Regulation of Intrinsic Plasticity in Neural Circuits

描述(申请人提供)：随着我们社会日益全球化和24小时的特点，昼夜节律和睡眠失调对公共健康和经济的影响已经大大增加，成本高达数十亿美元。尽管如此，我们对此却知之甚少。 睡眠和生物钟影响记忆电路的机制。记忆的形成对睡眠水平是双向敏感的。训练后的时间窗睡眠可以促进记忆的形成，而睡眠剥夺对记忆的形成有负面影响。在果蝇中，我们对记忆形成的基础过程以及生物钟和睡眠电路都有非常详细的了解。在这项提案中，我们将利用这一知识首次在细胞水平上了解记忆和睡眠/昼夜节律系统之间的直接联系。在目标1中，我们证明了苍蝇昼夜节律电路和苍蝇记忆电路有直接的解剖学联系。此外，我们还发现，正常记忆需要一种与觉醒相关的昼夜节律神经肽。我们假设，这些连接提供了生物钟的促唤醒功能，有助于在一天中保持认知功能。我们将研究这些肽能时钟细胞和记忆电路之间联系的分子功能和它们的行为作用。在这个水平上理解时钟和联想记忆过程的连通性将为我们提供开发新的认知保护和增强策略的能力。在目标2中，我们证明了稳定联想记忆形成的基础过程，也就是驱动记忆巩固的神经元的同时激活，也驱动了睡眠。这种睡眠与学习过程紧密相连，我们假设它对巩固学习至关重要。我们将定义在这个回路中引起睡眠和巩固的分子和细胞过程，并研究同时产生的睡眠在行为中的作用。理解这种联系将为如何利用睡眠操作来增强记忆形成提供重要的见解。

DESCRIPTION (provided by applicant): The public health and economic impact of circadian and sleep misalignment had grown enormously with the increasingly global and 24 hour nature of our society, and costs are in the billions. In spite of this, however, we know very little about the mechanisms by which sleep and the circadian clock influence memory circuits. Memory formation is bidirectionally sensitive to sleep levels. Sleep in the temporal window following training can enhance formation of memory, while sleep deprivation has negative effects on its formation. In Drosophila, we have a very detailed understanding both of the processes that underlie memory formation and of the circadian clock and sleep circuits. In this proposal we will leverage this knowledge to understand, for the first time at a cellular level, the direct links between memory and sleep/circadian systems. In Aim 1 we demonstrate that the fly circadian circuit and the fly memory circuits have direct anatomical connections. Further, we show that a circadian neuropeptide which has been associated with arousal is required for normal memory. We hypothesize that these connections provide the pro-arousal function of the circadian clock that helps maintain cognitive function over the course of the day. We will investigate the molecular function of the connections between these peptidergic clock cells and memory circuits and their behavioral role. Understanding connectivity of the clock and associative memory processes at this level will provide us with the ability to develop novel cognitive protection and enhancement strategies. In Aim 2 we demonstrate that the very process that underlies formation of stable associative memory, concurrent activation of neurons that drive memory consolidation, also drives sleep. This sleep is tightly linked to the learning process and we hypothesize that it is critical for consolidation. We will define the molecular and cellular processes that cause sleep and consolidation in this circuit and investigate the role of concurrently generated sleep in behavior. Understanding this linkage will provide important insight into how manipulation of sleep can be used to enhance memory formation.