University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Consequences of Brief Periods of Sleep Loss on Hippocampus- Dependent Memory and Synaptic Plasticity Toni-Moi N. Prince 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 Prince, Toni-Moi N., "Consequences of Brief Periods of Sleep Loss on Hippocampus-Dependent Memory and Synaptic Plasticity" (2013). Publicly Accessible Penn Dissertations. 913. https://repository.upenn.edu/edissertations/913 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/913 For more information, please contact [email protected]. Consequences of Brief Periods of Sleep Loss on Hippocampus-Dependent Memory and Synaptic Plasticity Abstract Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are dysregulated by sleep deprivation to impair memory consolidation and plasticity. In this dissertation, I describe experiments that we performed to identify the time window where memory consolidation is sensitive to sleep loss as well as to characterize two potential molecular players targeted by sleep deprivation. Because consolidation appears to have a particular window where it is sensitive to sleep loss, we explore the parameters of this time window in Chapter 2. Our results suggest that a specific 3-hour period of sleep loss during consolidation disrupts both memory and plasticity. In the second portion of this dissertation, I examine the mechanisms by which sleep deprivation impairs hippocampus-dependent memory consolidation. In Chapter 3, we show that loss of the phosphodiesterase (PDE) 4A, an enzyme responsible for decreasing cAMP signaling, rescues spatial memory disrupted by sleep loss. These results further implicate cAMP signaling with the negative effects of sleep deprivation on memory. Obtaining adequate sleep is challenging in a society that values "work around the clock." Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is critical. However, a limited number of therapeutics exists that are able to enhance cognition in the face of insufficient sleep. The identification of the temporal characteristics of sleep loss and the molecular pathways implicated in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Ted Abel Keywords Memory, Sleep Deprivation, Synaptic Plasticity Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/913 CONSEQUENCES OF BRIEF PERIODS OF SLEEP LOSS ON HIPPOCAMPUS-DEPENDENT MEMORY AND SYNAPTIC PLASTICITY Toni-Moi N. Prince 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 2013 Supervisor of Dissertation __________________________ Edwin (Ted) Abel, Ph.D., Professor of Biology Graduate Group Chairperson __________________________ Joshua I. Gold, Ph.D., Associate Professor of Neuroscience Dissertation Committee David Raizen, M.D., Ph.D., Assistant Professor of Neurology (Committee Chair) Amita Sehgal, Ph.D., Professor of Neuroscience Marcos Frank, Ph.D., Associate Professor of Neuroscience David Dinges, Ph.D., Professor of Psychology (External Member) ACKNOWLEDGEMENTS There are many individuals who I want thank. I would never have made it through this program without the instrumental role of all of them. They have all of my gratitude for continually pushing me to strive to be better and to do better in all aspects of my life, not just as a scientist. To my committee members: I want to thank David Raizen, Amita Sehgal, Marcos Frank and David Dinges for investing their time and insight into the development and trajectory of my career. Your expertise enhanced my work by aiding me in thinking critically to formulate my experiments. To the NGG administration: I want to thank Mikey Nusbaum, Rita Balice Gordon, and Josh Gold for developing such a strong neuroscience program. Your hard work has allowed our community to thrive. I would especially like to thank Mikey. You have been a great mentor to me. Any time that I felt lost I knew I could turn to you for support. Thank you for accepting me into this program. I feel extremely lucky to have your hand in my development. I would also like to thank Jane Hoshi and Angela Gilmore for all their assistance and words of kindness throughout this process. To the NGG students: I would like to thank all the students of this program, especially my cohort. I do not know how the program does it, but it recruits some of the brightest and most motivated students. More importantly, my class was social and caring. Over these years, my class has become my family. To the Abel lab: I would like to thank my mentor, Ted Abel, for accepting me into his lab. Thank you for giving me the opportunity to have my own project and to think critically about science. I think you have one of the most spectacular labs. I have had the chance to grow as a scientist and as a person by getting the opportunity to interact with so many intelligent and charismatic individuals in the lab. I thank you for that Ted. I would also like to thank all the members of the lab past and present. I do not know where I would be if you guys were not there to drag me though the finish line of graduate school. Especially Jennifer Choi- you are my mini-mentor, and you are definitely a role model for aspiring scientists. ii To my past mentors: Thank you Michael Brown, Peter Alfinito and Kim Wallen for patiently teaching me. From you, I picked up traits on how to persevere in every type of situation. To my friends: There are no words to describe my gratitude to all the friends I have made throughout the years. I must have done something spectacular in a past life to have the kind of friends I have. All of you mean so much to me. Thank you for providing me an outlet to get out all of the personal and professional frustrations that happens to every student. From Halloween parties to our “Sexy Valentine” dinner, I had so much fun. There have been so many times in the past few years that I struggled and every time, without fail, you all listened patiently and gave me the strength I needed to pick myself up. When I succeeded, you all were the first to celebrate my accomplishments. To my family: I would like to thank my family, especially my mom and sisters. Nicky and Danielle, thank you for always being proud of my tiny achievements. You say that I am an inspiration, but the truth is that you both inspire me. For most of my decisions, I factor in what would Nicky and Danielle do (WWNDD). Your accomplishments give me hope for myself. To my partner: Jason, you have been the most loving partner that I could have ever fathom. Thank you for always believing in me especially when I couldn’t believe in myself. You make me shine, and want to succeed. Having you as my main support system over the past years has gotten me to accomplish much more than I even knew I was capable of doing. You are the love of my life, and I know I can face anything with you beside me. My training was supported by a NIH/NIGMS T32 Training Grant (T32-GM07517), a NIH/NHLBI Training in Sleep and Sleep Disorders T32 Training Grant (T32-HL07953). Additional support came from the Abel Laboratory NIH grant (5P01AG017628, T.A.) iii ABSTRACT CONSEQUENCES OF BRIEF PERIODS OF SLEEP LOSS ON HIPPOCAMPUS-DEPENDENT MEMORY AND SYNAPTIC PLASTICITY Toni-Moi N. Prince Edwin “Ted” Abel, Ph.D. Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are dysregulated by sleep deprivation to impair memory consolidation and plasticity. In this dissertation, I describe experiments that we performed to identify the time window where memory consolidation is sensitive to sleep loss as well as to characterize two potential molecular players targeted by sleep deprivation. Because consolidation appears to have a particular window where it is sensitive to sleep loss, we explore the parameters of this time window in Chapter 2. Our results suggest that a specific 3-hour period of sleep loss during consolidation disrupts both memory and plasticity. In the second portion of this dissertation, I examine the mechanisms by which sleep deprivation impairs hippocampus-dependent memory consolidation. In Chapter 3, we show that loss of the phosphodiesterase (PDE) 4A, an enzyme responsible for decreasing cAMP signaling, rescues spatial memory disrupted by sleep loss. These results further implicate cAMP signaling with the negative effects of sleep deprivation on memory. Obtaining adequate sleep is challenging in a society that values "work around the clock." Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is critical. However, a limited number of therapeutics exists that are able to enhance cognition in the face of insufficient sleep. The identification of the temporal characteristics of sleep loss and the molecular pathways implicated iv in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs.