Fear Entrainment of Circadian Rhythms

昼夜节律的恐惧夹带

• 批准号: 10311536
• 负责人: Horacio O De La Iglesia
• 金额: $ 33.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311536
• 关键词: ARNTL gene; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Biological Clocks; Biological Rhythm; Bioluminescence; Brain; Circadian Rhythms; Complex; Cues; Dangerousness; Darkness; Disease; Elements; Enterobacteria phage P1 Cre recombinase; Estrous Cycle; Exposure to; Feeding behaviors; Female; Food; Fright; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Halorhodopsins; In Vitro; Injections; Knock-out; Laboratories; Lead; Light; Link; Location; Mammals; Molecular; Mus; Neurons; Optics; Organ; Output; Ovarian hormone; Perception; Periodicity; Peripheral; Phase; Post-Traumatic Stress Disorders; Process; Prosencephalon; Protocols documentation; Rattus; Rodent; Running; Sex Differences; Shock; Sleep Disorders; Sleep Wake Cycle; Slice; Stimulus; System; Testing; Time; Trauma; Viral; Water; Work; circadian; circadian pacemaker; conditioned fear; experimental study; feeding; foot; hormone regulation; in vivo; male; molecular clock; neuromechanism; optogenetics; response; sleep regulation; suprachiasmatic nucleus; transcription factor

SUMMARY Recent work in our laboratory has shown that cyclic fear can prevail over entrainment of circadian rhythms by the light-dark (LD) cycle and lead to diurnal foraging and feeding in nocturnal rodents. When mice or rats are housed in a cage setup in which they need to leave a safe nesting area to access a foraging area for food and water, they forage and feed during the dark phase of the LD cycle. If the foraging area is rendered dangerous with random footshocks during the active dark phase, the animals’ foraging and feeding activity shifts to the light phase. This switch to diurnal behavior represents the output of a circadian oscillator, which is entrained by the cyclic fear stimulus, and is dependent on an intact suprachiasmatic nucleus (SCN), where the master clock resides, and an intact amygdala, which encodes fear perception. Our working hypothesis for this proposal is that a circadian oscillator within the amygdala is entrained by cyclic fear and leads to a shift in the timing of foraging and feeding behavior. Specific Aim 1 will determine whether cyclic nocturnal fear entrains the circadian oscillators in the amygdala and/or the SCN in animals entrained to cyclic fear under LD or constant darkness (DD) conditions. Specific Aim 2 will determine whether cyclic fear can also entrain the circadian rhythms of foraging and feeding in female mice, and whether sex differences are explained by the ovarian hormone regulation. Specific Aim 3 will determine whether the evocation of fear by electrical or optogenetic stimulation of the basolateral amygdala (BLA) during the dark phase is sufficient to induce entrainment of feeding and foraging, and whether the activation of the BLA is necessary for fear entrainment by optogenetically inhibiting it while animals are exposed to the fear stimulus. This Aim will also assess whether in vitro optogenetic stimulation of the amygdala is sufficient to locally entrain the amygdala circadian oscillator. Specific Aim 4A,B will exploit region-specific KOs of the clock gene Bmal1 or global KOs of the clock genes Per1 and Per2 to determine whether canonical molecular clock of mammals is part of the fear-entrained oscillator. Aim 4C will assess whether amygdala-specific Bmal1 KOS fail to entrain to cyclic fear. Our finding that nocturnal fear entrains circadian rhythms indicates that limbic centers that encode fear are part of the circuitry that orchestrates circadian rhythms. It also provides a uniquely tractable system to unmask how the master circadian clock within the SCN and the amygdala integrate photic and fear cues to time complex behavioral processes. Circadian and sleep disorders are a hallmark of anxiety and fear disorders such as post- traumatic stress disorder; our findings could shed light into the neural mechanisms that link trauma to the regulation of sleep and circadian rhythms.

概括 我们实验室最近的工作表明，周期性恐惧可以通过以下方式战胜昼夜节律的影响： 当小鼠或大鼠处于夜间活动时，光暗（LD）循环会导致昼夜觅食和进食。 它们被安置在笼子里，需要离开安全的筑巢区才能进入觅食区寻找食物和 如果觅食区域变得危险，它们会在 LD 周期的黑暗阶段觅食和进食。 在活跃的黑暗阶段，通过随机的足部震动，动物的觅食和进食活动转移到 这种向昼夜行为的切换代表了昼夜节律振荡器的输出，这是由昼夜节律振荡器引起的。 周期性恐惧刺激，并且依赖于完整的视交叉上核（SCN），其中主时钟 存在，以及编码恐惧感知的完整杏仁核，我们对此提议的工作假设是。 杏仁核内的昼夜节律振荡器受到周期性恐惧的影响，并导致时间发生变化 觅食和摄食行为。 具体目标 1 将确定周期性夜间恐惧是否会影响杏仁核中的昼夜节律振荡器 和/或在 LD 或持续黑暗 (DD) 条件下陷入周期性恐惧的动物的 SCN。 具体目标 2 将确定周期性恐惧是否也能影响觅食和进食的昼夜节律 在雌性小鼠中，以及性别差异是否可以通过卵巢激素调节来解释。 具体目标 3 将确定是否通过电刺激或光遗传学刺激引起恐惧 基底外侧杏仁核（BLA）在黑暗阶段足以诱导摄食和觅食， 以及 BLA 的激活是否对于通过光遗传学抑制它来夹带恐惧是必要的 该目的还将评估动物是否受到恐惧刺激。 杏仁核足以局部带动杏仁核昼夜节律振荡器。 具体目标 4A,B 将利用时钟基因 Bmal1 的区域特异性 KO 或时钟基因的全局 KO Per1和Per2确定哺乳动物的规范分子钟是否是恐惧的一部分 Aim 4C 将评估杏仁核特异性 Bmal1 KOS 是否无法引发周期性恐惧。 我们发现夜间恐惧会影响昼夜节律，这表明编码恐惧的边缘中枢是其中的一部分 它还提供了一个独特的易于处理的系统来揭示如何调节昼夜节律。 SCN 和杏仁核内的主生物钟将光和恐惧线索整合到时间复合体中 昼夜节律和睡眠障碍是焦虑和恐惧症（例如后遗症）的标志。 创伤性应激障碍；我们的发现可以揭示创伤与应激障碍之间的神经机制。 睡眠和昼夜节律的调节。