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The Effect of Cortical and Pallidal Inputs on Striatal Microcircuit Activity and Behavioral Output The Effect of Cortical and Pallidal Inputs on Striatal Microcircuit Activity and Behavioral Output by Victoria Louise Corbit Bachelor's of Science, Lafayette College, 2013 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2019 Commi tte e Membership Page UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Victoria Louise Corbit It was defended on June 17, 2019 and approved by Robert S. Turner, Ph.D, Professor, Department of Neurobiology Susan R. Sesack, Ph.D, Professor, Department of Neuroscience Peter L. Strick, Ph.D, Distinguished Professor and Chair, Department of Neurobiology Patrick Rothwell, Ph.D, Assistant Professor, Department of Neuroscience, University of Minnesota Dissertation Director: Susanne E. Ahmari, M.D., Ph.D, Assistant Professor, Department of Psychiatry Dissertation Director: Aryn H. Gittis, Ph.D, Associate Professor, Department of Biological Sciences, Carnegie Mellon University ii Copyright © by Victoria Louise Corbit 2019 iii Abstract The Effect of Cortical and Pallidal Inputs on Striatal Microcircuit Activity and Behavioral Output Victoria Louise Corbit, PhD University of Pittsburgh, 2019 This dissertation focuses on the role of striatal microcircuits and how afferents from cortex and globus pallidus externa (GPe) play a role in striatal activity and behavioral output. In the first chapter I summarize the role of striatal subregions in behavioral selection and initiation and elaborate on how striatal activity in output neurons (SPNs) and fast-spiking interneurons (FSIs) has been associated with behavioral initiations. Chapter 2 highlights the capacity of an FSI-specific pallidostriatal projection for controlling the activity of SPNs, particularly under dopamine depletion conditions. These data suggest that GPe may provide bursts of inhibition to FSIs, allowing SPNs a disinhibition window of time in which to fire without strong regulation from FSIs. In Chapter 3 I investigate abnormalities in cortical input to central striatum (CS) of Sapap3- KO mice. I demonstrate that LOFC inputs to CS are reduced onto SPNs in Sapap3-KOs. In contrast, M2 inputs, which are weak in WTs, are strengthened in KOs. These data suggest a potential increase in motor control over CS in KOs, possibly contributing to the repetitive behavior observed in these mice. Chapter 4 presents work investigating the role of the M2-CS circuit in grooming behavior. I first describe data from the lab showing that CS is hyperactive at the start of a grooming bout in Sapap3-KOs. I then show that there is grooming-related activity in both M2 and terminals in CS, but that this activity doesn’t differ by genotype; this suggests that ex vivo post-synaptic strengthening may lead to a post-synaptic potentiation of M2 signals in CS. I then demonstrate the iv sufficiency of this circuit in grooming behavior by stimulating CS or M2 terminals in CS and showing evoked grooming behavior. In the final chapter I discuss what my data may suggest about the role of corticostriatal circuits in behavioral initiations. Based on data that cortical terminal stimulation doesn’t cause immediate evoked behavior but CS stimulation does, I propose that the site of grooming initiation signals is in striatum. I describe a model in which CS integrates inputs from cortex and GPe to overcome hyperpolarized membrane potentials and generate activity to initiate grooming. v Table of Contents Preface ..................................................................................................................................... xv 1.0 Introduction .........................................................................................................................1 1.1 Distinct Regions of Striatum Mediate Different Aspects of Behavioral Selection ....1 1.1.1 Dorsolateral Striatum Mediates Stimulus-Response Behavior ......................2 1.1.2 Dorsomedial Striatum is Important for Goal-Directed Behavior ..................4 1.1.3 Ventral Striatum Processes Reward ................................................................5 1.1.4 Central Striatum May Play a Role in Compulsive Behavioral Selection .......7 1.2 Striatal Microcircuits In Behavioral Selection And Initiation ..................................7 1.2.1 Cortical Inputs are a Prominent Driver of Striatal Activity...........................8 1.2.2 Fast-Spiking Interneurons are Positioned to Apply Cortical Feed-Forward Inhibition onto SPNs .................................................................................................8 1.2.3 Striatal Interactions Within Basal Ganglia .....................................................9 1.2.4 Striatal Cells Play a Role in Several Aspects of Behavioral Selection and Initiation .................................................................................................................. 11 1.2.5 SPNs and FSIs Participate in Ensembles....................................................... 13 1.3 Disease Abnormalities Can Inform the Understanding of Behavioral Selection and Initiation .......................................................................................................................... 14 1.3.1 Parkinson’s Disease Includes Reduced Computational Power in Striatal Microcircuits ........................................................................................................... 15 1.3.2 Compulsive Behaviors are Associated With Greater Activity in Striatum .. 16 1.4 Summary and Aims of Dissertation .......................................................................... 18 vi 2.0 Pallidostriatal Projections Promote β Oscillations in a Dopamine-Depleted Biophysical Network Model .................................................................................................... 19 2.1 Introduction ............................................................................................................... 19 2.2 Materials and Methods ............................................................................................. 21 2.2.1 Animal Surgery and Viral Injections ............................................................ 21 2.2.2 Electrophysiological Recordings .................................................................... 22 2.2.3 Immunohistochemistry .................................................................................. 23 2.2.4 GPe Viral Targeting Quantification .............................................................. 24 2.2.5 Biophysical Network Model ........................................................................... 24 2.2.6 Model Analysis ............................................................................................... 31 2.2.7 Statistical Methods ......................................................................................... 33 2.3 Results ........................................................................................................................ 33 2.3.1 Pallidostriatal Projections are Selective for Interneurons ............................ 33 2.3.2 Construction of a Biophysically Detailed Model of the GPe-FSI-MSN Loop ………………………………………………………………………………37 2.3.3 GPe-FSI-MSN Loop is Sufficient to Produce β Under DD Conditions ........ 39 2.3.4 GPe-MSN Connections Do Not Affect Model Rhythmicity .......................... 43 2.3.5 The GPe-FSI Projection Significantly Enhances Synchrony and is Necessary for β Oscillations ..................................................................................................... 45 2.3.6 Synchronous GPe Spikes Rhythmically Synchronize FSI Pauses and MSN Spikes…………………………………………………………………………………48 2.3.7 β Oscillations are Selectively Amplified in the GPe-FSI-MSN Loop............ 52 2.4 Discussion .................................................................................................................. 58 vii 2.4.1 Synaptic Properties of Pallidostriatal Projections ........................................ 59 2.4.2 Model β Activity is Generated Through GPe Synchronization at β Frequency ………………………………………………………………………………60 2.4.3 Relation to Previous Models .......................................................................... 64 2.4.4 Conclusion ...................................................................................................... 65 3.0 Strengthened Inputs From Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior............................................................................................... 67 3.1 Introduction ............................................................................................................... 67 3.2 Materials and Methods ............................................................................................. 69 3.2.1 Animals ........................................................................................................... 69 3.2.2 Stereotaxic Surgeries ...................................................................................... 70 3.2.3 Slice Electrophysiology................................................................................... 71 3.2.4 Histology ......................................................................................................... 72 3.2.5 Experimental Design and Statistical Analysis ............................................... 73 3.3 Results .......................................................................................................................
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