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Fear Entrainment of Circadian Rhythms

昼夜节律的恐惧夹带

基本信息

批准号：
10539261
负责人：
Horacio O De La Iglesia
金额：
$ 33.1万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10539261
关键词：
ARNTL gene Amygdaloid structure Animals Anxiety Anxiety Disorders Area Arrhythmia Behavior Behavioral Biological Clocks Biological Rhythm Bioluminescence Brain Circadian Rhythms Complex Cues Dangerousness Darkness Disease Electric Stimulation 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 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

项目摘要

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.

总结