Author ORCID Identifier

https://orcid.org/0000-0002-6196-3818

Semester

Summer

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Neurology

Committee Chair

A. Courtney DeVries

Committee Member

Randy J. Nelson

Committee Member

Paul D. Chantler

Committee Member

Zachary M. Weil

Committee Member

Gordon P. Meares

Abstract

Circadian rhythms are endogenous cycles that recur approximately every 24 h, and manifest in virtually every physiological and behavioral process among the vast majority of organisms. These rhythms, sustained by the central circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, allow for optimal timing of biological processes that ensure organisms’ homeostasis, and are entrained to precisely 24 h by daily exposure to light. Disruption of the molecular mechanisms that drive these rhythms have negative consequences on physiology and behavior that may impair survival. The molecular mechanisms that underlie these effects are widely studied and linked to multiple diseases and disorders; nevertheless, environmental contributors to disrupted circadian rhythms and the associated disorders have only recently been taken into consideration. Specifically, exposure to artificial light at night (ALAN) is associated with disruption of the biological clock, and the inability to regulate internal homeostatic processes.

Indeed, exposure to ALAN is associated with multiple disorders including cardiovascular diseases, and is classified as a risk factor for the development of various cancers. Notably, the risk of developing vascular and other metabolic disorders is salient among night shift workers, does not solely depend on current metabolic health or risk factor status (e.g., high body mass index, smoker, etc), and the risk of developing these is proportional to years spent engaged in night shift work.

Preclinical rodent studies modeling the two key aspects of disrupted circadian rhythms in night shift workers, altered day-night routines (i.e., shifting typical day-night schedules), and exposure to ALAN, have replicated the negative effects on health observed in this population. Specifically, disrupted circadian rhythms alter aspects of metabolism, such as body mass, glucose and insulin processing. However, this research was performed using males, limiting the applicability of the results to females.

To bridge this critical gap, the present dissertation work aimed to 1) uncover whether exposure to low level ALAN (5 lux), affects circadian regulation of aortic endothelial function, 2) determine whether sleep and metabolism are affected by ALAN, and 3) examine whether exposure to ALAN during recovery from ischemic stroke negatively affects outcomes, in a sex-dependent manner.

The central hypothesis tested through this dissertation is that exposure to artificial light during the night alters metabolism, sleep, and recovery from ischemia, and the effects differ as a function of biological sex.

In Chapter I, I discuss circadian rhythms and provide a literature review of the effects of exposure to ALAN on human and animal health, with a focus on cardiometabolic health, and an emphasis on inclusion of sex as a key biological variable. In Chapter II, I demonstrate that endothelial dilation varies throughout the day, and that exposure to ALAN alters diel variability in a sex-specific manner. Further, I demonstrate that, relative to mice housed in dark nights, ALAN increases the respiratory exchange ratio (RER) in both male and female mice during phase transitions. Moreover, I demonstrate that alterations to the timing of food consumption and the body mass increase typically associated with ALAN in males, differs in females. These data suggest that 1) decreased lipid metabolism, in males, may mediate the increased body mass accumulation observed with ALAN, and that 2) the mechanisms that regulate body mass in females differ from those in males.

To further elucidate the effects of ALAN on metabolism, in Chapters III and IV I examine whether the effects observed in Chapter II extend with chronic (≥ 20 weeks) exposure to ALAN, and investigate whether sleep is altered. My data indicate that ALAN dampens daily rhythms in all metabolic parameters assessed in both sexes, and dampens sleep rhythms in females.

One of the hallmarks of the effects of exposure to ALAN on male Swiss Webster mice, is increased body mass without changes in total caloric intake. Upon realizing that mice did not gain the anticipated mass, further investigation revealed that the vivarium lighting had been altered. I then tested the hypothesis that daytime light exposure affects body mass gain in male mice (Chapter V).

Finally, in Chapter VI, I provide preliminary results for an ongoing study examining how ALAN alters post-stroke recovery in aged male mice, using neurobehavioral assessments, cognitive testing, and infarct quantification. Together, my data indicate that ALAN alters aspects of metabolism and sleep, and the effects are dose- and sex-dependent.

Embargo Reason

Publication Pending

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