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Transcriptome Analysis of the Hypothalamic-Pituitary-Adrenal Axis in the Experimentally Domesticated Fox

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Transcriptome Analysis of the Hypothalamic-Pituitary-Adrenal Axis in the Experimentally Domesticated Fox TRANSCRIPTOME ANALYSIS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN THE EXPERIMENTALLY DOMESTICATED FOX BY JESSICA PERRY HEKMAN DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Animal Sciences in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee Assistant Professor Anna Kukekova, Chair Professor Jonathan Beever Associate Professor Allison Bell Associate Professor Lori Raetzman Professor Lisa Stubbs ABSTRACT Variation in activity of the hormonal stress response, or hypothalamic-pituitary-adrenal (HPA) axis, has been associated with different personality traits and coping styles in humans and animals, while its dysregulation has been implicated in psychological disorders. The molecular basis of HPA axis regulation, however, is not yet well understood. Here, foxes selectively bred for tameness or aggression are used as a model to investigate differences in regulation of the HPA axis. Activity of this axis is markedly reduced in tame compared to aggressive foxes, with reduced levels of HPA axis hormones such as adrenocorticotrophic hormone (ACTH) and cortisol both basally and in response to a stressor. Gene expression differences were analyzed using RNA sequencing in the anterior pituitary and adrenal glands of foxes from the tame and aggressive lines, and variant analysis was performed on RNA reads from hypothalamus, anterior pituitary, and adrenal tissues from the same foxes. Pituitary analysis revealed expression differences in genes related to exocytosis and cellular signaling; adrenals analysis identified differences in similar pathways, in addition to genes related to fatty acid and cholesterol synthesis. Variant analysis also implicated cell signaling and exocytosis, as well as ion transport and DNA damage repair. These findings suggest the importance of regulation of hormone release in the control of ACTH and cortisol levels. They also suggest that metabolism of precursors to cortisol, such as fatty acids and cholesterol, may be of greater importance in HPA axis regulation than synthesis of cortisol itself. Finally, in conjunction with previous genomic findings, they suggest an association between DNA repair mechanisms and selection for tameness. These findings provide possible new lines of investigation into biological underpinnings of the phenotypic differences between the tame and aggressive lines of foxes. More broadly, as the tame foxes are considered experimentally domesticated, the findings from this project may prove applicable to HPA axis regulation differences associated with domestication in other species. Additionally, a deeper understanding of HPA axis regulation and dysregulation may be applicable both to variation in the normal population, particularly as related to behavioral traits such as coping styles, and to a number of psychiatric disorders in humans, as well as to behavioral disorders in other species, such as dogs. ii To Jack iii ACKNOWLEDGEMENTS My sincerest thanks to all the members of Kukekova Laboratory for their support, particularly Anna Kukekova, Jennifer Johnson, my fellow graduate students, Halie Rando and Ali Ford, and my research assistant Naomi Won. I am also grateful to my committee members, Jonathan Beever, Allison Bell, Lori Raetzman, and Lisa Stubbs, for their guidance, as well as Sandra Rodriguez-Zas and Carolyn Thomas. I am grateful for Dr. Lyudmila Trut’s fortitude in shepherding the tame fox project for so many years, and for her kindness when I met her. Thank you to everyone at the Institute for Cytology and Genetics, especially my guides when I visited, Anastasia Kharlamova and Darya Shepeleva. Thank you to Andy Clark and Xu Wang for their hospitality in Ithaca and their help in the early stages of this project; Michael Saul and Waqar Arif for invaluable bioinformatics advice; and Whitney Edwards and Lori Raetzman for, among many other things, the crucial insight about what was going on with the pseudopodia. I was personally supported by the Jonathan Baldwin Turner Fellowship and by Temple Grandin; without these sources none of this would have been possible. Dr. Grandin particularly provided advice and support that I much appreciated. Finally, many thanks to Chris, Jack, Jenny, Rosie, and Dashiell, for their (varying amounts of) patience as I worked on this project. iv TABLE OF CONTENTS CHAPTER 1: INTRODUCTION ..........................................................................................1 CHAPTER 2: TRANSCRIPTOME ANALYSIS IN DOMESTICATED SPECIES: CHALLENGES AND STRATEGIES ...................................................................................11 CHAPTER 3: TRANSCRIPTOME ANALYSIS OF TAME AND AGGRESSIVE FOX PITUITARIES SUGGESTS A ROLE FOR PITUITARY CELL NETWORKS AND PSEUDOPODIA IN REGULATION OF ACTH RELEASE ...............................................32 CHAPTER 4: TRANSCRIPTOME ANALYSIS OF TAME AND AGGRESSIVE FOX ADRENAL GLANDS DESCRIBES DIFFERENTIAL REGULATION OF CHOLESTEROL METABOLISM .....................................................................................................................61 CHAPTER 5: VARIANT ANALYSIS OF TAME AND AGGRESSIVE FOX RNA READS .................................................................................................................................90 CHAPTER 6: CONCLUSIONS ............................................................................................110 REFERENCES ......................................................................................................................113 APPENDIX A: SUPPLEMENTARY INFORMATION FOR CHAPTER 3 .......................160 APPENDIX B: SUPPLEMENTARY INFORMATION FOR CHAPTER 4 ........................170 APPENDIX C: SUPPLEMENTARY INFORMATION FOR CHAPTER 5 ........................177 v CHAPTER 1: INTRODUCTION 1.1 BACKGROUND AND SIGNIFICANCE Hyper- or hypo-activity of the hypothalamic-pituitary-adrenal (HPA) axis have been associated with psychological disorders such as generalized anxiety disorder (Greaves-Lord et al., 2007; Mantella et al., 2008), major depressive disorder (Burke et al., 2005; Doane et al, 2013; Hardeveld et al., 2014), and post-traumatic stress disorder (Wessa et al., 2006; Meewisse et al., 2007). Moreover, non-pathological variation in HPA activity has been associated with different personality traits (Shoal et al., 2003; Oswald, 2006), with different coping styles in laboratory and wild animals (Koolhaas et al., 2007; Baugh et al., 2013; Clary et al., 2014), and with domesticated compared to wild animals (Künzl et al., 2003; Ericsson et al., 2014). While some genomic variation in HPA axis regulation has been described (Rosmond et al., 2001; Wagner et al., 2006; Keck et al., 2008), a full understanding of HPA axis regulation at the molecular level, and its associated cellular mechanisms, has yet to be reached. Such an understanding could contribute to better description of the mechanisms in animals and humans affecting both pathological HPA axis dysregulation, as well as normal variation in behavior, such as coping styles. Reaching this understanding is made more difficult by the complexity of the hormonal stress response. The response to a psychological or physical stressor begins in the central nervous system and is transmitted out to organs and tissues via translation into hormones that are released into the systemic circulation. This process begins in the paraventricular nucleus (PVN) of the hypothalamus, initiated by input from higher structures such as the hippocampus, prefrontal cortex, and amygdala (Herman et al, 2003). This region of the hypothalamus releases corticotropin-releasing hormone (CRH), which travels through a portal venous system to the anterior pituitary to trigger the release of adrenocorticotropic releasing hormone (ACTH) from corticotrophic cells. CRH binds with greater affinity to a CRH type 1 receptor, which is mainly expressed in the pituitary, cerebellum, and neocortex. Deficiency of this receptor is associated with reduced anxiety-like behavior in mice (Leonard, 2005) CRH binds with lesser affinity to a type 2 receptor, which is mainly expressed in the hypothalamus, amygdala, dorsal raphe, and 1 hippocampus, and which appears to have opposing effects on behavior to the type 1 receptor (Leonard, 2005). ACTH travels through the peripheral circulation where it is taken up by the adrenal glands and triggers the release of cortisol and/or corticosterone (CORT), depending on species, from the adrenal cortex (Bornstein and Chrousos, 1999). CORT release is also modulated by direct sympathetic innervation to the adrenal cortex (Bornstein and Chrousos, 1999). CORT is a steroid hormone that is bound in the bloodstream by corticosteroid binding globulin (CBG); availability of CBG affects the activity of CORT, as protein-bound CORT is not biologically available, so that reduced CBG availability is associated with increased biological activity of CORT (Sapolsky and Meaney, 1986). CORT is bound by the mineralocorticoid receptor (MR) at high affinity and the glucocorticoid receptor (GR) at low affinity (Rupprecht et al., 1993) so that the GR may mediate cellular responses to stress levels of CORT while the MR may mediate cellular responses to basal levels of CORT. When CORT elevation causes increased MR receptor occupancy, binding of CORT to the GR receptor causes it to translocate into the nucleus of the cell and act as a transcription factor. Here it affects gene expression in peripheral tissues
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