From Sleep to attention in Drosophila: Coordinating Brain Regions

描述(申请人提供)：时间协调被认为是哺乳动物大脑中基本的潜在注意机制，时间协调障碍在许多大脑疾病中被发现，包括自闭症和精神分裂症，它们可能是缺陷的核心。我们开发了果蝇睡眠和注意力的模型，发现果蝇大脑中的唤醒水平与不同水平的时间协调(一致性)有关。这一提议检验了这样一种观点，即果蝇大脑中的唤醒状态，从睡眠到注意力，是由生理耦合或联系的程度和组合所调节的全脑过程。这在电生理学上是可以测量的，因为大脑不同区域之间的时间协调(一致性)水平，在睡眠中最低，在注意力类状态下最高。此外，我们使用遗传变异来测试这一想法，即在哺乳动物和果蝇中，两个在分子水平上控制和调节唤醒的高度保守的系统(多巴胺和EGFR信号转导途径)是通过它们对一致性的作用来实现的。最后，我们测试了与低或超兴奋的转基因的一致性的直接、局部扰动是否会改变唤醒状态。因此，目标是整合分子、生理和行为水平，以努力了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1.从睡眠到注意力的整个大脑的时间协调：大脑有多少参与？哪些地区？对于睡眠和注意力来说，它们是一样的吗？2.已知的果蝇唤醒系统对注意力和时间协调有什么影响？3.不对称地和通过操纵连合的时间协调的遗传扰动如何改变唤醒状态？ 与公共健康相关：大脑中的计时障碍是许多大脑疾病的共同特征，也是潜在的关键特征，包括自闭症和精神分裂症。因此，我们解决与这些疾病相关的损害的能力将受益于更好地理解大脑不同部分之间的时间选择的作用以及调节它的机制。

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.