Fear Entrainment of Circadian Rhythms

总结 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诱导： 光-暗（LD）周期，并导致夜间啮齿动物的昼夜觅食和进食。当小鼠或大鼠 被安置在笼子里，在笼子里，它们需要离开一个安全的筑巢区，进入觅食区觅食， 水，他们饲料和饲料在黑暗阶段的LD周期。如果觅食区变得危险 在活跃的黑暗阶段，随着随机的脚步震动，动物的觅食和进食活动转移到 光相位这种昼夜行为的转换代表了昼夜节律振荡器的输出， 循环恐惧刺激，并依赖于一个完整的视交叉上核（SCN），其中主时钟 和一个完整的杏仁核，它编码恐惧感知。我们对这个提议的工作假设是 杏仁核内的昼夜节律振荡器被周期性的恐惧所携带，并导致时间的转变。 觅食和取食行为。 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或恒定黑暗（DD）条件下陷入周期性恐惧的动物中的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 以及卵巢激素调节是否可以解释性别差异。 具体目标3将确定是否通过电或光遗传刺激引起的恐惧， 基底外侧杏仁核（BLA）在暗相期间足以诱导摄食和觅食的夹带， 以及BLA的激活是否是通过光遗传学抑制恐惧夹带所必需的， 动物暴露于恐惧刺激。该目的还将评估体外光遗传学刺激是否 杏仁核足以局部携带杏仁核昼夜节律振荡器。 特定目标4A、B将利用时钟基因Bmal 1的区域特异性科斯或时钟基因的全局科斯 Per 1和Per 2来确定哺乳动物的典型分子钟是否是恐惧的一部分。 振荡器目的4C将评估杏仁核特异性Bmal 1科斯OS是否未能引起循环性恐惧。 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系统中心是 协调昼夜节律的电路。它还提供了一个独特的易于处理的系统， 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 行为过程昼夜节律和睡眠障碍是焦虑和恐惧障碍的标志，例如， 创伤性应激障碍;我们的研究结果可以揭示将创伤与创伤联系起来的神经机制。 调节睡眠和昼夜节律。

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.