Behavioral and Electrophysiological Properties of Nucleus Reuniens: Role in Arousal, Spatial Navigation and Cognitive Processes

Behavioral and Electrophysiological Properties of Nucleus Reuniens: Role in Arousal, Spatial Navigation and Cognitive Processes

BEHAVIORAL AND ELECTROPHYSIOLOGICAL PROPERTIES OF NUCLEUS REUNIENS: ROLE IN AROUSAL, SPATIAL NAVIGATION AND COGNITIVE PROCESSES by Tatiana Danela Viena A Dissertation Submitted to the Faculty of Charles E. Schmidt College of Science In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Florida Atlantic University Boca Raton, FL December 2018 Copyright 2018 by Tatiana Danela Viena ii ACKNOWLEDGEMENTS First, I wish to express my sincere thanks to my advisor Dr. Robert P. Vertes for the opportunity to work on these experiments and for his guidance and patience in completing this project. I also would like to thank the members of my committee, Dr. Robert W. Stackman and Dr. Timothy A. Allen for their challenging questions and suggestions regarding this project, but more importantly for their support. In addition, I want to thank Dr. Stephanie Linley for patiently teaching, guiding and empowering me whenever it was needed. I am grateful to all of the undergraduate research assistants who volunteered their time to assist in the many aspects of this project. They are too many to be named here, but you know who you are! I also would like to extend my gratitude to all of the wonderful individuals who one way or another assisted me over my graduate years and the many programs that sponsored my research activities. I also want to give a special recognition to my family (Bernardo, Randee and Elysse) for their unconditional love and support; and my mother and her daily words of encouragement. Thanks for always believing in me and pushing me to get to the finish line. Finally, I want to thank God for this journey and for giving me the patience and strength to accomplish this goal. All of you contributed to my success and for that, I humbly THANK YOU! iv ABSTRACT Author: Tatiana Danela Viena Title: Behavioral and Electrophysiological Properties of Nucleus Reuniens: Role in Arousal, Spatial Navigation and Cognitive Processes Institution: Florida Atlantic University Dissertation Advisor: Dr. Robert P. Vertes Degree: Doctor of Philosophy Year: 2018 The hippocampal-medial prefrontal circuit has been shown to serve a critical role in decision making and goal directed actions. While the hippocampus (HF) exerts a direct influence on the medial prefrontal cortex (mPFC), there are no direct return projections from the mPFC to the HF. The nucleus reuniens (RE) of the midline thalamus is strongly reciprocally connected with the HF and mPFC and represents the major link between these structures. We investigated the role of RE in functions associated with the hippocampus and the mPFC -- or their interactions. Using two different inactivation techniques (pharmacological and chemogenetic), we sought to further define the role of RE in spatial working memory (SWM) and behavioral flexibility using a modified delayed non-match to sample (DNMS) working memory task. We found that the reversible inactivation of RE with muscimol critically impaired SWM performance, abolished well-established spatial strategies and produced a profound inability to correct non-rewarded, incorrect v choices on the T-maze (perseverative responding). We observed similar impairments in SWM following the chemogenetic (DREADDs) inactivation of RE or selective RE projections to the ventral HF. In addition, we showed that the inhibition of RE terminals to the dorsal or ventral HF altered task related behaviors by increasing or decreasing the time to initiate the task or reach the reward, respectively. Finally, we examined discharge properties of RE cells across sleep-wake states in behaving rats. We found that the majority of RE cells discharge at high rates of activity in waking and REM and at significantly reduced rates in SWS, with a subpopulation firing rhythmically in bursts during SWS. We identified five distinct subtypes of RE cells that discharged differently across vigilant states; those firing at highest rates in waking (W1, W2), in REM sleep (R1, R2) and SWS (S1). Given the differential patterns of activity of these cells, we proposed they may serve distinct functions in waking – and possibly in SWS/REM sleep. In sum, our findings indicate that RE is critically involved in mnemonic and executive functions and the heterogeneous activity of these cells support a role for RE in arousal/attention, spatial working memory and cognition. vi DEDICATION This manuscript is dedicated to my daughters Randee and Elysse, who I constantly tell they can achieve anything they want in life through honesty, persistence and hard work. Let this be proof and a constant reminder that the sky is the limit, and when you get there, you can still fly!! Therefore, chase your dreams and never, EVER give up! BEHAVIORAL AND ELECTROPHYSIOLOGICAL PROPERTIES OF NUCLEUS REUNIENS: ROLE IN AROUSAL, SPATIAL NAVIGATION AND COGNITIVE PROCESSE LIST OF TABLES ......................................................................................................... xiv LIST OF FIGURES ........................................................................................................ xv ABBREVIATIONS ....................................................................................................... xvii GENERAL INTRODUCTION ........................................................................................ 1 The Ventral Midline Thalamus ................................................................................... 1 Reuniens and rhomboid nuclei: Inputs/outputs ......................................................... 2 Nucleus reuniens inputs ............................................................................................ 2 Nucleus reuniens outputs .......................................................................................... 5 RE connections with mPFC ...................................................................................... 8 RE connections with HF ........................................................................................... 8 Rhomboid nucleus...................................................................................................... 9 Arousal related inputs to RE/RH ............................................................................ 12 Ventral midline thalamus: Electrophysiological studies ......................................... 13 Role of nucleus reuniens in mnemonic functions ..................................................... 18 Role of nucleus reuniens in executive functions ....................................................... 20 viii Role of the thalamus in arousal/attention ................................................................. 24 Purpose and Dissertation Organization .................................................................... 26 CHAPTER 1: INACTIVATION OF NUCLEUS REUNIENS IMPAIRS SPATIAL WORKING MEMORY AND BEHAVIORAL FLEXIBILITY IN THE RAT ......................................................................................................................... 28 Executive Summary .................................................................................................... 28 CHAPTER 2: CHEMOGENETIC INACTIVATION OF NUCLEUS REUNIENS OR RE FIBERS SELECTIVELY DISTRIBUTING TO THE MPFC AND HIPPOCAMPUS: MEMORY AND GOAL DIRECTED ACTIONS ........................................................................................................................ 30 Introduction ................................................................................................................. 30 The role of hippocampal and prefrontal interactions in the delayed nonmatch to sample paradigm..................................................................................................... 31 RE as a mediator of HF-mPFC interactions in cognition ....................................... 33 Materials and Methods ............................................................................................... 34 Subjects ..................................................................................................................... 34 DREADDs Technique .............................................................................................. 34 Surgery and Viral Vector Delivery .......................................................................... 35 Drugs and microinfusion procedures...................................................................... 36 Apparatus ................................................................................................................. 39 Behavioral Testing ................................................................................................... 39 ix Data Analysis............................................................................................................ 43 Coding of behavioral data .................................................................................... 43 Performance measures.......................................................................................... 43 Immunohistology ................................................................................................... 44 Statistical Analysis ................................................................................................ 46 Results .......................................................................................................................... 47 DREADDs viral expression and histological verification ...................................... 47 Chemogenetic inhibition of RE alters choice accuracy across

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