Circadian rhythms are 24-hour biological cycles, and are evident as both behavioral and physiological outputs of biological clocks distributed throughout the brain and peripheral organs. In mammals, coordination between rhythms and clocks is attained primarily by the function of a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is in turn entrained to the light- dark (LD) cycle. When mice need to leave a nesting area and access a foraging area for food and water, they primarily forage and feed during the dark phase of the LD cycle. However, when uncued footshocks occur randomly in the foraging area during the active dark phase, activity shifts to the light phase resulting in avoidance of the dangerous environment. Behavioral rhythms can also be shifted by uncued footshocks applied with a 24-h cycle in constant darkness (DD), but not if these shocks are cued by a tone. After both LD and DD exposure to cyclic unpredictable fear, the rhythms of foraging and feeding persist upon removal of all cyclic environmental time cues, indicating that these rhythms are the output of a fear-entrained oscillator.
The Aims of our funded R01 Award are to identify the location of this oscillator and its underlying molecular mechanism, and to determine whether cyclic-fear entrainment differs between female and male mice. Experiments in the parent award test our underlying hypothesis that a circadian oscillator in the amygdala, relying on the canonical clock gene transcriptional-translational loop, is entrained by fear, leading to a shift in foraging and feeding activity. This Supplement proposal seeks to extend these goals in three experimental Specific Aims, which will serve as the framework for graduate training of Asad Beck, a graduate student of African American descent, at the University of Washington Graduate Program in Neuroscience.
Specific Aim 1 will determine whether the recall of the circadian time-stamped contextual fear memory of the foraging area is sufficient to reinstate light phase foraging and feeding even in the absence of actual fear.
The second Aim will determine whether sleep architecture during the first stages of exposure to nocturnal fear, which is predictive of how effective contextual fear learing is, predicts the speed of entrainment to nocturnal fear. Finally, the third Aim will characterize the sleep architecture in fear-entrained animals, which in animals entrained to nocturnal fear under an LD cycle should reflect the internal misalignment between SCN master clock and circadian oscillators within fear-coding centers. Our proposal also includes a thorough mentoring plan for Asad Beck. A detailed timeline for the 2.5 years of funding is intended to thoroughly train the candidate to accomplish the following goals: acquire quantitative and computational skills, develop mentoring abilities, develop critical thinking, written and oral communication skills, and establish a sense of self-confidence compatible with a leadership role. The mentoring plan takes advantage of the ample resources available for graduate training at the Program in Neurocience and the University of Washington as a whole.
When mice are exposed cyclically to fear while they spontaneously forage and feed during the nighttime they eventually become day active. This is the result of the entrainment of a circadian clock by the cyclic fear. The goal of this proposal is to elucidate the role of sleep changes in fear entrainment, and conversely the long-term effects of fear entrainment on sleep. Our findings may have implication for understanding and treating sleep disorders in post-traumatic stress disorder.