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.
Although it well-established that stable circadian (daily) rhythms are important for adult health and disease prevention, little is known about the impact of disruptions to circadian rhythms on early life development. Artificial lights and shift work negatively impact body and brain rhythms, with lasting health impacts, suggesting that daily disruptions of this sort during fetal and early life development can lead to life-long damage. This proposal seeks to understand the role of daily stability in early development, identify the risks o early life instability, and test interventions and preventions to mollify these risks when daily instability is unavoidable.
| Smarr, Benjamin L; Grant, Azure D; Perez, Luz et al. (2017) Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice. Sci Rep 7:3326 |
| Smarr, Benjamin L; Grant, Azure D; Zucker, Irving et al. (2017) Sex differences in variability across timescales in BALB/c mice. Biol Sex Differ 8:7 |
| Smarr, Benjamin L; Zucker, Irving; Kriegsfeld, Lance J (2016) Detection of Successful and Unsuccessful Pregnancies in Mice within Hours of Pairing through Frequency Analysis of High Temporal Resolution Core Body Temperature Data. PLoS One 11:e0160127 |
