University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Somatotopic Organization Of The Mammalian Pain System And Developmental Mechanisms William Paul Olson 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 Olson, William Paul, "Somatotopic Organization Of The Mammalian Pain System And Developmental Mechanisms" (2018). Publicly Accessible Penn Dissertations. 2876. https://repository.upenn.edu/edissertations/2876 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2876 For more information, please contact [email protected]. Somatotopic Organization Of The Mammalian Pain System And Developmental Mechanisms Abstract Commonly, different regions of sensory maps are used to meet separate functional requirements. For the somatosensory system (which mediates sensation from the skin including touch, pain, and related modalities), the distal limbs have special behavioral importance for exploration and object manipulation. Accordingly, the hands and fingertips show heightened sensitivity for both touch and pain sensation in human subjects. In contrast to the touch system, the neural mechanisms for region-specific pain sensation are poorly understood. Despite over a century of research into the neural basis of pain, past work has not clearly defined the functional organization of the pain system across the body (somatotopic) map. In Chapter 2, we use a novel genetic mouse line to map the organization of one major class of mammalian pain-sensory neurons (the Mrgprd+ non-peptidergic nociceptors) across the body map. While we find no obvious peripheral mechanisms for high sensitivity in the distal limbs (mouse plantar paw skin has a low density of Mrgprd+ terminals, and single-cell arbor areas are comparable between paw and trunk skin), we reveal a novel region-specific organization in the spinal cord terminal arbors of these neurons. Specifically, paw and trunk neurons grow ‘round’ and ‘long’ arbor morphologies, respectively, such that paw neurons have a wider mediolateral spread in the spinal cord. We show that this region-specific morphology closely correlates with increased signal transmission for paw pain circuits. We conclude that region-specific organization of Mrgprd+ spinal cord terminals provides a possible mechanism for the high pain sensitivity of the distal limbs. In Chapter 3, we investigate potential developmental mechanisms for region-specific arbor morphologies. Disruption of peripheral target innervation does not alter their central arbor morphologies, suggesting that this central somatotopic difference develops independent of cues/processes from the periphery. However, this difference is present from very early developmental stages, suggesting that pre-programming mechanisms might govern this somatotopic pattern. Collectively, this work reveals that region-specific organization is a fundamental principle for the pain system with clear implications for our understanding of pain in both normal and pathological conditions. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Wenqin Luo Keywords pain, region-specific organization, somatosensation, somatotopy Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2876 SOMATOTOPIC ORGANIZATION OF THE MAMMALIAN PAIN SYSTEM AND DEVELOPMENTAL MECHANISMS William P. Olson 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 2018 Supervisor of Dissertation ____________________ Wenqin Luo, MD, PhD Assistant Professor Neuroscience Graduate Group Chairperson ____________________ Joshua I Gold, PhD Professor of Neuroscience Dissertation Committee: Steven S. Scherer, MD, PhD, Professor of Neurology Minghong Ma, PhD, Professor of Neuroscience Diego Contreras, MD, PhD, Professor of Neuroscience Xinzhong Dong, PhD, Professor of Neuroscience, Johns Hopkins University DEDICATION This thesis is dedicated to my parents David and Diane, my sister Anna, and my partner Jun. I would not have been able to do this without them. ii ACKNOWLEDGEMENT I want to first express my sincere gratitude for my mentor, Dr. Wenqin Luo, for all her guidance and support during my PhD training. She has been an amazing mentor and role model, and her knowledge, intelligence, and insight were instrumental for all of the research in this thesis. I also want to thank my thesis committee, Drs. Steven Scherer, Minghong Ma, Diego Contreras, and Xinzhong Dong. Their questions, comments, and suggestions played a major role in this thesis, and I sincerely appreciate their time serving on my committee. I want to thank all the past and present members of the Luo Lab: Dr. Ishmail Abdus- Saboor, Katherine Beattie, Dr. Lian Cui, Dr. Peter Dong, Dr. Michael Fleming, Dr. Nathan Fried, Omar Johnson, Kim Kridsada, Suna Li, Dr. Jingwen Niu, Dr. Paclink Thaweerattanasinp, and Anna Vysochan. Working with such a talented, fun group of people has been motivating and inspiring, and I will truly miss working with all of them. I want to thank all of my family: my parents David and Diane, my sister Anna, my aunts Mary and Karen, my uncles Dennis, Beau, and Jim, all of my cousins, and my grandparents Paul, Dorothy, Ewald, and Doris. Their intelligence and unending support are the reason I have been able to reach this point, and I cannot thank them enough. Lastly, I want to thank my partner Jun Kang. His patience, kindness and love have meant everything to me during these last years of my thesis. iii ABSTRACT SOMATOTOTPIC ORGANIZATION OF THE MAMMALIAN PAIN SYSTEM AND DEVELOPMENTAL MECHANISMS William P. Olson Wenqin Luo Commonly, different regions of sensory maps are used to meet separate functional requirements. For the somatosensory system (which mediates sensation from the skin including touch, pain, and related modalities), the distal limbs have special behavioral importance for exploration and object manipulation. Accordingly, the hands and fingertips show heightened sensitivity for both touch and pain sensation in human subjects. In contrast to the touch system, the neural mechanisms for region-specific pain sensation are poorly understood. Despite over a century of research into the neural basis of pain, past work has not clearly defined the functional organization of the pain system across the body (somatotopic) map. In Chapter 2, we use a novel genetic mouse line to map the organization of one major class of mammalian pain-sensory neurons (the Mrgprd+ non-peptidergic nociceptors) across the body map. While we find no obvious peripheral mechanisms for high sensitivity in the distal limbs (mouse plantar paw skin has a low density of Mrgprd+ terminals, and single-cell arbor areas are comparable between paw and trunk skin), we reveal a novel region-specific organization in the spinal cord terminal arbors of these neurons. Specifically, paw and trunk neurons grow ‘round’ iv and ‘long’ arbor morphologies, respectively, such that paw neurons have a wider mediolateral spread in the spinal cord. We show that this region-specific morphology closely correlates with increased signal transmission for paw pain circuits. We conclude that region-specific organization of Mrgprd+ spinal cord terminals provides a possible mechanism for the high pain sensitivity of the distal limbs. In Chapter 3, we investigate potential developmental mechanisms for region-specific arbor morphologies. Disruption of peripheral target innervation does not alter their central arbor morphologies, suggesting that this central somatotopic difference develops independent of cues/processes from the periphery. However, this difference is present from very early developmental stages, suggesting that pre-programming mechanisms might govern this somatotopic pattern. Collectively, this work reveals that region-specific organization is a fundamental principle for the pain system with clear implications for our understanding of pain in both normal and pathological conditions. v TABLE OF CONTENTS DEDICATION ............................................................................................................................................ II ACKNOWLEDGEMENTS ........................................................................................................................... III ABSTRACT ............................................................................................................................................... IV CHAPTER 1: INTRODUCTION .....................................................................................................................1 REGION-SPECIFIC ORGANIZATION IN SENSORY AND MOTOR SYSTEMS.......................................................................2 PHYSIOLOGICAL, ANATOMICAL, MOLECULAR GENETIC, AND FUNCTIONAL DESCRIPTIONS OF THE MAMMALIAN PAIN SYSTEM ........................................................................................................................................................... 10 DOWNSTREAM CENTRAL PARTNERS/PATHWAYS OF NOCICEPTORS ........................................................................ 25 DEVELOPMENT OF THE MAMMALIAN PAIN SYSTEM ..........................................................................................