Author ORCID Identifier
Year of Publication
Doctor of Philosophy (PhD)
Arts and Sciences
Dr. Bruce F. O'Hara
Sleep is a process essential for the well-being of an animal and in humans as much as one-third of our life is spent in sleep. Yet, the biological need for sleep still remains a conundrum. Our knowledge of the genes influencing sleep and the mechanisms regulating the process can be advanced with the utilization of genetic and genomic approaches which, in turn, may inform us about the functions of sleep as well. With this goal, I have investigated and examined sleep-wake phenotypes for a variety of transgenic and knock out animals.
For the first part of my research (Chapter 3), I examined mouse models of Alzheimer’s disease, and a combined model of Alzheimer’s disease (AD) and Diabetes. Sleep disturbances in case of AD are evident long before the onset of cognitive decline. I investigated sleep-wake alterations in 5XFAD, a double transgenic mouse model of AD which displays an early onset of AD pathology and cognitive impairments. We found that these mice have shorter bout lengths under baseline conditions. This was true for both sexes, however, the effect was more prominent in females. Additionally, females also had a shorter duration of sleep compared to control animals. These overall bout length reductions are indicative of increased sleep fragmentation similar to the ones seen in human AD patients.
Inadequate sleep is associated with increased risk for metabolic disorders such as diabetes besides neurodegenerative diseases such as AD. There is also growing evidence that type 2 diabetes mellitus (T2DM) poses an increased risk of AD. To understand how the two conditions interact, we studied a combined mouse model of AD and diabetes (db/AD) which was generated by crossing of db/db (diabetic obese mice) and APP-PS1 (knock-in AD mouse model). The resulting mice showed profound cerebrovascular as well as AD pathology. Both females and males, diabetic AD animals had longer sleep duration compared to non-diabetic AD animals. They also exhibited attenuated sleep-wake rhythms. Females were found to have shorter sleep bouts than males. In addition, significant two way interactions were found for the age and db/AD genotype. Our findings suggest that db genotype and not cerebrovascular pathologies affect sleep in our mouse model. For the last part of my research, we analyzed over 300 single gene knock out mouse lines generated on a C57BL6/NJ background, monitored at The Jackson Laboratory. With this unbiased approach where the knockouts were chosen at random, we identified 55 novel genes affecting various sleep traits, utilizing a variety of statistical approaches. Sex differences were found for a number of knockouts as well as controls. Control females were found to have shorter bout lengths and less sleep duration compared to male littermates.
Digital Object Identifier (DOI)
Sethi, Mansi, "SLEEP ALTERATIONS IN MOUSE GENETIC MODELS OF HUMAN DISEASE" (2016). Theses and Dissertations--Biology. 38.