Abstract: Life on Earth has adapted to a consistent 24-h solar cycle. Circadian rhythms in physiology and behavior remain synchronized to the environment using light as the most potent entraining cue. During the past century, however, the widespread adoption of electric light has led to `round-the-clock’ societies. Instead of aligning with the environment, individuals follow artificial and often erratic light cycles created by social and work schedules. In particular, exposure to artificial light at night (LAN), termed “light pollution”, has become pervasive over the past 100 years. Virtually every individual living in the U.S. and Europe experiences this aberrant light exposure, and moreover about 20% of the population performs shift work. LAN may disrupt physiological timekeeping, leading to dysregulation of internal processes and misalignment between behavior and the environment. Recent evidence suggests that individuals exposed to excessive LAN, such as night shift workers, have increased risk for depressive disorders, but the biological mechanism remains unspecified. In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) project light information to (1) the suprachiasmatic nucleus (SCN) in the hypothalamus, regulating circadian rhythms, and (2) to limbic regions, putatively regulating mood. Thus, LAN has the potential to affect both circadian timekeeping and mood. In this dissertation, I present evidence from rodent studies supporting the novel hypothesis that night-time exposure to light disrupts circadian organization and contributes to depressed mood. First, I consider the physiological and behavioral consequences associated with unnatural exposure to LAN. The effects of LAN on circadian output are considered in terms of locomotor activity, the diurnal cortisol rhythm, and diurnal clock protein expression in the brain in Chapter 2. The influence of LAN on behavior and brain plasticity is discussed, with particular focus on depressive-like behavior (Chapter 3) and effects of SSRI treatment (Chapter 4). Effects of LAN on structural plasticity and gene expression in the brain are described, with emphasis on potential correlates of the depressive-like behavior observed under LAN in Chapter 5. Given the prevalence of LAN exposure and its importance, strategies for reversing the effects are offered. Specifically, eliminating LAN quickly reverses behavioral and physiological effects of exposure as described in Chapter 5. In Chapter 6 I report that administration of a pharmacological cytokine inhibitor prevents depressive-like behaviors in LAN, implicating brain inflammation in the behavioral effect. Finally, I demonstrate in Chapter 7 that exposure to red wavelength LAN reduces the effects on brain and behavior, suggesting that LAN acts through specific retinal pathways involving melanopsin. Taken together, these studies demonstrate the consequences of LAN, but also outline potential avenues for prevention or intervention.

Abstract: PURPOSE OF REVIEW: This review aims to explore how circadian rhythms influence disease susceptibility and potentially modify the effect of environmental exposures. We aimed to identify biomarkers commonly used in environmental health research that have also been the subject of chronobiology studies, in order to review circadian rhythms of relevance to environmental health and determine if time-of-day is an important factor to consider in environmental health studies. Moreover, we discuss opportunities for studying how environmental exposures may interact with circadian rhythms to structure disease pathology and etiology. RECENT FINDINGS: In recent years, the study of circadian rhythms in mammals has flourished. Animal models revealed that all body tissues have circadian rhythms. In humans, circadian rhythms were also shown to exist at multiple levels of organization: molecular, cellular, and physiological processes, including responding to oxidative stress, cell trafficking, and sex hormone production, respectively. Together, these rhythms are an essential component of human physiology and can shape an individual's susceptibility and response to disease. Circadian rhythms are relatively unexplored in environmental health research. However, circadian clocks control many physiological and behavioral processes that impact exposure pathways and disease systems. We believe this review will motivate new studies of (i) the impact of exposures on circadian rhythms, (ii) how circadian rhythms modify the effect of environmental exposures, and (iii) how time-of-day impacts our ability to observe the body's response to exposure.

Abstract: Previous studies have indicated that minimal exposure to light at night (LAN) increases depression risk, even at 5 lux, in nocturnal and diurnal mammals. Although such low-level LAN may affect human circadian physiology, the association between exposure to LAN and depressive symptoms remains uncertain. In the present study, bedroom light intensity was measured objectively, and depressive symptoms were assessed, during 2010-2014 in Nara, Japan. Of 863 participants (mean age = 71.5 years) who did not have depressive symptoms at baseline, 73 participants reported development of depressive symptoms during follow-up (median, 24 months). Compared with the “dark” group (average of <5 lux; n = 710), the LAN group (average of >/=5 lux; n = 153) exhibited a significantly higher depression risk (hazard ratio = 1.89; 95% CI: 1.13, 3.14), according to a Cox proportional hazards model adjusting for age, sex, body mass index, and economic status. Further, the significance remained in a multivariable model adjusting for hypertension, diabetes, and sleep parameters (hazard ratio = 1.72; 95% CI: 1.03, 2.89). Sensitivity analyses using bedroom light data with a cutoff value of >/=10 lux suggested consistent results. In conclusion, these results indicated that exposure to LAN in home settings was independently associated with subsequent depression risk in an elderly general population.