Testing the role of sleep in homeostatic plasticity

测试睡眠在稳态可塑性中的作用

• 批准号: BB/X000273/1
• 负责人: Andrew Lin
• 金额: $ 55.63万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX000273%2F1
• 关键词: Testing; role; sleep; homeostatic; plasticity

We spend 1/3 of our lives asleep, unconscious and disconnected from the world. It seems like a waste of time, yet all animals sleep, so it seems sleep must fulfill some important biological purpose. What might that purpose be?Sleep improves memory and our minds work less well when we're sleep-deprived, suggesting that sleep has a neurological function. Indeed, one hypothesis posits that sleep is required for the brain to maintain stable levels of activity. This is important because neurons in the brain are all connected: when a neuron fires an electrical impulse, it sends chemical signals to other neurons that either excite them (make them fire) or inhibit them (stop them from firing). If excitation and inhibition become imbalanced, a neural network can spiral out of control into a seizure (too much excitation) or silence (too much inhibition). Yet our brains are constantly changing as we learn based on sensory experience. To stop these changes from unbalancing excitation and inhibition, the brain readjusts neurons and their connections to compensate for the changes and restore stable activity levels, a process called "homeostatic plasticity". It's thought that this process might be best carried out during sleep, a time of inactivity with little sensory input - much as shops do inventory checks after hours.Although this idea has much supporting evidence, it's not clear exactly how sleep is involved in homeostatic plasticity. First, is sleep specifically required for particular *kinds* of homeostatic plasticity? One influential hypothesis posits that connections between neurons are mainly strengthened when we're awake, and weakened when we're asleep. This idea is supported by much, but not all, evidence. Could sleep's role in homeostatic plasticity be governed by a different logic? For example, perhaps sleep is important for adjusting the strength of connections between neurons but not neurons' own intrinsic ability to be excited by other neurons ('excitability'), or for adjusting the activity of excitatory but not inhibitory neurons. Second, by what molecular mechanisms does sleep influence homeostatic plasticity? Two interesting candidates are "reactive oxygen species" (byproducts of metabolism that can be dangerous yet also play important signaling roles) and levels of certain synaptic proteins (molecules that help neurons signal to each other). Each one is regulated by sleep and plays a role in homeostatic plasticity. Could one or both be a common nexus by which sleep influences homeostatic plasticity?We will address these questions using the olfactory system of the fruit fly Drosophila. Like humans, flies sleep, and we have developed a new model system for studying homeostatic plasticity in the intact brain in flies. Here, neurons called "Kenyon cells" excite, and are inhibited by, a neuron called "APL". If we artificially activate APL for 4 days (producing excess inhibition), the circuit compensates for the perturbation, which is revealed as higher activity in Kenyon cells when we lift the artificially imposed excess inhibition. This effect arises both because APL becomes less active and because Kenyon cells get more excitation, and it requires sleep: it's reduced when we stop flies from sleeping, and it's enhanced when we use a genetic trick to force them to sleep extra.We will test what kinds of homeostatic plasticity sleep is required for, by testing whether sleep is required for (1) a variety of forms of homeostatic plasticity (e.g., excess excitation from Kenyon cells, excess exposure to natural odours) and (2) different possible underlying cellular mechanisms (e.g., changing connection strength between neurons or intrinsic excitability). We will test *how* sleep modulates homeostatic plasticity by measuring and manipulating reactive oxygen species and synaptic protein levels in normal and sleep-deprived flies and testing how this affects homeostatic plasticity.

我们的生命中的1/3与世界睡着，无意识和脱节。这似乎是浪费时间，但所有动物都睡着了，因此似乎睡眠必须实现一些重要的生物学目的。这种目的可能是什么？睡眠会改善记忆力，当我们睡眠不足时，我们的思想效果不佳，这表明睡眠具有神经功能。确实，一个假设认为大脑保持稳定的活动水平需要睡眠。这很重要，因为大脑中的神经元都连接在一起：当神经元发射电脉冲时，它会向其他神经元发送化学信号，以激发它们（使它们发射）或抑制它们（阻止它们发射）。如果激发和抑制变得不平衡，神经网络可能会失控地发作（过多的激发）或沉默（过多的抑制）。然而，随着我们根据感官体验学习的过程，我们的大脑在不断变化。为了阻止这些变化不平衡激发和抑制，大脑重新调整神经元及其连接以补偿变化并恢复稳定的活动水平，这一过程称为“稳态可塑性”。据认为，这个过程可能在睡眠期间最好地进行，这是一个不活动的时期，几乎没有感觉输入 - 就像商店在几个小时后进行库存检查一样。尽管这个想法有很多支持证据，但尚不清楚确切的睡眠与稳态可塑性有关。首先，特定 *类型的稳态可塑性需要特别需要睡眠吗？一个有影响力的假设认为，当我们醒着时，神经元之间的联系主要得到加强，并且在我们睡着时会减弱。这个想法得到了很多但不是全部证据的支持。睡眠在稳态可塑性中的作用是否由其他逻辑支配？例如，睡眠对于调整神经元之间的连接强度而不是神经元之间的固有能力（“兴奋性”）或调整兴奋性但不是抑制性神经元的活性很重要。其次，通过哪种分子机制，睡眠会影响稳态可塑性？两个有趣的候选者是“活性氧”（代谢的副产物，可能是危险的，又扮演重要的信号传导作用）和某些突触蛋白的水平（可以帮助神经元相互信号的分子）。每个人都受睡眠调节，并在稳态可塑性中发挥作用。睡眠会影响稳态可塑性的一个或两个都可以成为一个常见的联系吗？我们将使用果蝇果蝇的嗅觉系统解决这些问题。像人类一样，苍蝇睡眠，我们开发了一种新的模型系统，用于研究果蝇完整大脑中的稳态可塑性。在这里，神经元称为“ Kenyon细胞”，并受到称为“ APL”的神经元的抑制。如果我们人为地激活APL 4天（产生过多的抑制作用），则该电路会补偿扰动，当我们提高人为施加过多的抑制时，肯尼因细胞的活性较高。 This effect arises both because APL becomes less active and because Kenyon cells get more excitation, and it requires sleep: it's reduced when we stop flies from sleeping, and it's enhanced when we use a genetic trick to force them to sleep extra.We will test what kinds of homeostatic plasticity sleep is required for, by testing whether sleep is required for (1) a variety of forms of homeostatic plasticity (e.g., excess excitation from Kenyon cells, excess exposure to natural气味）和（2）不同可能的基本细胞机制（例如，神经元之间的连接强度或固有兴奋性之间的连接强度改变）。我们将通过测量和操纵反应性氧和突触蛋白水平在正常和睡眠不足的果蝇中测量和操纵突触蛋白水平来测试 * *睡眠如何调节体内稳态可塑性，并测试这如何影响稳态可塑性。

项目成果

Neuroscience: Hacking development to understand sensory discrimination

神经科学：通过黑客开发来理解感觉辨别

• DOI: 10.1016/j.cub.2023.06.072
• 发表时间: 2023
• 期刊: Current Biology
• 影响因子: 9.2
• 作者: Lin A