FUNCTIONAL ANALYSIS OF SLEEP HOMEOSTASIS IN DROSOPHILA

描述（由申请人提供）：虽然睡眠的功能仍然是一个谜，但许多关于睡眠功能的最成功的理论，包括突触缩小、记忆巩固、发育成熟，甚至许多关于睡眠恢复的理论都要求睡眠必须实质性地影响大脑可塑性的各个方面。我们证明，增加睡眠可以恢复12种经典记忆突变体中支持短期记忆的大脑功能，而不会特异性地挽救因果分子损伤或结构缺陷。我们还证明，睡眠可以挽救支持长期记忆的大脑功能，正如求爱条件反射所评估的那样。阐明潜在的分子机制可能会揭示与睡眠功能相关的过程，并可能最终为利用睡眠作为一种治疗方法来减缓或逆转与退行性疾病和发育障碍相关的认知衰退提供一个路线图。因此，在本提案中，我们将：1)确定支持适应行为中睡眠依赖变化所需的回路，2)操纵特定基因以确定它们是否需要睡眠诱导的记忆恢复，以及3)确定睡眠的治疗作用是否延伸到有毒蛋白质物种可以积极损害神经元功能和/或杀死神经元的疾病。

DESCRIPTION (provided by applicant): While the function of sleep remains a mystery, many of the most successful theories on sleep function, including synaptic downscaling, memory consolidation, developmental maturation, and even many theories on sleep restoration require that sleep must substantially influence aspects of brain plasticity. We demonstrate that increasing sleep restores brain functions supporting short-term memory in each of 12 classic memory mutants without specifically rescuing the causal molecular lesion or structural defect. We also demonstrate that sleep can rescue brain functions supporting long-term memory as assessed by courtship conditioning. Elucidating the underlying molecular mechanisms may shed new light on processes related to sleep function and may ultimately provide a roadmap for using sleep as a therapeutic to slow or reverse cognitive decline associated with degenerative disease and perhaps developmental disorders. Thus, in this proposal we will: 1) identify the circuits that are required to support sleep-dependent changes in adaptive behavior, 2) manipulate specific genes to determine if they are required for sleep induced restoration of memory, and 3) Determine whether the therapeutic role of sleep extends to disorders in which species of toxic proteins can actively impair neuronal functions and/or kill neurons.