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BORN NEURONS in the MOUSE OLFACTORY BULB by Daniel A

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BORN NEURONS in the MOUSE OLFACTORY BULB by Daniel A COMPETITIVE CELL-SPECIFIC INTEGRATION AND SURVIVAL OF ADULT- BORN NEURONS IN THE MOUSE OLFACTORY BULB by Daniel Alexander Jimenez B.S. in Chemical Engineering with an additional Major in Biomedical Engineering, Carnegie Mellon University, 2004 Submitted to the Graduate Faculty of the Kenneth P. Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh lenti-tdTomato 2012 UNIVERSITY OF PITTSBURGH Dietrich School of Arts and Sciences This dissertation was presented by Daniel Alexander Jimenez It was defended on May 5, 2011 and approved by Susan G. Amara, Ph.D., Neurobiology, University of Pittsburgh Alison L. Barth, Ph.D., Biological Sciences, Carnegie Mellon University Laura E. Lillien, Ph.D., Neurobiology, University of Pittsburgh Carlos Lois, Ph.D., M.D., Neurobiology, University of Massachusetts A. Paula Monaghan-Nichols, Ph.D., Neurobiology, University of Pittsburgh Dissertation Advisor: Nathan N. Urban, Ph.D., Biological Sciences, Carnegie Mellon University ii COMPETITIVE CELL-SPECIFIC SURVIVAL AND INTEGRATION OF ADULT- BORN NEURONS IN THE MOUSE OLFACTORY BULB Daniel A. Jimenez, Ph.D. University of Pittsburgh, 2012 Copyright © by Daniel Alexander Jimenez 2012 iii Dissertation advisor: Nathan N. Urban, Ph.D . COMPETITIVE CELL-SPECIFIC INTEGRATION AND SURVIVAL OF ADULT- BORN NEURONS IN THE MOUSE OLFACTORY BULB Daniel Alexander Jimenez, Ph.D. University of Pittsburgh, 2012 In several areas of the adult brain, notably the olfactory bulb, new neurons are generated and integrated into existing mature circuits. This observation raises questions about how an ongoing developmental process shapes adult brain circuitry and opens potential treatment avenues for neurological disorders such as traumatic brain injury, ischemia, depression, and degenerative diseases. In the networks where adult neurogenesis occurs, the integration of adult-born neurons is modulated by activity. The experiments in this dissertation are designed to address the hypothesis that adult-born neurons integrate into mature circuits in a competitive, activity- dependent manner. Specifically, we sought to address the question of whether activity in adult-born neurons directly causes enhanced survival of particular active newborn neurons in a cell-autonomous fashion, or whether survival is a competitive process in which the most active cells in the network have the highest chance of survival. To differentiate between these two hypotheses required manipulating activity both of the adult-born neurons and other neurons within the network. Here we used both virus-mediated reduction of cell intrinsic activity and reduced sensory stimuli to show that survival is a competitive process in which the most active cells in iv the network have the highest chance of survival. RNA-based knockdown of Na+ channels resulted in decreased survival of adult-born neurons from 10-21 d.p.i. We then investigated the role of circuit level activity by inducing sensory deprivation through naris occlusion. Adult-born neurons with normal cell-intrinsic activity showed a reduction in survival in a sensory deprived circuit. But, interestingly, adult-born neurons with reduced intrinsic excitability showed an increased rate of survival in a sensory deprived circuit. These results provide important insights into the role of activity in the integration and therapeutic potential of neural stem cells in mature functional brain circuits. v TABLE OF CONTENTS PREFACE ............................................................................................................................... XVII 1.0 INTRODUCTION ........................................................................................................ 1 1.1 ADULT NEUROGENESIS................................................................................. 2 1.1.1 History .............................................................................................................. 2 1.1.2 Mammalian adult neurogenesis ..................................................................... 4 1.1.3 Adult neurogenesis in the olfactory bulb ....................................................... 6 1.1.3.1 Subventricular zone proliferation ....................................................... 9 1.1.3.2 RMS Migration ................................................................................... 10 1.1.3.3 Radial migration ................................................................................. 11 1.1.3.4 Subtype differentiation ....................................................................... 14 1.1.3.5 Survival ................................................................................................ 17 1.1.4 Adult neurogenesis in the hippocampus ...................................................... 17 1.1.4.1 Adult born neurons are born in the dentate gyrus of the hippocampus ...................................................................................................... 18 1.1.5 Functional role of hippocampal adult neurogenesis ................................... 19 1.1.5.1 Adult hippocampal neurogenesis and learning ................................ 20 1.2 ORGANIZATION OF THE OLFACTORY BULB ....................................... 21 1.2.1 Sensory stimuli and olfactory receptor neurons ......................................... 21 vi 1.2.2 The gross anatomy of the olfactory bulb ..................................................... 22 1.2.3 Mitral cells ...................................................................................................... 24 1.2.4 Periglomerular cells ....................................................................................... 25 1.2.5 Granule Cells.................................................................................................. 26 1.2.6 Self inhibition of mitral cells ......................................................................... 29 1.2.7 Lateral inhibition of mitral cells................................................................... 30 1.2.8 The effect of adult-neurogenesis on inhibition in the olfactory bulb ........ 31 1.3 LENTIVIRAL MANIPULATION OF GENE EXPRESSION ..................... 33 1.3.1 Lentivirus ....................................................................................................... 34 1.3.2 From shRNA expression to protein expression knockdown ...................... 35 1.4 DEVELOPMENT OF CHANNELS REGULATING ACTIVITY IN ADULT BORN NEURONS OF THE OLFACTORY BULB ......................................... 38 1.4.1 Voltage gated sodium channels .................................................................... 38 1.4.2 Voltage-dependent calcium channels ........................................................... 39 1.4.3 Participation in neuronal development ....................................................... 39 1.4.4 Compensatory responses to a reduction in expression of voltage gated sodium channels ......................................................................................................... 41 1.5 EXPERIENCE DEPENDENT PLASTICITY AND THE EFFECT OF SENSORY DEPRIVATION ON THE DEVELOPMENT OF NEURONAL CIRCUITS ........................................................................................................................... 42 1.5.1 A critical period for experience dependent plasticity in the visual cortex 42 1.5.2 Critical period plasticity in the somatosensory cortex ............................... 43 vii 1.6 THE INFLUENCE OF ACTIVITY ON ADULT NEUROGENESIS IN THE OLFACTORY BULB ......................................................................................................... 44 1.6.1 Extrinsic activity ............................................................................................ 44 1.6.2 Intrinsic activity ............................................................................................. 45 1.7 DATA CHAPTERS INTRODUCTION .......................................................... 46 1.7.1 Hypothesis and expected results ................................................................... 47 2.0 COMPETITIVE SURVIVAL OF ADULT-BORN NEURONS IN THE MOUSE OLFACTORY BULB ................................................................................................................. 48 2.1 CHAPTER SUMMARY ................................................................................... 48 2.2 INTRODUCTION ............................................................................................. 49 2.3 MATERIALS & METHODS ........................................................................... 51 2.3.1 Lentivirus preparation .................................................................................. 51 2.3.2 Stereotaxic lentivirus injections ................................................................... 51 2.3.3 Lentivirus mixtures used to make experimental comparisons .................. 52 2.3.4 Unilateral olfactory deprivation ................................................................... 53 2.3.5 Odor exposure ................................................................................................ 54 2.3.6 Immunohistochemistry ................................................................................. 55 2.3.7 Imaging procedures ....................................................................................... 56 2.3.8 Confocal imaging ........................................................................................... 56
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