初步研究表明，这种物种在缺氧中经历了强大的代谢抑制，但仍保持清醒、温暖和活跃。这是一个重要的区别，因为在低氧期间避免麻木允许裸鼠在自然低氧环境中觅食、交配和防御捕食者。这些不同的策略表明了对低氧的根本不同的适应，特别是表明裸鼠可能进化出了独特的细胞和神经元机制，即局部代谢抑制，使这种动物能够避免麻木。然而，尽管氧稳态具有重要的性质，但我们对低氧环境中保护耐低氧物种的细胞机制还没有完全了解。尤其是对这种耐缺氧物种在缺氧期间保护脑细胞的机制知之甚少。该研究计划旨在通过确定1)突触功能如何促进耐缺氧脑中的代谢抑制和神经保护，以及2)耐缺氧物种细胞能量如何改变来解决这一差距。这项研究将从根本上推动这一领域的发展，揭示有利于调节突触活动和细胞能量学的自然进化机制，以实现代谢稳态和神经元在低氧中的存活。我们将回答有关低氧耐受脑在发育背景下进化的重要基础研究问题。我们还将介绍生物医学领域的重要翻译研究，重点是在低氧条件下实现神经保护(例如，新生儿癫痫、心脏病发作/中风、旅居/高原锻炼等)。

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.).