Nearly all animals exhibit behaviors that can be classified as sleep. The distinctly disadvantageous nature of the asleep state, evolutionarily speaking, accentuates its role as a critical physiological process, yet chronic inadequate sleep is prevalent in today’s society. Among the multitude of health problems that have been linked to chronic sleep disruption, increased inflammation and alterations to the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis indicate that the sleep-deprived state may result in a vulnerability to a second hit of an acute stressor. The project described in this dissertation examines this relationship between sleep disruption and stress vulnerability and investigates novel approaches to increase stress robustness in the context of disrupted sleep, focusing on the role of a newly characterized system: the gut microbiome. Our intestinal tracts are home to trillions of microbes with a collective genetic diversity that dwarfs our own and which strongly influence our gastrointestinal, metabolic, endocrine, immune, and nervous systems. These discoveries have opened the door for research into microbiome-based interventions such as vaccination with immunomodulatory bacteria and manipulation of the microbiome with prebiotic diets that aim to improve health. This dissertation begins with a chapter reviewing our current understanding of sleep, stress responses, and the microbiome, with an emphasis on how sleep disruption may interact with both the microbiome and stress vulnerability. The second chapter describes results from a study in mice characterizing the effect of repeated sleep disruption on the fecal microbiome and fecal metabolome. Next, the third chapter reports findings from a larger mouse study investigating the impact of repeated sleep disruption on vulnerability to a secondary acute stressor, and the ability of immunization with a heat-killed bacterium called Mycobacterium vaccae NCTC 11659 to improve resilience to these manipulations. The fourth chapter reports a detailed characterization of the gut microbiomes and metabolomes from mice studied in Chapter III, identifying candidate molecules that may be contributing to stress vulnerability/resilience in the context of sleep disruption. Then, the Chapter V discusses the findings from a study in rats that used a similar protocol of combined repeated sleep disruption and acute stress, but half of these animals were instead fed a microbiome-modifying prebiotic diet. Finally, the entirety of these results are discussed in relation to the project goals and current/future research directions are outlined in Chapter VI. Overall, the series of experiments and analyses contained in this dissertation contribute to our understanding of the relationship between sleep and stress vulnerability, and provide evidence supporting microbiome-based interventions such as M. vaccae immunization and prebiotic diets as intriguing new countermeasures to improve resilience to sleep disruption. There were 4 supplemental files submitted with this dissertation. Supplemental File 2.1 is a spreadsheet depicting complete statistical results for the PERMANOVA, ANOVA, and mixed-effects models that are reported in Chapter II. Supplemental File 2.2 is also a spreadsheet that reports the results of the PICRUSt2 analysis that was run in Chapter II and reported in Figure 2.7i. Supplemental File 3.1 is a spreadsheet reporting complete statistical results for the linear mixed models and post-hoc comparisons reported in figures of Chapter III. Supplemental File 3.2 is a spreadsheet containing the details of the correlational analyses reported in Figures 3.10 and 3.11.

Creator

• Bowers, Samuel James

DOI

• https://doi.org/10.21985/n2-2r7m-9f78

Subject

• Biology
• Neurosciences

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:15162
• etdadmin_upload_749831

Keyword

• Metabolome
• Stress
• Sleep
• Sleep Deprivation
• Microbiome
• PTSD

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright