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 我们实验室的最新工作表明，环保恐惧可能会因围困的昼夜节律而盛行 浅黑色（LD）周期，并导致夜间啮齿动物的昼夜觅食和进食。当老鼠或老鼠是 安置在笼子设置中，他们需要离开安全的筑巢区，以获取食物和食物的觅食区 在LD循环的黑暗阶段，他们的水，觅食和进食。如果觅食区域变得危险 在活跃的黑阶段中随机脚印，动物的觅食和进食活动转移到 光阶段。此切换到昼夜行为代表昼夜节律振荡器的输出，该振荡器由 循环恐惧刺激，并取决于完整的上核（SCN），其中主钟 居住，以及完整的杏仁核，它编码恐惧感知。我们为此提出的工作假设是 杏仁核内的昼夜节律振荡器充满了循环恐惧，并导致了时间安排的转变 觅食和进食行为。 具体目标1将确定循环夜间恐惧是否进入杏仁核中的昼夜节律振荡器 和/或动物中的SCN在LD或恒定黑暗（DD）条件下引起循环恐惧。 特定的目标2将确定循环恐惧是否也可以进入觅食和喂养的昼夜节律节奏 在雌性小鼠中，以及性别差异是否由卵巢马酮调节来解释。 具体目标3将确定恐惧的演变是通过电气或光遗传学刺激的 黑暗相期间的基底外侧杏仁核（BLA）足以诱导喂养和觅食的启发， 以及对于通过光源抑制恐惧的恐惧而激活BLA是否需要激活 动物暴露于恐惧刺激中。该目标还将评估是否在体外光遗传学刺激 杏仁核足以在局部进入杏仁核昼夜节律振荡器。 特定的目标4A，B将利用时钟基因BMAL1或时钟基因的全局KO的特定区域特异性KO PER1和PER2确定哺乳动物的规范分子时钟是否是恐惧感染的一部分 振荡器。 AIM 4C将评估杏仁核特异性的BMAL1 KOS是否未能引起周期性恐惧。 我们发现夜间恐惧吸引昼夜节律的发现表明，编码恐惧的边缘中心是一部分 编排昼夜节律的电路。它还提供了一个独特的寓言系统，可以揭示如何 SCN中的昼夜节律大师时钟和杏仁核整合了光学和恐惧提示到时复杂 行为过程。昼夜节律和睡眠障碍是动画和恐惧障碍的标志，例如 创伤性应激障碍；我们的发现可能会阐明将创伤联系到的神经机制 对睡眠和昼夜节律的调节。