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Pitx3 KNOCKOUT MICE ENTRAIN to SCHEDULED FEEDING DESPITE

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Pitx3 KNOCKOUT MICE ENTRAIN to SCHEDULED FEEDING DESPITE Pitx3 KNOCKOUT MICE ENTRAIN TO SCHEDULED FEEDING DESPITE FREE-RUNNING LIGHT ENTRAINED RHYTHMS A Thesis Presented to the Faculty of California State Polytechnic University, Pomona In Partial Fulfillment Of the Requirements for the Degree Master of Science In Biological Sciences By Lori L. Scarpa 2019 SIGNATURE PAGE THESIS: Pitx3 KNOCKOUT MICE ENTRAIN TO SCHEDULED FEEINDING DESPITE FREE-RUNNING LIGHT ENTRAINED RHYTHMS AUTHOR: Lori L. Scarpa DATE SUBMITTED: Fall 2019 Department of Biological Sciences Dr. Andrew D. Steele Thesis Committee Chair Biological Sciences Dr. Juanita Jellyman Biological Sciences Dr. Robert Talmadge Biological Sciences ii ACKNOWLEDGEMENTS Funding for this project was provided by the Whitehall Foundation and California State Polytechnic University of Pomona, California. I would like to thank the many people who assisted in the daily labors required to complete this project: Raymundo Miranda, Michael Sidikpramana, Jeffrey Falkenstein, Michael Williams, Jaskaran Dhanoa, and many other members of the Steele lab. I would like to specially recognize fellow graduate students in the Steele lab, Damien Wolfe and Andrew Villa, for their unconditional encouragement and support. I would like to thank Dr. Juanita Jellyman for her kindness and nurturing spirit. Dr. Jellyman never wavered her belief in me and it was this that kept me working harder towards my goals. Lastly, I would like thank Dr. Andrew Steele for accepting me into his lab, for being my personal mentor, and for pushing me towards success. Through him, I have grown to become a better scientist and found greater inspiration in my pursuit to further study neuroscience. Thank you, Dr. Steele, for your support and patience, and for playing a leading role in my success as a graduate student in your lab. iii ABSTRACT It is well known that many of our biological processes are regulated by circadian rhythms. Photic input is the best characterized stimulus for entraining circadian rhythms. In mammals, light input is conveyed to a brain structure called the suprachiasmatic nucleus (SCN), which serves as a central clock, controlling the timing of sleep-wake, hormone secretion, and many other physiological functions. Feeding is another modulator of circadian rhythms, acting in an SCN-independent manner, as rodents with lesions to the SCN show normal anticipation of scheduled meals. Recent studies implicate dopamine signaling as a key mediator of entraining circadian rhythms to scheduled feeding. Mice with impairments in dopamine production or in dopamine receptors show decreased food anticipatory activity (FAA), a measure of food entrainment. Here, we are studying the influence of food on circadian rhythms in paired- like homeodomain 3 (Pitx3) knockout mice, which are severely depleted for dopamine neurons of the substantia nigra. These knockout mice also lack retinal ganglion cells and exhibit free-running behavioral rhythms that are not linked to the light:dark cycle, making it difficult to determine whether their activity entrains to scheduled feeding. By making continuous measurements of their activity, our home cage behavioral data suggests that the Pitx3 knockouts exhibit FAA. In addition, we demonstrated that metabolic rhythms in these mice entrain to scheduled feeding rapidly. To study the contribution of Pitx3-expressing dopamine neurons to FAA in a cleaner system, we attempted to perform a follow-up experiment where we deleted the dopamine producing enzyme, tyrosine hydroxylase, from Pitx3 expressing neurons. However, these mice die about 2 weeks after birth, making it impossible for us to study food entrainment in this iv conditional deletion model. Future studies to further verify our findings that a small population of dopamine neurons in the midbrain are sufficient for FAA are warranted. v TABLE OF CONTENTS SIGNATURE PAGE ..........................................................................................................ii ACKNOWLEDGEMENTS ..............................................................................................iii ABSTRACT ......................................................................................................................iv LIST OF TABLES............................................................................................................ vii LIST OF FIGURES .........................................................................................................viii INTRODUCTION ..............................................................................................................1 METHODS AND MATERIALS .......................................................................................11 RESULTS ..........................................................................................................................17 DISCUSSION ....................................................................................................................50 REFERENCES .................................................................................................................55 vi LIST OF TABLES Table 1. Primer sequences for amplification of Pitx3....................................................... 14 vii LIST OF FIGURES Figure 1: Transcriptional-translational feedback loop controlling circadian rhythms........ 3 Figure 2: Average daily food intake measurements of Pitx3 control and Pitx3 KO mice.22 Figure 3: Survival plot of Pitx3 mice on 60% CR. ........................................................... 22 Figure 4: Average weekly body weights of Pitx3 control and Pitx3 KO mice on 60% CR. ........................................................................................................................................... 23 Figure 5: Average weekly activity measurements from video recording in Pitx3 control and Pitx3 KO mice on 60% CR. ....................................................................................... 23 Figure 6: Weekly activity waveforms on 60% CR. .......................................................... 24 Figure 7: Activity monitoring of individual Pitx3 mice on 60% CR via photobeam breaks. ........................................................................................................................................... 25 Figure 8: Survival plot of Pitx3 mice on 80% CR. ........................................................... 29 Figure 9: Average weekly body weights of Pitx3 control and Pitx3 KO mice on 80% CR. ........................................................................................................................................... 29 Figure 10: Average weekly activity measurements from video recording in Pitx3 control and Pitx3 KO mice on 80% CR. ....................................................................................... 30 Figure 11: Weekly activity waveforms on 80% CR. ........................................................ 31 Figure 12: Activity monitoring of individual Pitx3 mice on 80% CR via photobeam breaks. ............................................................................................................................... 35 Figure 13: Activity monitoring of individual Pitx3 control mice on 60% CR via photobeam breaks. ............................................................................................................ 36 Figure 14: Activity monitoring of individual Pitx3 KO mice on 80% CR via photobeam breaks. ............................................................................................................................... 37 Figure 15: Averaged activity waveforms on 80% CR. ..................................................... 40 Figure 16: Total activity and FAA ratios on AL and 80% CR. ........................................ 39 Figure 17: Average body composition measurements in Pitx3 control and Pitx3 KO mice on AL. ............................................................................................................................... 42 Figure 18: Average waveforms of total activity in Pitx3 mice on AL and 80% CR. ....... 43 Figure 19: Gas exchange of Pitx3 mice on AL and 80% CR. .......................................... 43 Figure 20: Identification of midbrain dopaminergic neurons via IF staining for TH and DAPI at 10x magnification in Pitx3 control brain tissue. ................................................. 45 Figure 21: Identification of midbrain dopaminergic neurons via IF staining for TH and DAPI at 10x magnification in Pitx3 KO brain tissue. ...................................................... 46 Figure 22: In situ Hybridization staining for TH and DAPI at 20x magnification. .......... 47 Figure 23: Visualization of dopaminergic projections via IF staining for TH and DAPI. 47 Figure 24: Visualization of dopaminergic positive areas in the forebrain of Pitx3 mice. 48 Figure 25: Survival plot of Pitx3-cre mice during first 30 days of life…………………..52 viii INTRODUCTION Biological Rhythms In 1729, Jacques d’Ortous de Mairan demonstrated that the leaves of the mimosa plant continued to open and close with the same daily rhythm when kept in constant darkness (de Marian, 1729). This experiment was the first evidence of an autonomous clock regulating biological rhythms even. Biological rhythms are natural cycles of change in a body’s function. In order to qualify as a biological rhythm, the cycle must persist in the absence of a time-cue, often referred to as a zeitgeber (Aschoff, 1965). There are three main types of biological rhythms: circadian, infradian,
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