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A Variant Mode of Mammalian Olfaction A Variant Mode of Mammalian Olfaction The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37944989 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA A Variant Mode of Mammalian Olfaction A dissertation presented by Daniel Marcus Bear to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Neurobiology Harvard University Cambridge, Massachusetts November 2016 © 2016 Daniel Marcus Bear All rights reserved. Dissertation Advisor: Dr. Sandeep R. Datta Daniel Marcus Bear A Variant Mode of Mammalian Olfaction Abstract Olfaction – the sense of smell – informs animals about food, mates, threats, and other chemical signals. The odors most relevant to survival and reproduction vary across species and ecology; for this reason, olfactory nervous systems have evolved to perceive select stimuli and to elicit adaptive responses. The mammalian olfactory system accomplishes this with families of olfactory receptors – proteins that bind characteristic odor molecules and signal through parallel neural pathways. Each animal expresses a diverse repertoire of receptors, geared to its chemical environment, in a canonical mode of one receptor gene per olfactory sensory neuron. This arrangement produces precise neural representations for individual odors, which are capable of driving a range of behaviors. However, it is not known whether this conserved architecture is suited for all aspects of odor sensation. Here I report that part of the olfactory system breaks from this predominant organization. An atypical sensory subsystem, the so-called olfactory “necklace,” does not express traditional olfactory receptors, but instead detects several classes of chemical stimuli with the previously unknown MS4A receptor family. MS4A proteins are unrelated to other olfactory receptors, suggesting that they have evolved to detect distinct odors and to transduce signals by a different mechanism. Moreover, multiple members of the Ms4a family are iii expressed in each necklace neuron. The violation of the “one receptor per neuron” rule endows this subsystem with broader sensory responses than granted by a single receptor. By way of this variant organization, the necklace may play a unique role in shaping odor perception. iv TABLE OF CONTENTS Abstract iii Acknowledgements vi Chapter 1. General Introduction: Selective Sensation 1 References 5 Chapter 2. The Evolving Architecture of Vertebrate Olfaction 7 Summary 9 References 44 Chapter 3. A Family of non-GPCR Chemosensors Defines an 55 Alternative Logic for Mammalian Olfaction Summary 57 Introduction 58 Results 62 Discussion 106 Experimental Procedures 113 References 149 Chapter 4. General Discussion and Conclusion 157 General Discussion 158 Conclusion 172 References 175 v! Acknowledgments The work presented here is the result of extraordinary mentorship and friendship. It traces back to a sequence of extreme luck during my first year of college: I was forced to find a research lab for summer work because I had missed the deadline for a fancy trip. I don’t know where I would be now, a decade later, if I hadn’t first written Mike Greenberg, or if Mike hadn’t suggested I work with Steve Flavell (then a graduate student in his lab). My time working with Steve convinced me to become a scientist; and it also introduced to two more of Mike’s former students, Paul Greer and Bob Datta, whose roles in my life should be obvious to anyone who has spoken to me since then, or to anyone who reads this work. Mike and Steve are among the most rigorous, insightful, and imaginative scientists I’ve known. However impressive their professional qualities were to a 19-year- old, though, their strongest influences on me have come through their patience and guru-like guidance. In ten years, neither has ever offered advice or answered my millions of questions with anything less than the greatest care and sincerity. I did not realize, in the beginning, how rare these traits are in professional scientists, in one of the most competitive environments in the world no less. I still have plenty to learn from their mentorship. Steve and Mike are something much more impressive than first-rate scientists: they are wonderful people, and I hope lifelong friends. Paul is a brilliant scientist and, to me, a unique combination of colleague, mentor, and friend. I would not be able to express my joy and gratitude for our relationship without doubling the length of this dissertation. Like Mike and Steve, he has been endlessly patient and kind over the years in giving me advice about my work, my career, vi! and most importantly my life – which as for many scientists is all too inseparable from work and career. But Paul has been consistent in his conviction that the relationships one has with other people should always be the highest priority. He has said it and he has lived it. I expect that after another decade of his friendship and wisdom, I will be even more thankful. Sandeep “Bob” Datta, my Ph.D. advisor, expresses more than anyone I’ve met the excitement and wonder of being a researcher. He is open to new scientific ideas and to the world. At the same time he demands only the highest quality work from himself and from others. During the first few years of graduate school, when Bob, Paul, and I were trying to start a research program from scratch, Bob’s uncompromising nature seemed sometimes like more of a hindrance than an advantage. My feelings have changed. I have a better sense, now, of how difficult research is under even the best conditions; I have never met a graduate student, postdoctoral fellow, or young investigator who did not at some point buckle under the stresses of science. Many days begin with the thought of how long it’s been since you found something new and worth your extreme effort to pursue; others end with the worry that you’ve missed something simple, which would negate your prior work. Bob has always confronted these anxieties head-on. I am impressed and proud that as his lab has matured, he has learned to allow others to deal with the difficulties of research in their own lives and in their own ways, while never wavering in his belief that we are all enormously privileged to be scientists. He has passed this mindset on to me and my fellow students – Stan Pashkovski, Tari Tan, Alex Wiltschko, and Maria Bloom – who, through our growing together, have become permanent mentors and friends. ! vii! I could not have survived graduate school without the help of other members of the Datta Lab and the Department of Neurobiology. This is true of all graduate students – science is not a solo endeavor – but it is especially true of me. I apologize for my many (though hopefully all minor) lapses in responsible behavior. In particular, thank you to the Datta Lab managers – Alexandra Nowlan, Allison Petrosino, and Neha Bhagat – for keeping our workplace away from the edge of Chaos. Similarly, thank you to my dissertation advisory committee – Rachel Wilson, Josh Kaplan, and David Corey – for keeping my work away from the edge of Chaos. I would also like to acknowledge the outstanding and sometimes thankless guidance of Karen Harmin, the administrator for the Program in Neuroscience: if not for her patient reminders, the happy missed deadline that landed me in the department would have been undone by many more. Finally, I have neither the space nor the words to truly thank the people who know me best. Fortunately I have no plans to inflict this dissertation on them. They have absorbed my worst torrents of frustration and self-doubt with their stoic support, and they have given me what science cannot: the reassurance that their love depends not on what I learn or what I accomplish, but only on who I am. I haven’t always made it easy for them, but I hope they feel my respect and my love all the same. I think they do. Andrew, Eric, Dann, Dan, Lisa, Adam, Dad, and Mom – thank you for being there behind all of this. ! viii! “The Brain, within its Groove Runs evenly – and true – ” Emily Dickinson (1863) ! ix! Chapter 1 General Introduction: Selective Sensation General Introduction Every animal has a unique view of the world. For each species, natural selection has shaped the senses to detect, interpret, and remember critical features of the physical environment that aid its survival and reproduction. The brain extracts, in stages, progressively more complex information from sensory stimuli – about visual edges, contours, shapes, and abstract objects, for instance (DiCarlo et al., 2012). Neural representations magnify some facets of the external world to discern them more carefully, while ignoring others that have less adaptive value. The senses therefore detect and process a fraction of natural stimuli. Selective perception originates in sensory neurons themselves. The limited scope of sensation is easiest to illustrate in the case of vision: photoreceptor cells in the eye respond to only a tiny segment of the electromagnetic spectrum, with photon wavelengths outside this narrow span going undetected. Restricted interaction with the environment is a result of both biophysical constraints – the thermal noise of retinal opsin photopigments makes them poor sensors of infrared light – as well as the cost-to-benefit ratio of constructing a functional sensory system (Laughlin, 2001; Luo et al., 2011). For example, many insects use patterns of ultraviolet light for foraging and mating, but mammals do not; ultraviolet- sensitive opsins were not advantageous enough to persist in mammalian lineages (Hunt et al., 2001).
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