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University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2009 Multiscale Genomic Analysis of the Corticolimbic System: Uncovering the Molecular and Anatomic Substrates of Anxiety-Related Behavior Khyobeni Mozhui University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Mental and Social Health Commons, Nervous System Commons, and the Neurosciences Commons Recommended Citation Mozhui, Khyobeni , "Multiscale Genomic Analysis of the Corticolimbic System: Uncovering the Molecular and Anatomic Substrates of Anxiety-Related Behavior" (2009). Theses and Dissertations (ETD). Paper 180. http://dx.doi.org/10.21007/etd.cghs.2009.0219. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Multiscale Genomic Analysis of the Corticolimbic System: Uncovering the Molecular and Anatomic Substrates of Anxiety-Related Behavior Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Anatomy and Neurobiology Research Advisor Robert W. Williams, Ph.D. Committee John D. Boughter, Ph.D. Eldon E. Geisert, Ph.D. Kristin M. Hamre, Ph.D. Jeffery D. Steketee, Ph.D. DOI 10.21007/etd.cghs.2009.0219 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/180 MULTISCALE GENOMIC ANALYSIS OF THE CORTICOLIMBIC SYSTEM: UNCOVERING THE MOLECULAR AND ANATOMIC SUBSTRATES OF ANXIETY-RELATED BEHAVIOR A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Khyobeni Mozhui 2009 Chapter 2 © 2007 by Springer Netherlands Chapter 3 © 2008 by Nature Publishing Group Chapter 5 © 2008 by Mozhui et al. All other material © 2009 by Khyobeni Mozhui All rights reserved ii ACKNOWLEDGEMENTS My heartfelt gratitude to my research supervisor and mentor, Dr. Rob Williams, for the guidance and inspiration I have received from him. I am thankful for the many opportunities he has provided to develop my scientific faculties. Beyond his role as my research adviser, he has also instilled in me a sense of confidence and independence. I consider him a rare and brilliant teacher. I also thank all the members of my committee, Drs. John Boughter, Eldon Geisert, Kristin Hamre, and Jeff Steketee, for their advice and their critical and constructive comments. I feel most fortunate to have this group to guide me during the course of my research. I must also thank Drs. Susan Brasser and Chris Lemon. They were my guides during the early stages of my studies. And I express my most sincere gratitude to Dr. Matt Ennis for giving me courage and counsel, and to Dr. Bill Armstrong for his support during unexpected and trying times. And to Dr. David Smith, I remain thankful. I extend my gratitude to Dr. Lu Lu, Dr. Daniel Ciobanu, Arthur Centeno, and all the other members of the Williams’ Lab. Their help have been invaluable. I am also thankful to Dr. Andrew Holmes for being such a beneficial collaborator. I acknowledge all the funding sources that have sponsored my graduate studies (NIAAA INIA grants grants U01AA13499, U24AA13513, and U01AA014425; NIDA, NIMH, and NIAAA grant P20-DA 21131; NCI NMHCC grant U01CA105417). Finally, to my dear ones, I am truly grateful. Apvü and Apo for their ceaseless love, their blessings, and their fervent prayers. Dear Sis, for the courage and strength I draw from her. And Ashley, for her cherished company, her encouraging words, and her excitement over my research and dissertation. iii ABSTRACT Genetic diversity generates variation at multiple phenotypic levels, ranging from the most basic molecular to higher-order cognitive and behavioral traits. The far-reaching impact that genes have on higher traits is apparent in several neuropsychiatric conditions such as stress and anxiety disorders. Like most, if not all, neural phenotypes, stress, anxiety, and other emotion-related traits are extremely complex and are defined by the interplay of multiple genetic, environmental, experiential, and epigenetic factors. The work presented in this dissertation is a multi-scalar, integrative analysis of the molecular and neuroanatomic substrates that underlie emotion-related behavior. The amygdala is a principle component of the limbic system that controls emotionality. Using BXD recombinant inbred (RI) mice as model organisms, the anatomy and cellular architecture of the amygdala—specifically, the basolateral amygdala (BLA)—was examined to assess the level of structural variation in this brain region. Quantitative trait locus (QTL) analysis was done to identify genetic loci that modulate the neuroanatomical traits of the BLA. The BXD RI mice were also tested using a variety of behavioral assays, and this showed a significant association between the BLA size and emotion- related behavior. The effect of chronic stress on subsequent behavior and endocrine- response was also examined in several genetically diverse inbred mice. Finally, to explore the molecular mediators of stress and anxiety, microarrays were used to assay gene expression in three key corticolimbic brain regions—the prefrontal cortex, amygdala, and hippocampus. Several large transcriptome data sets were also analyzed. These expression data sets brought focus on an interval on mouse distal chromosome 1 that modulates diverse neural and behavioral traits, and also controls the expression of a plethora of genes. This QTL rich region on mouse distal chromosome 1 (Qrr1) provides insights into how the information in the DNA sequence is conveyed by networks of co-regulated genes that may in turn modulate networks of inter-related phenotypes. iv TABLE OF CONTENTS CHAPTER 1. INTRODUCTION .................................................................................1 1.1 Complex Traits.......................................................................................................1 1.2 Genetics of Neural and Behavioral Phenotypes.......................................................1 1.3 Neuroanatomy of Stress and Emotion-Related Behavior.........................................2 1.4 Mapping Loci that Modulate Complex Traits..........................................................3 1.4.1 Basics of QTL Analysis............................................................................3 1.4.2 Inbred and Recombinant Inbred Mice.......................................................4 1.5 Systems Genetics Approach to Complex Traits.......................................................6 1.5.1 Gene Expression as an Intermediate Phenotype........................................6 1.5.2 Systems Genetics .....................................................................................6 1.6 Organization of the Dissertation..............................................................................7 CHAPTER 2. GENETIC AND STRUCTURAL ANALYSIS OF THE BASOLATERAL AMYGDALA COMPLEX IN BXD RECOMBINANT INBRED MICE .............................................................................................................9 2.1 Synopsis ................................................................................................................9 2.2 Introduction............................................................................................................9 2.3 Materials and Methods..........................................................................................11 2.3.1 Subjects..................................................................................................11 2.3.2 Fixation and Sectioning..........................................................................11 2.3.3 Volumetric Measurement .......................................................................11 2.3.4 Stereological Methods............................................................................13 2.3.5 Statistics.................................................................................................14 2.3.6 Genotyping and QTL Mapping...............................................................14 2.4 Results..................................................................................................................15 2.4.1 Volume of the BLA Complex.................................................................15 2.4.2 BLA Cell Counts....................................................................................17 2.4.3 QTL Analysis for BLA Volume .............................................................18 2.4.4 QTL Specificity......................................................................................21 2.4.5 Correlations between BLA Volume and Cell Populations.......................21 2.4.6 Neuroanatomical Correlates of BLA and Comparative QTL Analysis ....24 2.4.7 Behavioral Correlates of BLA and Comparative QTL Analysis..............26 2.4.8 Candidate Genes ....................................................................................29 2.5 Discussion ............................................................................................................31 2.5.1 Summary................................................................................................31
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