Sleep and Activity Problems in Mouse Models of Neurodevelopmental Disorders
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University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Sleep And Activity Problems In Mouse Models Of Neurodevelopmental Disorders Christopher Angelakos University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons Recommended Citation Angelakos, Christopher, "Sleep And Activity Problems In Mouse Models Of Neurodevelopmental Disorders" (2017). Publicly Accessible Penn Dissertations. 2748. https://repository.upenn.edu/edissertations/2748 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2748 For more information, please contact [email protected]. Sleep And Activity Problems In Mouse Models Of Neurodevelopmental Disorders Abstract Adequate sleep is important for long-term health and day-to-day function. Compared to the general population, patients diagnosed with neurodevelopmental disorders have substantially higher prevalence of sleep, activity, and circadian problems, dramatically affecting their quality of life, and potentially exacerbating other adverse symptomologies. Despite this, the neurobiological underpinnings of sleep problems in neurodevelopmental disorders remain unknown, and accurate rodent models capable of recapitulating human sleep and activity problems are lacking. In this dissertation, I investigate sleep, activity, and circadian rhythms in genetic mouse models of human neurodevelopmental disorders, with a focus on autism spectrum disorder (ASD). In Chapter 1, I review the importance of—and mechanisms contributing to—sleep/wake regulation, sleep problems in neurodevelopmental disorders, and the utility of rodent genetic models to address these problems. In Chapter 2, I investigate hyperactivity and male- specific sleep deficits found in the 16p11.2 del/+ chromosomal copy number variation mouse model of neurodevelopmental disorders (Angelakos et al., 2016). In Chapter 3, I highlight REM sleep reductions and altered electroencephalography (EEG) spectra in the SYGNAP1+/- mouse model of intellectual disability and ASD. In Chapter 4, I discuss home-cage hypoactivity observed in four different mouse models of ASD. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Ted Abel Keywords Autism, Circadian Rhythms, Mouse Models, Neurodevelopmental Disorders, Sex Differences, Sleep Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2748 SLEEP AND ACTIVITY PROBLEMS IN MOUSE MODELS OF NEURODEVELOPMENTAL DISORDERS Christopher Caleb Angelakos A DISSERTATION in Neuroscience Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation _______________________ Ted Abel Brush Family Professor of Biology Graduate Group Chairperson _______________________ Joshua Gold Professor of Neuroscience Dissertation Committee: David Raizen, Associate Professor of Neurology (Committee Chair) Max Kelz, David E. Longnecker Associate Professor of Anesthesiology and Critical Care Claire Mitchell, Professor of Anatomy and Cell Biology Mark Opp, Professor of Anesthesiology and Pain Medicine and Vice Chair for Basic Research ACKNOWLEDGMENT I would like to thank my advisor, Dr. Ted Abel, for his mentorship and guidance over the last five years. Ted has challenged me to ask pertinent questions and encouraged me to be an independent thinker. He has been patient and understanding with me as I made mistakes, and afforded me the time to troubleshoot problems. I have grown substantially as a scientist, critical thinker, and writer thanks to Ted’s mentorship. I would also like to thank my thesis committee—Dr. David Raizen, Dr. Max Kelz, Dr. Claire Mitchell, Dr. Amita Sehgal, and Dr. Mark Opp. Their intellectual input has been immensely helpful, and they are all tremendously supportive and compassionate people. I could not have asked for a better committee. I would like to thank Amita for taking me into her lab and providing me with a sense of community after Ted’s lab moved, and Mark for serving as my external reviewer and providing me with a strong foundation in sleep research when I was an undergraduate at the University of Michigan. I would like to acknowledge all the members of the Abel lab, past and present, for helping me along the way. In particular, I would like to recognize Jen, Robbert, Sarah, Rolf, and Vince for their tutelage during my time in the lab. I would also like to thank the many undergraduates and technicians who kept the lab running smoothly. I have made many great relationships via the Abel lab, but Sarah and Vince deserve special recognition for being tremendous friends, for helping me during the thesis-writing process, and for always being there for me in lab and life in general. Thank you to my friends in the Neuroscience Graduate Group for keeping graduate school enjoyable. Specifically, I would like to acknowledge the West Philly group: Greg, ii Peter, Andrew, Jen, and Preetika. Thank you all for your kindness, generosity, hospitability, and friendship over the past five years. I would especially like to thank Greg for being an amazing friend, co-worker, and for his scientific input and comments on this dissertation and throughout graduate school. I would like to acknowledge the National Defense Science and Engineering Graduate Fellowship, which funded me for the last three years of my graduate study. I would also like to thank the mice who gave their lives for these studies. I have worked very hard to do efficient and purposeful studies, and I hope their sacrifices were not in vain. Finally, and most importantly, I need to thank my family. Thank you for all your love and support over the past 28 years. Mom and dad, thank you for always supporting me, encouraging me, believing in me, providing for me, and pushing me to be better. To my siblings—Matt, Kaily, and Taya—thank you for being lifelong friends and unwavering supporters. Thank you to my grandparents, aunts, uncles, and cousins for supporting me and indulging my passion for science. To my cousins and fellow neuroscientists, Ashley and Aaron, thank you for helping me to get started in the field and for your scientific discussions around the holidays. I could not have done any of this without my incredible family. iii ABSTRACT SLEEP AND ACTIVITY PROBLEMS IN MOUSE MODELS OF NEURODEVELOPMENTAL DISORDERS Christopher Caleb Angelakos Ted Abel Adequate sleep is important for long-term health and day-to-day function. Compared to the general population, patients diagnosed with neurodevelopmental disorders have substantially higher prevalence of sleep, activity, and circadian problems, dramatically affecting their quality of life, and potentially exacerbating other adverse symptomologies. Despite this, the neurobiological underpinnings of sleep problems in neurodevelopmental disorders remain unknown, and accurate rodent models capable of recapitulating human sleep and activity problems are lacking. In this dissertation, I investigate sleep, activity, and circadian rhythms in genetic mouse models of human neurodevelopmental disorders, with a focus on autism spectrum disorder (ASD). In Chapter 1, I review the importance of—and mechanisms contributing to—sleep/wake regulation, sleep problems in neurodevelopmental disorders, and the utility of rodent genetic models to address these problems. In Chapter 2, I investigate hyperactivity and male-specific sleep deficits found in the 16p11.2 del/+ chromosomal copy number variation mouse model of neurodevelopmental disorders (Angelakos et al., 2016). In Chapter 3, I highlight REM sleep reductions and altered electroencephalography (EEG) spectra in the SYGNAP1+/- mouse model of intellectual disability and ASD. In Chapter 4, I discuss home-cage hypoactivity observed in four different mouse models of ASD. iv TABLE OF CONTENTS ACKNOWLEDGMENT ................................................................................................... ii ABSTRACT....................................................................................................................iv LIST OF TABLES ........................................................................................................ viii LIST OF FIGURES .........................................................................................................ix CHAPTER 1: Mechanisms and functions of sleep and circadian rhythms ......... Error! Bookmark not defined. 1.1 Mechanisms of sleep and circadian regulation ............................................. 2 1.1.1 Circadian rhythms and regulation ............................................................... 2 1.1.2 Sleep homeostat (Process S) ....................................................................... 4 1.1.3 Sleep-state switching ................................................................................... 5 1.2 Functions of sleep and circadian rhythms, and consequences of their dysfunction ................................................................................................................... 6 1.2.1 Consequence of inadequate sleep .............................................................. 7 1.2.2 Consequence of circadian dysfunction ...................................................... 9 1.3 Summary of the functional importance of sleep and circadian