Ovarian Hormone-Induced Neural Plasticity in the Hypothalamic Ventromedial Nucleus

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Ovarian Hormone-Induced Neural Plasticity in the Hypothalamic Ventromedial Nucleus University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2013 Ovarian Hormone-Induced Neural Plasticity in the Hypothalamic Ventromedial Nucleus Sarah L. Ferri University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Neuroscience and Neurobiology Commons, and the Psychology Commons Recommended Citation Ferri, Sarah L., "Ovarian Hormone-Induced Neural Plasticity in the Hypothalamic Ventromedial Nucleus" (2013). Publicly Accessible Penn Dissertations. 857. https://repository.upenn.edu/edissertations/857 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/857 For more information, please contact [email protected]. Ovarian Hormone-Induced Neural Plasticity in the Hypothalamic Ventromedial Nucleus Abstract Ovarian hormones act throughout the brain and body to influence a anger of functions and behaviors. Estrogens and progesterone are neuroprotective and have important health implications. However, our understanding of the mechanisms underlying many of their actions is incomplete. The goal of this thesis is to elucidate details of ovarian hormone-induced neural plasticity, specifically as it elatesr to female reproductive behavior and dendritic morphology in the hypothalamic ventromedial nucleus (VMH). First, I tested the hypothesis that the mechanisms of female receptivity are conserved across two species with very different mating strategies: prairie voles, which exhibit monogamy, induced estrous, and induced ovulation, and rats, which do not. Utilizing Golgi impregnation, I demonstrated that, as in rats, dendrite length in the VMH of female prairie voles is correlated with mating status, which in turn is associated with estradiol concentration. Next, I tested the hypothesis that oxytocin, a neuromodulator that promotes mating behavior, is a marker for estradiol-induced synaptic reorganization in the VMH. Using immunoelectron microscopy, I revealed that estradiol reduces the presence of dendrites that extend out into the adjacent lateral fiber plexus and increases the innervation of the remaining dendrites, which have internalized oxytocin. Finally, I tested the hypothesis that estradiol has short-term effects on proteins associated with synaptic reorganization, namely the actin-associated protein cofilin and ionotropic AMPA glutamate receptor subunits GluA1 and GluA2 in the VMH. Using immunohistochemistry, I discovered that estradiol rapidly alters phosphorylation of cofilin and the levels of GluA1. Together, these findings demonstrate that estradiol actions in the VMH are evolutionarily conserved, affect oxytocin synapses, and rapidly alter regulation of actin polymerization and glutamate signaling. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Psychology First Advisor Loretta M. Flanagan-Cato Keywords dendrite, dendritic spines, estradiol, neural plasticity, sexual behavior, ventromedial hypothalamus Subject Categories Neuroscience and Neurobiology | Psychology | Social and Behavioral Sciences This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/857 OVARIAN HORMONE-INDUCED NEURAL PLASTICITY IN THE HYPOTHALAMIC VENTROMEDIAL NUCLEUS Sarah L. Ferri A DISSERTATION in Psychology 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 ______________________ Loretta M. Flanagan-Cato Associate Professor of Psychology Graduate Group Chairperson ______________________ John Trueswell, Professor of Psychology Dissertation Committee Ted Abel, Brush Family Professor of Biology Javier Medina, Assistant Professor of Psychology Marc Schmidt, Associate Professor of Biology OVARIAN HORMONE-INDUCED NEURAL PLASTICITY IN THE HYPOTHALAMIC VENTROMEDIAL NUCLEUS COPYRIGHT 2013 Sarah L. Ferri This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit http://creativecommons.org/licenses/by-ny-sa/2.0/ ACKNOWLEDGMENTS I would like to extend my deepest gratitude to my advisor, Lori Flanagan-Cato. From day one she has been an excellent mentor and friend. Her exceptional knowledge of neuroendocrinology and behavioral neuroscience has instilled in me a passion for the fields as well, which I will always cherish. She is a model scientist and teacher and I truly admire her intellect, dedication, and patience. I have profound appreciation for her open door, willingness to spontaneously brainstorm with me, and her invaluable insight. I am forever indebted to her for her continual support and for pushing me to think more deeply and explore experiments and mechanisms out of my comfort zone. She has provided me with the knowledge base, confidence, and skills I need to succeed in science and in life in general. Finally, I will always have fond memories of our “lady lab” and of course, the occasional happy hours! I am also incredibly lucky to have an endlessly supportive family. My mother and sister are the epitome of strong, beautiful, intelligent women. My mother, Elaine is the most generous person I know. She is a kind and inspiring role model who willingly answers my calls at all hours of the night. She always knows what to say and is my number one supporter; I couldn’t have come this far without her. My sister Amanda has been so understanding and encouraging, especially in the past several years. She can always make me think, and importantly, laugh, and I’m grateful to have her as my best friend. They keep me going and make me a better person. I am proud to call them family. I have had the honor and pleasure of working closely with Laura (Felgendreger) Grafe for the past five years. Her intelligence and resourcefulness in the lab are extremely admirable and her close friendship in and out of the lab means the world to me. I will always remember how much fun we’ve had talking through everything from signaling cascades and stoichiometry to shopping and relationships. I would like to thank my committee for making me think about electrophysiology even when I didn’t really want to; they helped me develop critical thinking and a breadth of information, iii and motivated me to search deeper and ask better questions. The chair of my committee, Javier Medina, has provided advice and support from the day I interviewed for graduate school throughout my academic career. He can always be counted on to ask thought-provoking questions and encourage consideration of alternate hypotheses. Ted Abel has also been an extremely valuable and engaged committee member. He has provided an amazing breadth of knowledge, an abundance of suggestions for follow-up experiments, and very helpful feedback and insight. I am honored to be joining his lab shortly as a postdoctoral fellow. I am also thankful to Marc Schmidt for joining my committee and providing input and guidance in my final stages. I have also had the pleasure of working with some truly talented and knowledgeable lab members. I would like to thank our collaborator Daniel Yee of University of Pennsylvania Vet School for his encouragement, advice, abundant technical assistance with Western blots, and for listening to numerous practice talks of mine. I would additionally like to acknowledge Samantha Way for all of her scientific assistance over the past few years and for her amazing friendship. I am also lucky to have worked with Carlos Rohrbach for several years during his time as an undergraduate and later a technician in our lab. He was always so pleasant and willing to help. I am also thankful to have worked with former graduate student Gerald Griffin, who helped introduce me to the lab and a variety of techniques. Finally, I want to thank my grandparents and aunt, and my absolutely wonderful friends for their infinite support and encouragement, advice, and comic relief throughout my graduate career. They are all remarkable and inspiring in different ways. I am truly privileged to have worked with so many brilliant, inspiring, and supportive faculty and staff in the Psychology and Neuroscience groups. Every day I was grateful to be part of this institution, part of the Psychology and Neuroscience programs, and part of Lori’s lab. iv ABSTRACT OVARIAN HORMONE-INDUCED NEURAL PLASTICITY IN THE HYPOTHALAMIC VENTROMEDIAL NUCLEUS Sarah L. Ferri Loretta M. Flanagan-Cato Ovarian hormones act throughout the brain and body to influence a range of functions and behaviors. Estrogens and progesterone are neuroprotective and have important health implications. However, our understanding of the mechanisms underlying many of their actions is incomplete. The goal of this thesis is to elucidate details of ovarian hormone-induced neural plasticity, specifically as it relates to female reproductive behavior and dendritic morphology in the hypothalamic ventromedial nucleus (VMH). First, I tested the hypothesis that the mechanisms of female receptivity are conserved across two species with very different mating strategies: prairie voles, which exhibit monogamy, induced estrous, and induced ovulation, and rats, which do not. Utilizing Golgi impregnation, I demonstrated that, as in rats, dendrite length in the VMH of female prairie voles is correlated with mating status, which in turn is associated with estradiol concentration. Next, I tested the hypothesis that oxytocin, a neuromodulator that promotes mating behavior, is a marker
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