Role of orexin in non-photic phase shifting of the circadian clock

我们每天24小时的工作给生物体带来了它们已经适应的规律性和可预测的挑战。我们以一种方式组织我们的生物学和行为，以预测这些可预测的挑战。在动物中，预测这些需求并在24小时内组织我们的行为和生理的工作福尔斯在我们大脑下丘脑的生物钟上。这种生物钟在生理和行为上产生这些日常节奏。为了有效地预测这些节奏挑战的时间，我们的时钟必须与我们环境中的时间线索同步。虽然光是大多数生物体用来实现这种同步的最可靠和最主要的线索，但生物钟对光以外的线索也很敏感。这些所谓的“非光”线索以不同于光的方式影响时钟。值得注意的是，运动、睡眠不足和觉醒似乎都是相关的非光信号，它们以类似的方式调整我们的生物钟，这意味着类似的潜在神经机制。有了这个提议，我们将揭示这些非光线索如何输入到生物钟及其更广泛的网络中。最近，我们已经确定了大脑中的关键唤醒系统（即，来自基底前脑的乙酰胆碱），这对这些非光反应至关重要。这些信号与另一个定义明确的系统平行运作，该系统对非光反应也是必不可少的，即起源于丘脑膝状体间叶（IGL）的神经肽Y。IGL嵌入在视觉区域中，所以令人惊讶的是，这个结构在视觉反应中，而不是在这些非视觉反应中起着如此重要的作用。唤醒如何在非光反应中招募IGL尚不清楚。我们假设关键的唤醒信号来自大脑中另一个关键的唤醒系统，该系统使用神经递质食欲素。我们将通过一些互补的实验方法来测试这一假设，包括药理学（目标1），解剖学研究（目标2），化学遗传学方法（目标3），以及在非光治疗期间监测体内细胞活性。此外，由于该领域的许多历史数据来自雄性动物，我们还将开发一种新的实验方法，使我们能够在雌性动物中研究这种现象（目标5）。昼夜节律系统已经成为理解行为的遗传和神经控制的模型系统。在这项提案中进行的工作不仅将揭示昼夜节律系统的内部工作，还将揭示睡眠/觉醒系统的内部工作，有助于证明它们之间的相互作用。从事这项工作的年轻科学家将发展一套强大的技能，这将有助于他们自己过渡到独立的科学家。生活在北方，加拿大人感受到季节性光周期变化的影响。了解我们的昼夜节律系统如何工作将有助于减轻不利的光周期效应。

Our 24-hour day presents organisms with regular and predictable challenges to which they have adapted. We organize our biology and behavior in a manner to anticipate these predictable challenges. In animals, the job of anticipating these needs and organizing our behavior and physiology across the 24-hour day falls to our circadian clock located in the hypothalamus of our brains. This circadian clock generates these daily rhythms in physiology and behavior. To effectively anticipate the timing of these rhythmic challenges our clock must be synchronized to the time cues in our environment. While light is the most reliable and dominant cue used by most organisms to achieve this synchrony, the circadian clock is also sensitive to cues other than light. These so-called "non-photic" cues affect the clock in a manner distinct from light. Notably, exercise, loss of sleep and arousal all seem to be related non-photic cues that adjust our circadian clocks in a similar fashion, implying a similar underlying neural mechanism. With this proposal, we will uncover how these non-photic cues input to the circadian clock and its wider network. Recently we have identified key arousal systems in the brain (i.e., acetylcholine from the basal forebrain) that are critical to these non-photic responses. These signals operate in parallel to another well defined system that is also essential to non-photic responses, namely Neuropeptide Y that originates in the thalamic intergeniculate leaflet (IGL). The IGL is embedded in a visual area, so it is surprising that this structure plays such a critical role not in visual responses, but rather in these non-visual responses. How arousal recruits the IGL in non-photic responses is unknown. We hypothesize that the critical arousal signal comes from another critical arousal system in the brain that uses the neurotransmitter Orexin. We will test this hypothesis through a number of complementary experimental approaches including pharmacology (Objective 1), anatomical investigation (Objective 2), chemogenetic approaches (Objective 3), and monitoring cellular activity in vivo during non-photic treatments. Furthermore, as much of the historical data in this field derives from male animals, we will also be developing a novel experimental approach that will allow us to study this phenomenon in female animals (Objective 5). The circadian system has become a model system for understanding both genetic and neural control of behavior. The work carried out in this proposal will uncover the inner workings of not only the circadian system, but also of the sleep/wake system, helping to demonstrate the interplay between them. The young scientists conducting this work will develop a strong skill-set that will facilitate their transition into independent scientists themselves. Living in the north, Canadians feel the impact of seasonal photoperiod changes. Understanding how our circadian system works will help mitigate adverse photoperiod effects.