Effects of Methamphetamine on Circadian Rhythms of Mice

Abstract

The circadian system allows an organism to anticipate rhythmic changes in the external conditions and thereby increases its fitness. In rodents, the circadian clock resides in a pair of nuclei called the suprachiasmatic nuclei (SCN) which regulates rhythms of locomotor behavior, body temperature and some other physiological variables. However, this hierarchical organization of the circadian system is challenged by the discovery of two SCN-independent major oscillators; a feeding-entrainable oscillator (FEO) and a methamphetamine-sensitive circadian oscillator (MASCO). The presence of SCN, FEO and MASCO suggests a central multi-oscillatory organization of the circadian system in rodents, similar to the organization found in non-mammal vertebrates. At present, we know very little about how this complex multi-oscillator system is integrated.Although there is substantial information available about the SCN, the molecular components, localization and natural role of MASCO in the body are unknown. In fact, it is still debated whether MASCO is a bona fide circadian oscillator rather than a simple hourglass mechanism. This is largely due to the lack of a robust circadian model to study the effects of methamphetamine (MAP) on circadian rhythms. This thesis aims to fill some of these gaps in our understanding of this fascinating major oscillator 3 Using mice, we successfully replicated the published effects of chronic MAP on the circadian rhythms of rats. In fact, the differences such as more robust and clear activity rhythms, more pronounced MAP-induced second components of the rhythm and obvious sex and strain differences make the mice a better model.The results also indicated that MASCO interacts with the SCN in a manner that is strain, sex and dose dependent. Our experiments testing the hourglass explanation showed that the effects of MAP can not be explained by such a mechanism. This suggests that MASCO has circadian properties and is indeed a bona fide circadian clock. We also tried to elucidate the similarities between the molecular components of SCN and MASCO using several circadian mutant mice that were available to us. Although, the results of these experiments are not adequate to propose a list of known circadian genes that are involved in MASCO function, they provide the background for future studies that will determine the differences between the molecular components of SCN and MASCO.Utilization of the mouse strains presented in this thesis will provide an easy to obtain standard model where MASCO can be studied using latest developments in genetics and molecular biology. Identification of the natural role of MASCO in the body and its interactions with other oscillators in the body is of both scientific and clinical significance and will greatly improve our understanding of the circadian system in mammals.4 Acknowledgements I would like to thank Dr.Menaker for his continuous support and outstanding mentoring. I owe whatever I accomplished during my time at UVA to him and could never repay my debt. I a...