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Thesis Behavioral Effects Of THESIS BEHAVIORAL EFFECTS OF ESTROGEN RECEPTOR BETA ACTING LOCALLY TO REGULATE THE EXPRESSION OF TRYPTOPHAN HYDROXYLASE 2 (TPH2) IN SEROTONERGIC NEURONS OF THE DORSAL RAPHE NUCLEI submitted by Nina Caroline Donner Department of Biomedical Sciences In partial fulfillment of the requirements for the Degree of Master of Science Colorado State University Fort Collins, CO Fall 2008 COLORADO STATE UNIVERSITY November 7, 2008 WE HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER OUR SUPERVISION BY NINA CAROLINE DONNER ENTITELDED: “BEHAVIORAL EFFECTS OF ESTROGEN RECEPTOR BETA ACTING LOCALLY TO REGULATE THE EXPRESSION OF TRYPTOPHAN HYDROXYLASE 2 (TPH2) IN SEROTONERGIC NEURONS OF THE DORSAL RAPHE NUCLEI” BE ACCEPTED AS FULFILLING IN PART REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE. Committee on Graduate Work ________________________________________ (Dr. Ronald Tjalkens) ________________________________________ (Dr. Colin Clay) ________________________________________ (Dr. Stuart Tobet) ________________________________________ Advisor (Dr. Robert Handa) ________________________________________ Department Head/Director ii ABSTRACT OF THESIS BEHAVIORAL EFFECTS OF ESTROGEN RECEPTOR BETA ACTING LOCALLY TO REGULATE THE EXPRESSION OF TRYPTOPHAN HYDROXYLASE 2 (TPH2) IN SEROTONERGIC NEURONS OF THE DORSAL RAPHE NUCLEI Affective disorders often involve serotonin (5-HT)-related dysfunctions and are twice as common in women than men. Interactions between estrogen and the brain 5-HT system have long been proposed to contribute to sex differences in mood and anxiety disorders, but the mechanisms underlying this phenomenon have yet to be revealed. Estrogen signaling is mediated by two different receptors termed estrogen receptor alpha and estrogen receptor beta. While estrogen receptor alpha (ERalpha) has mainly reproductive responsibilities, in brain, estrogen receptor beta (ERbeta) has been shown to attenuate anxiety- and despair-like behaviors in rodent models. However, little is known about ERbeta regulation of function in the brainstem raphe nuclei. The raphe nuclei are the main 5-HT system of the brain, and projections from the dorsal raphe nuclei (DRN) innervate many important forebrain and limbic areas. The work presented in this thesis addressed the possibility that ERbeta may be involved in the iii regulation of 5-HT gene expression specifically in DRN neurons. My studies examined the effects of systemic versus local, intracerebral application of the selective ERbeta agonist diarylpropionitrile (DPN) and the nonselective ER- ligand estradiol (E) on tryptophan hydroxylase 2 (TPH2) mRNA expression within the DRN of female rats. TPH2 is the brain-specific, rate-limiting enzyme catalyzing 5-HT synthesis, and is expressed in every 5-HT neuron. Thus, it provides an excellent tool to assess the capacity for 5-HT production with the DRN. In these studies, TPH2 mRNA expression was assessed via in situ hybridization. In addition, relevant behavioral parameters were tested in all animals to evaluate each compound’s effect on two closely related, but yet different mental states, anxiety-like and despair-like behavior. Both, chronic systemic and chronic local DPN administration to ovariectomized (OVX) female rats significantly enhanced TPH2 mRNA expression in mid- and caudal subregions of the DRN after 8 days of treatment. Respective controls received systemic vehicle (27% hydroxypropyl-beta- cyclodextrin) or blank control pellets. Local application of DPN caused a stronger effect than systemic drug delivery. Chronic local delivery of E (0.5 µM) increased TPH2 mRNA expression in the same subregions of the DRN as did DPN, but its overall effect was weaker compared to the selective ERbeta agonist. Interestingly, while systemic DPN-administration confirmed the anxiolytic nature of ERbeta in two separate anxiety tests (elevated plus maze and open field test), iv the effect was lost when DPN was delivered locally. However, local DPN- as well as E-treatment both resulted in attenuated despair-like behavior, as measured in the forced-swim test. Chapter 3 describes the experimental design, results and interpretation of these studies in depth. Taken together, my data indicate that local actions of ERbeta agonist onto DRN neurons are sufficient to decrease despair-like behavior, whereas ERbeta stimulation of other brain regions is necessary to alter anxiety-like behaviors. Correspondingly, ERbeta acts locally to control TPH2 mRNA expression and presumably 5-HT synthesis in the certain subregions of the rat DRN. These results suggest an important role of ERbeta for regulating cellular events in the female DRN, and offer new opportunities for therapeutic treatments of depressive disorders. Nina Caroline Donner Department of Biomedical Sciences Colorado State University Fort Collins, CO 80523 Fall 2008 v ACKOWLEDGEMENTS I thank my advisor Dr. Robert Handa for scientific advice and financial support, and my committee members Drs. Stuart Tobet, Colin Clay and Ronald Tjalkens for helpful critique. I especially thank Dr. Stuart Tobet for his availability and mental support in difficult times. In addition, the work presented would not have been possible without the other Handa Lab members, the social network they provided and their outstanding sense of humor. It was a pleasure to work with all of them, I am very grateful for that. To Michael Weiser I am thankful for de novo synthesis and provision of the ERbeta-selective compound diarylpropionitrile, and to Andrea Kudwa for help with ovariectomies. Most grateful, I am still for my early mentors and role models Dr. Gottfried Scholl, who sparked my fascination with biology, and Dr. Inga Neumann who never loses her excitement about science, and will always remain a great mentor and friend to me in scientific and non-scientific situations. I also sincerely thank my parents who did not have the chance to enjoy a high school or university education themselves, but constantly provided an intellectually stimulating atmosphere during childhood. It is them who Anja, my sister, and I have to thank most for our deep interest in nature and the biology of living organisms and for encouraging us to pursue our dreams. My boyfriend John deserves big thanks for being so supporting and understanding throughout the challenging last year, and for barbecuing so many awesome steaks to keep my metabolism going. Thanks! vi To Amelia, Julia, John and all of my family Chopping wood is so popular because it is the one and only activity that makes success instantly visible. Albert Einstein vii TABLE OF CONTENTS ABSTRACT……………………………………………………………………………...iii ACKNOWLEDGEMENTS……………………………………………………………...vi LIST OF FIGURES………………………………………………………………...…. ix LIST OF TABLES……………………………………………………………………….xi CHAPTERS CHAPTER 1 - GENERAL INTRODUCTION…………………………………1 CHAPTER 2 - REVIEW OF LITERATURE 5-HT and its role in depressive disorders……………………………..5 The neuronal tryptophan-hydroxylase: discovery & disorders….…12 Sex differences in mood disorders…………………………………...13 Estrogen receptors: structure & function………………………….…16 Localisation & function of estrogen receptor beta in the brain…….21 Estrogen receptor-mediated gene regulation in 5-HT neurons…...23 Summary & Hypothesis……………………………………………….27 CHAPTER 3 - Estrogen receptor beta acts locally to regulate TPH2 mRNA expression within serotonergic neurons of the rat dorsal raphe nuclei Abstract………………………………………………………………….28 Introduction……………………………………………………………..30 Materials & Methods…………………………………………………...34 Results…………………………………………………………………..45 Figures & Tables……………………………………………………….51 Discussion………………………………………………………………65 CHAPTER 4 – DISCUSSION………………………………………………...71 Conclusions…………………………………………………………….80 LIST OF ABBREVIATIONS…………………………………………………………..81 REFERENCES………………………………………………………………………...85 viii LIST OF FIGURES Chapter 2: 1. Schematic illustration of serotonin (5-HT) synthesis…………………….8 2. Schematic illustration of 5-HT projections from the dorsal raphe nuclei in the human brain…………….……………………………..…….11 3. Overview of peripheral TPH1 versus brain-specific TPH2 functions…14 4. Chemical structure of the selective ERbeta agonist diarylpropionitrile (DPN)………………………………………………………………………..16 5. Schematic representation of the relative homology between ERalpha and ERbeta protein and ER β splice variant exon structure..19 6. Seven days of daily s.c. treatment with DPN decreases acute c-Fos stress-reactivity of TPH2 neurons. …………………………..…..25 7. Original images of dual-label ICC: ERbeta2-positive TPH2 neurons and ERalpha-negative TPH2 cells in the female rat DRN…………….26 Chapter 3: 8. Systemic delivery of ERbeta agonist DPN was anxiolytic when animals were tested on the elevated plus maze and in the open field……….…………………………………………………………………52 9. Effect of local DPN- or E-treatment on behavior on the elevated plus maze and the open field, compared to vehicle control animals...53 ix 10. Effects of local E- and DPN-treatment of female OVX rats in the forced swim test. ………………………………………………………….54 11. Systemic DPN-treatment of OVX females significantly enhanced the expression of TPH2 mRNA in the caudal, but not in the rostral DRN, compared to vehicle controls. …………………………………....55 12. Representative dark-field pictures of TPH2 mRNA in the rostral, mid-, and caudal DRN of s.c. vehicle- or DPN-treated OVX animals..58 13. Localization of wax pellets implanted in experiment 2.……………….59 14. Local DPN- and E-pellets flanking the DRN in OVX rats elevated the expression of TPH2 mRNA in the mid- and caudal DRN………..61 15. Representative dark-field pictures
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