The role of circadian stability during development in adult health and behavior

描述（由申请人提供）：绝大多数生命，从细菌到人类，在基因调控、生理和行为方面进化出24小时的节律（circadian；源自拉丁语circa - about - and diem - day）。稳定的昼夜节律对于维持正常的身心健康至关重要。在哺乳动物（包括人类）中，昼夜节律存在于大多数组织中，但由下丘脑视交叉上核（SCN）中的主昼夜节律时钟协调。SCN不会在24小时内精确振荡，而是利用眼睛发出的光线索与地球自转对齐。异常的光信号（如夜间人造光、时区变化或不规则的睡眠模式）会扰乱SCN节律，并使整个系统的下属振荡组织不同步。严重的是，这些昼夜节律中断会导致不适和认知障碍，直到重新建立同步。然而，慢性昼夜节律中断（CCDs）（例如，轮班或频繁旅行）可能导致持久的损害，包括但不限于：癌症、溃疡、心脏病和成人抑郁症。昼夜节律不稳定对更脆弱的发育中的生物体的影响尚不清楚。因此，鉴于发育对扰动的相对敏感性，本研究探讨了CCD在生命早期是否具有持久的影响。我的试点数据表明，怀孕和断奶期间的CCD对子代形态和成虫行为有不利影响，为实证研究提供了动力。有可能CCD通过使发育中的生物体的全系统生理不同步，或通过后代和母亲的节律不协调，对发育产生负面影响。也有可能是CCD引起母亲的压力，这种压力通过化学方式传递给胎儿，并通过行为传递给新生儿。确定CCD对早期发育的影响，并将生理和行为紊乱的影响与母亲压力的影响区分开来，将为孕妇和幼儿的预防和消除策略提供信息。在本提案中，我将首先研究CCD暴露对母亲护理、后代身体发育和后代成年行为产生负面影响的确切时间，以阐明对生命早期昼夜节律中断最敏感的发育时间。接下来，为了确定母亲压力对观察到的缺陷的具体贡献，我将探讨CCD对母亲和后代糖皮质激素（一种关键的应激激素）的影响，这种激素与正常母亲护理和后代学习所需的神经发生率有关，并与已知的调节压力的表观遗传修饰有关。最后，我会采取一些策略来保护母亲免受负面影响

DESCRIPTION (provided by applicant): The vast majority of life, from bacteria to humans, evolved 24 h rhythms (circadian; from the latin circa - about - and diem - day) in genetic regulation, physiology and behavior. Stable circadian rhythms are critical for maintaining normal mental and physical health. In mammals (including humans), circadian rhythms are present in most tissues, but orchestrated by a master circadian clock in the hypothalamic suprachiasmatic nucleus (SCN). The SCN does not oscillate at exactly 24 h, and is aligned to the Earth's rotation using light cues from the eye. Abnormal light cues (e.g., artificial light at night, time-zone changes, or irregular sleep patterns) perturb SCN rhythms, and desynchronize subordinate oscillating tissues system-wide. Acutely, these circadian disruptions cause discomfort and cognitive impairment until synchrony is reestablished. Chronic circadian disruptions (CCDs), (e.g., rotating shifts or frequent travel), however, can cause lasting impairments, including but not limited to: cancer, ulceration, heart disease, and depression in adults. The impact of circadian instability on more vulnerable, developing organisms is not known. Thus, given the relative sensitivity of development to perturbation, the present proposal explores whether CCD, early in life, has an enduring impact. My pilot data indicate that CCD during pregnancy and weaning adversely affects offspring morphology and adult behavior, providing impetus for empirical examination. It is possible that CCD negatively affects development by desynchronizing system-wide physiology in the developing organism, or through disharmony between offspring rhythms and those of their mother. It is also possible that CCD causes maternal stress, which is communicated to the fetus chemically and to the neonates behaviorally. Establishing the impact of CCD across early development, and disambiguating effects of physiological and behavioral disruption from those of maternal stress, will inform strategies for prevention and abrogation in pregnant mothers and young children. In the present proposal I will first examine the precise timing during which CCD exposure negatively impacts maternal care, offspring physical development, and offspring adult behavior to clarify the times of development most sensitive to early-life circadian disruptions. Next, to determine the specific contribution of maternal stress to observed deficits, I will explore the impact of CCD on maternal and offspring glucocorticoid - a key stress hormone - rhythms relative to rates of neurogenesis required for normal maternal care and offspring learning, and with epigenetic modifications known to regulate stress. Finally, I will employ strategies to 1) protect mothers from the negative impact of circadian disruption by genetically protecting new neurons from glucocorticoids, and 2) rescue the rhythms of disrupted offspring with exercise, a treatment that also reduces stress and enhances neurogenesis. Together, these studies will clarify the specific developmental impact of circadian disruption, the mechanisms by which CCD negatively impacts development, and identify targets of opportunity for clinical interventions to reduce the impact of CCD in those affected.