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

发育过程中昼夜节律稳定性对成人健康和行为的作用

• 批准号: 8784435
• 负责人: Benjamin Lee Smarr
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-16 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784435
• 关键词: Acute; Adrenal Glands; Adult; Adult Children; Affect; Agreement; Bacteria; Behavior; Behavioral; Brain; Caring; Child; Chronic; Circadian Rhythms; Clinical; Cues; Data; Development; Epigenetic Process; Event; Exercise; Eye; Fetus; Genetic; Glucocorticoids; Health; Health behavior; Heart Diseases; Hormones; Hour; Human; Hypothalamic structure; Impaired cognition; Impairment; Intervention; Jet Lag Syndrome; Lead; Learning; Life; Light; Malignant Neoplasms; Mammals; Maternal Physiology; Mental Depression; Mental Health; Methylation; Modification; Morphology; Mothers; Neonatal; Neurobiology; Neurons; Organ; Organism; Paris, France; Pattern; Peripheral; Physiological; Physiology; Pituitary Gland; Pregnancy; Prevention; Prevention strategy; Regulation; Relative (related person); Retina; Risk; Role; Rotation; Signal Transduction; Sleep; Sorting - Cell Movement; Stress; Surface; System; Testing; Time; Tissues; Travel; Ulcer; Weaning; circadian pacemaker; disorder prevention; fetal; maternal stress; neonate; neurobehavioral; neurobiological mechanism; neurogenesis; offspring; physical conditioning; pregnant; prenatal; prevent; preventive intervention; public health relevance; relating to nervous system; shift work; suprachiasmatic nucleus

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.

描述（由申请人提供）：从细菌到人类的绝大多数生活，在遗传调节，生理学和行为中演变为24 h节奏（昼夜节律；从拉丁语大约 - 大约和Diem-日）。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，大多数组织中都存在昼夜节律，但在下丘脑上张力肌核（SCN）中由昼夜节律的主钟进行了策划。 SCN在24小时内不会振荡，并且使用眼睛的光提示与地球旋转​​对齐。异常的光线提示（例如，夜间人造光，时区变化或不规则的睡眠模式）扰动SCN节奏，以及对系统范围内的下属振荡组织。急性，这些昼夜节律破坏会导致不适和认知障碍，直到重新建立同步为止。然而，慢性昼夜节律破坏（CCD）（例如，旋转班次或频繁旅行）可能会造成持久的损害，包括但不限于：成人的癌症，溃疡，心脏病和抑郁症。昼夜节律对更脆弱的生物体的影响尚不清楚。因此，鉴于发展对扰动的相对敏感性，本提案探讨了CCD在生命的早期是否具有持久的影响。我的飞行员数据表明​​，怀孕期间的CCD和断奶会对后代形态和成人行为产生不利影响，从而为经验检查提供动力。 CCD可能会通过使发展中国家的系统范围内的系统生理学或后代的节奏与母亲的不和谐对发展产生负面影响。 CCD也可能导致孕产妇应力，该应力通过化学和新生儿在行为上传达给胎儿。在早期发展中建立CCD的影响，并消除孕产妇压力的生理和行为破坏的影响，将为怀孕的母亲和幼儿的预防和废除策略提供依据。在本提案中，我将首先研究CCD暴露会对孕产妇护理，后代身体发展和后代成人行为产生负面影响的确切时机，以阐明对早期生命昼夜节律干扰最敏感的发展时代。接下来，为了确定母体应力对观察到的缺陷的具体贡献，我将探讨CCD对孕妇和后代糖皮质激素的影响 - 一种关键应激激素 - 相对于正常孕产妇护理和后代学习所需的神经发生率的节奏以及表观遗传学的速度已知可以调节压力的修改。最后，我将采用策略来1）保护母亲免受负面影响 通过遗传保护新神经元免受糖皮质激素的影响，以及2）通过运动来挽救破坏后代的节奏，这种治疗方法还可以减轻压力并增强神经发生，从而挽救了疾病的节奏。这些研究将共同​​阐明昼夜节律破坏的具体发展影响，CCD对开发产生负面影响的机制，并确定了临床干预措施的机会目标，以减少CCD的影响 做作的。