Date of Award

12-1-2021

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Tischkau, Shelley

Abstract

The circadian system uses environmental cues to coordinate the plethora of physiological functions that occur with diurnal rhythmicity, with light being one of the strongest regulators of the circadian system. The suprachiasmatic nucleus (SCN) is positioned at the top of the circadian hierarchy, receiving photic input from the retina and using neuronal, humoral and endocrine signals to synchronize oscillatory patterns across virtually all organ systems. Though the circadian system is plastic to deviations from a normal light/dark (LD) cycle, there are biological limits as to the rate and degree to which the SCN can adapt to these deviations, with peripheral oscillators responding in a delayed manner to the master clock. Alzheimer’s disease (AD) has long been linked to disruptions in the circadian system, with circadian deficits generally portrayed as a consequence of disease development. Recent evidence, however, suggests that circadian disruptions may precede noticeable cognitive deficits associated with AD. Our study aims to determine whether inducible circadian disruption via exposure to our social jetlag protocol, taking advantage of manipulating light exposure to disrupt the circadian system, can exacerbate the rate and severity of AD pathology in both the AβPP/PS1 and APPNL-F/NL-F mouse models of AD. AβPP/PS1 and APPNL-F/NL-F subjected to a preliminary study at 2-4 months in which overall activity in normal LD conditions, re-entrainment to a maintained 8-hour phase advance of the LD cycle, and endogenous period in constant darkness were measured. Glucose Tolerance Test (GTT) was used to assess metabolic health. Following the preliminary study, wild type (WT; C57BL/6J) controls, AβPP/PS1 and APPNL-F/NL-F AD models were entrained to a control light/dark cycle starting at 6 weeks of age. Following 2-weeks of entrainment, half of the animals were maintained on the control schedule, and half were exposed to the social jetlag protocol, involving an 8-hour phase advance on day 5 and an 8-hour phase delay on day 7 of repeated 7-day sessions, effectively inducing chronic circadian disruption until the assigned 6 and 12-month endpoints. One month prior to the endpoint, activity measures and GTT were performed, following which the animals were all entrained to a normal 12:12 LD schedule for 3-5 weeks. Finally, animals underwent an 8-day Morris Water Maze (MWM) to assess effects of chronic disruption on AD-related cognitive decline. Animals were then sacrificed and tissues collected at Zeitgeber time (ZT) 12, time of lights off. At 2-4 months of age, preclinical stages in both AD models, APPNL-F/NL-F males displayed significantly higher fasting glucose levels and circadian period (day length). There were trending increases in overall activity levels under normal 12:12 LD conditions in both AD models over WT controls. 2-4 month females re-entrained to an 8-hour phase advance in significantly less time than males in all genotypes. AβPP/PS1 mice demonstrated hyperactivity as compared to age and sex-matched WT controls. Chronic circadian disruption dampened lights off activity in all cohorts. In all genotypes, female animals showed a higher degree of re-entrainment to the phase advancement of the lighting schedule going into the subjective weekend (day 6-7). Metabolic data as measured by glucose tolerance test on day 7 of the (social jet lag) SJL schedule indicated that disrupted animals were metabolically entrained to the day 1-5 schedule at the peak of rhythmic metabolic function, whereas control animals were at a low point in metabolic rhythms at the time of testing, indicating that circadian regulation of metabolic function was not able to adapt to the weekend phase shifts. Arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) expression in the SCN were significantly dampened as a result of chronic disruption in 12-month male AD mice. Amyloid plaque analysis indicated a severely worsened pathological phenotype in AβPP/PS1 mice as compared to age and sex-matched APPNL-F/NL-F mice. MWM data provides evidence for impaired spatial learning in both AD models that is significantly worsened by chronic jetlag exposure. Taken together, the data suggests that chronic exposure to the social jet lag schedule disrupts rhythmic behavior, metabolic function, and spatial learning significantly in both AD animal models.

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