Author ORCID Identifier

https://orcid.org/0000-0002-2770-1320

Semester

Fall

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

A. Courtney DeVries

Committee Co-Chair

Randy J. Nelson

Committee Member

Randy J. Nelson

Committee Member

Zachary M. Weil

Committee Member

Candice M. Brown

Committee Member

Gordon P. Meares

Abstract

The circadian system is composed of a subset of temporal oscillators that function through a transcriptional and post-translational molecular and functional negative feedback loop cycling approximately every 24 hours. The central clock located in the suprachiasmatic nucleus is responsible for entrainment using light as the key timekeeper (zeitgeber); it is responsible for synchronizing and optimizing physiological behavior and function to the environment. Exogenous information, such as day length and light-dark cycles, provide critical temporal cues for adjusting to environmental conditions. Proper alignment to natural light dark cycles and circadian rhythms is optimal for vital health, fitness, and survival in organisms. Although considered previously innocuous, exposure to nighttime lighting is becoming increasingly prevalent due to development and urbanization. This can disrupt time of day variations to environmental adaptations and current literature has demonstrated that light at night (LAN) substantially disrupts physiological function and behavior, dysregulates circadian organization of immune function, metabolism. Further, this is associated with increased cardiometabolic disease, cancer, and other significant health risks. Exposure to LAN is becoming more pervasive to modern life and environments, where over 80% globally, and up to 99% of the United States and European populations are exposed to nighttime lighting. Circadian disruption has been linked to poor disease outcome in cases such as stroke, sepsis, and global ischemia, and critically ill and compromised patients may be especially at risk and vulnerable to the detrimental impacts of nighttime light.

During acute injury, critically ill hospital patients require modern intensive care, which often results in nighttime lighting exposure. Circadian disruption through dim lighting exposure has been demonstrated to dysregulate pro-inflammatory cytokine production and neuroinflammation, and immune function. This is a concern given that chronic neuroinflammation can potentiate increased secondary damage in patients experiencing injury or exacerbate the effects of aging. However, there are critical gaps of knowledge that delineate the molecular and cellular mechanisms that are identifying how circadian disruption directly affects physiology. Because previous literature has identified neuroinflammation as a key aspect of physiological changes after exposure to light at night, a strategy for delineating how nighttime lighting exposure can change physiology after injury and in aged populations would involve focusing on immune system changes that would likely contribute to injury progression, and physiological aging and cognitive impairments. In this dissertation, I propose that disruptions to circadian rhythms through exposure to dim white light at night (dLAN) disrupts the circadian clock, resulting in increased health risks after ischemic injury, changes to immunological function, and greater susceptibility to cognitive impairments in aged mice. The central hypothesis tested in this dissertation is that exposure to light at night changes immune physiology and parameters that adversely affects injury progression in a murine model of stroke, physiology, and cognitive aging. The studies presented in this dissertation characterize the role of light at night affecting ischemic injury and infarct progression across two murine models of stroke. Further in Chapter 2, a cellular mechanism was identified. driving changes in immune response through shifts in microglial population phenotypes that drives increased infarct progression from nighttime lighting. The effect of nighttime lighting on immune activation and stroke outcome was prevented by using alternative spectral lighting that minimally activates intrinsically photosensitive retinal ganglion cells (ipRGCs) (Chapter 3). Next, the role of dLAN was investigated in aged populations that resulted in sex-specific alterations in physiology, immune response, and lifespan in Chapter 4. Lastly, I identified the role of disrupted circadian rhythms in aged populations to identify that chronic phase advances increase cognitive impairment and alters a component of vascular structure in aged populations in Chapter 5. Taken together, these studies indicate that exposure to ecologically relevant levels of dim broad spectrum (white) LAN can result in changes to physiology that adversely affect the development of neuronal damage and ischemic injury producing poor functional outcomes. Further, these results suggest that disruptions to circadian rhythms in aged populations could be an additional risk factor for cognitive impairments and dementia, and LAN accelerates physiological aging. Together, these studies provide evidence that characterizes and further emphasizes the harmful consequences of disruptions to circadian rhythms and nighttime lighting exposure. These data can provide foundational research required to identify potential chronotherapeutic targets for pharmacological intervention or to improve thrombolytic therapy intervention in ischemic strokes that occur across time of day.

Embargo Reason

Publication Pending

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