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Dopamine and the Temporal Dependence of Learning and Memory Annie Handler

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Dopamine and the Temporal Dependence of Learning and Memory Annie Handler Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2019 Dopamine and the Temporal Dependence of Learning and Memory Annie Handler Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons DOPAMINE AND THE TEMPORAL DEPENDENCE OF LEARNING AND MEMORY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Annie Handler June 2019 © Copyright by Annie Handler 2019 DOPAMINE AND THE TEMPORAL DEPENDENCE OF LEARNING AND MEMORY Annie Handler, Ph.D. The Rockefeller University 2019 Animal behavior is largely influenced by the seeking out of rewards and avoidance of punishments. Positive or negative reinforcements, like a food reward or painful shock, impart meaningful valence onto sensory cues in the animal’s environment. The ability of animals to form associations between a sensory cue and a rewarding or punishing reinforcement permits them to adapt their future behavior to maximize reward and minimize punishments. Animals rely on the timing of events to infer the causal relationships between cues and outcomes –– sensory cues that precede a painful shock in time become associated with its onset and are imparted with negative valence, whereas cues that follow the shock in time are instead associated with its cessation and imparted with positive valence. While the temporal requirements for associative learning have been well characterized at the behavioral level, the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Using the simple architecture of the mushroom body, an olfactory associative learning center in Drosophila, I examined how the relative timing of olfactory inputs and dopaminergic reinforcement signals is encoded at the molecular, synaptic, and circuit level to give rise to learned odor associations. I show that in Drosophila, opposing olfactory associations can be formed and updated on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement during conditioning. Additionally, both negative and positive reinforcements equivalently instruct appetitive and aversive olfactory associations –– odors preceding a negative reinforcement or following a rewarding reinforcement acquire an aversive valence, while odors instead following a negative reinforcement or preceding a rewarding reinforcement become attractive. Furthermore, functional imaging revealed that synapses within the mushroom body are bidirectionally modulated depending on the temporal ordering of odor and dopaminergic reinforcement, leading to synaptic depression when an odor precedes dopaminergic activity or synaptic facilitation when dopaminergic activity instead precedes an odor. Through the synchronous recording of neural activity and behavior, I found that the bidirectional regulation of synaptic transmission within the mushroom body directly correlates with the emergence of learned olfactory behaviors. This temporal sensitivity arises from two dopamine receptors, DopR1 and DopR2, that couple to distinct second-messengers and direct either synaptic depression or potentiation. Loss of either receptor renders the synapses of the mushroom body capable of only unidirectional plasticity and prevents the behavioral flexibility of writing opposing associations depending on the temporal structure of conditioning. Together, these results reveal how the distinct intracellular signaling pathways of two dopamine receptors can detect the order of events within an associative learning circuit to instruct opposing forms of synaptic and behavioral plasticity, providing a mechanism for animals to use both the onset and offset of a reinforcement signal to instruct distinct associations. Additionally, this bidirectional modulation allows animals to flexibly update olfactory associations on a trial-by- trial basis when temporal relationships are altered, permitting them to contend with a complex and changing sensory world. To my parents, Ann and Henry, for nourishing my curiosity and intellectual growth To Josh, my partner in life, for unwavering support and love iii Acknowledgements I would first like to thank the people who contributed throughout the evolution of the work presented in this thesis. Raffi Cohn laid the foundation for describing the bidirectional plasticity in the mushroom body circuitry, and in my early years as a PhD student, we worked together closely in characterizing the temporal dependence for neural modulation. He taught me how to perform two-photon imaging and designed the closed-loop olfactory paradigm that was central to linking neural and behavioral plasticity. Ianessa Morantte, who in addition to providing steadfast support as I learned basic molecular biology, offered her immense intellectual and technical skills throughout this work. She created the first DopR1 mutant animal compatible with two-photon imaging, a resource the field has already shown great appreciation for. I am lucky to have worked with and learned from Thomas Graham, a former post-doc in the lab, who designed the behavioral chambers and provided immense support in experimental design and analysis throughout this project. I would also like to thank Andy Siliciano, a talented MD/PhD student in the lab, who carried out beautiful experiments characterizing the signaling properties of Drosophila dopamine receptors and who spent many afternoons thinking deeply with me about this project and Josie Clowney, a former post-doc in the lab, who was instrumental in the sorting and sequencing of the different Kenyon Cell populations. Nathan Hu, a very talented SSRP high school student, and Tom Hindmarsh Sten, a graduate student in the lab, provided great insight into how Drosophila learn new memories through their behavioral experiments. In addition, I’d like to thank Jim Petrillo and the Rockefeller Precision Fabrication Facility, and Patrick Stock, an engineer in the lab, for their technical support and design of novel behavioral equipment used in this study. Jaime de Juan-Sanz, a post-doc in the Ryan lab, provided the ER calcium sensor iv and helped with preliminary experiments. I am also grateful to Yulong Li and his graduate student, Jianzhi Zeng, for providing the dopamine and acetylcholine sensor. Many people also contributed their thoughts and provided feedback on our manuscript, including Sandeep Datta, Larry Abbott, Barbara Noro, and other members of the Ruta lab. I also feel very fortunate to have overlapped with the members of the Ruta lab, past and present, with whom I have shared countless conversations that both aided me in my science and kept my grounded throughout my PhD. Ari Zolin, my long-term baymate, Rory Coleman, Joel Butterwick, and Josefina del Mármol were always gracious in providing technical help and helpful feedback through informal scientific discussions and through their thoughtful questions during lab meetings. I would like to thank the Rockefeller community for providing such a fervent environment for pushing the boundaries of science. Especially, I would like to thank Dr. Paul Greengard, who welcomed me into his lab in the summer of 2011 and taught me how to think like a scientist. I feel indebted to the Dean’s office—Cris Rosario, Emily Harms, Stephanie Fernandez, Sid Strickland, Marta Delgado, and Kristen Cullen—for inviting me to be a SURF student at Rockefeller in 2011 and for their continued support throughout my time at Rockefeller and for the assistance they provided to the Summer Neuroscience Program. Also, I would like to acknowledge all the help and support provided by the members of RockEDU that helped the growth of the Summer Neuroscience Program over the years. I would like to thank all the invertebrate neuroscience labs at Rockefeller, BSVMRKYZ, for the engaging scientific discourse and helpful feedback on this project throughout my PhD. I am also incredibly grateful to all the friends and colleagues I’ve met throughout my time here at Rockefeller, including all my classmates; especially, I’d like to thank Elisabeth Murphy and Ryan Farrell for all the dog walks and morning swims. v I am fortunate to have learned from the members of my faculty advisory committee: Tim Ryan, Cori Bargmann, and Gaby Maimon. Their scientific advice throughout my PhD forced me to think critically and rigorously about my research and helped shape the work presented in this document. I must also thank Nic Tritsch for serving as my external examiner of my thesis committee. Most of all, I consider myself incredibly fortunate to have had Vanessa Ruta as my advisor and mentor at Rockefeller. On a warm summer afternoon in 2014, I sat side-by-side with Vanessa as she taught me her tricks for whole-cell patching a Drosophila neuron that I would end up studying for the next five years of my PhD. At the time, I didn’t realize my studies would focus on the properties of this one particular neuron; however, in that moment it was obvious that I was under the guidance of an incredible scientist who carried infectious enthusiasm for science and discovery and a strong dedication to mentorship and teaching. As such, the work I present in this document would not have been possible without the unwavering support and intellectual guidance from Vanessa. Finally, I must thank my family, by blood and by marriage, for their dedicated support throughout my studies—for always asking how my flies were
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