From Sleep to attention in Drosophila: Coordinating Brain Regions

描述（由申请人提供）：时间协调被认为是哺乳动物大脑中注意力的基本潜在机制，时间协调障碍在许多脑部疾病中都被发现，包括自闭症和精神分裂症，它们可能是这些缺陷的核心。我们已经开发了果蝇的睡眠和注意力模型，并发现果蝇大脑中的觉醒水平与不同水平的时间协调（连贯性）有关。这一提议验证了这样一种观点，即果蝇大脑中的觉醒状态，从睡眠到注意力，是由生理耦合或联系的程度和组合所介导的全脑过程。这是电生理学上可以测量的，即大脑各区域之间的时间协调（一致性）水平，在睡眠状态下最低，在类注意力状态下最高。此外，我们使用遗传变异来测试两个高度保守的系统在分子水平上控制和调节哺乳动物和苍蝇的觉醒（多巴胺和EGFR信号转导途径）通过它们对一致性的作用来实现这一想法。最后，我们测试是否直接，局部扰动一致性与低或超兴奋转基因改变唤醒状态。因此，我们的目标是整合分子、生理和行为水平，努力理解时间协调在产生不同大脑状态中的作用和调节。具体目标大脑从睡眠到注意力的时间协调：大脑有多少参与？在哪个地区呢?睡眠和注意力是一样的吗？2. 已知的果蝇觉醒系统对注意力和时间协调有什么影响？3. 时间协调的基因扰动，不对称的和通过控制交流，是如何改变觉醒状态的？

DESCRIPTION (provided by applicant): Temporal coordination has been proposed as a fundamental underlying mechanism of attention in the mammalian brain and disturbances in temporal coordination are found in many brain disorders, including autism and schizophrenia, where they are potentially central to the defects. We have developed models for sleep and attention in the fruit fly Drosophila, and found that arousal levels in the fly brain are associated with different levels of temporal coordination (coherence). This proposal tests the idea that arousal states in the Drosophila brain, from sleep to attention, are brain-wide processes mediated by the degree and combinations of physiological coupling or linkage. This is measurable electrophysiologically as the level of temporal coordination (coherence) between various regions of the brain, being lowest in sleep and highest in attention-like states. Furthermore, we use genetic variants to test the idea that two highly conserved systems that control and modulate arousal at the molecular level in mammals and flies (dopamine and the EGFR signal transduction pathway) do so by their action on coherence. Finally, we test whether direct, local perturbations of coherence with hypo- or hyper-exciting transgenes alter arousal states. Thus, the goal is to integrate the molecular, physiological, and behavioral levels in an effort to understand the role and regulation of temporal coordination in producing different brain states. Specific Aims 1. Temporal coordination across the brain from sleep to attention: How much of the brain participates? Which regions? Are they the same for sleep and attention? 2. What effect do the known arousal systems in Drosophila have on attention and on temporal coordination? 3. How do genetic perturbations of temporal coordination, asymmetrically and by manipulation of commissures, alter arousal states? PUBLIC HEALTH RELEVANCE: Disturbances of timing in the brain are a shared and potentially critical feature of many brain disorders, including autism and schizophrenia. Our ability to address the impairments associated with these disorders would therefore benefit from a better understanding of the role of timing between different parts of the brain and the mechanisms that regulate it.