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Interaction of Genetic Predisposition and Epigenetic Factors in the Development of Anxiety

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Interaction of Genetic Predisposition and Epigenetic Factors in the Development of Anxiety Interaction of genetic predisposition and epigenetic factors in the development of anxiety Dissertation der Fakultät für Biologie der Ludwig-Maximilian-Universität München zur Erlangung des akademischen Grades Doctor rerum naturalium (Dr. rer. nat.) Vorgelegt von Patrick Oliver Markt, Diplom Biologie Universität München, 19. September 2012 i Tag der mündlichen Prüfung: 8. Januar 2013 Erster Gutachter: Prof. Rainer Landgraf Zweiter Gutachter: Prof. Gisela Grupe ii Angst haben wir alle. Der Unterschied liegt in der Frage wovor. Frank Thiess († 22. Dezember 1977) …………………………………….…Dedicated to the ones that I love iii Abstract It is becoming increasingly clear by current research that the continuum of physiological anxiety up to psychopathology is not merely dependent on genes, but is orchestrated by the interplay of genetic predisposition, gene x environment and epigenetic interactions. To consider this interplay, we here took advantage of the rigid genetic predisposition of a selectively bred mouse model exhibiting high anxiety-related behavior (HAB) and tested whether and how enriched environment, a manipulation of housing conditions, is capable of rescuing the genetically driven high anxiety phenotype via gene x environment and/or epigenetic interactions. Indeed, enriched environment exerts a significant anxiolytic effect on HABs of both sexes indicating for the first time that even a rigid genetic predisposition of high anxiety can be rescued by beneficial environmental stimuli. Thereby, a reduced neophobia and a bigger behavioral repertoire of HABs (e.g. social interactions) have been observed with a stronger anxiolysis in males than in females. The behavioral shift is accompanied by an attenuated release of corticosterone after application of a mild stressor. A hyperreactive hypothalamic-pituitary-adrenal (HPA) axis and amygdala constitute the most common symptoms of anxiety disorders, and decreased corticosterone release seems to entail a reduced release of noradrenaline from locus caeruleus (LC) to the medial prefrontal cortex (mPFC), thereby increasing the top-down control of mPFC on amygdala. This would entail less activation of amygdala and thus HPA axis, a consequence we indeed can observe as decreased neuronal activity flow through the amygdala of enriched housed (EE) compared to standard housed (SE) HABs. We suggest that corticotropin-releasing hormone receptor 1 (Crhr1) is critically involved in this phenomenon since (i) HABs compared to low anxiety-related behavior (LAB) mice exhibit higher Crhr1 mRNA in the basolateral amygdala (BLA), (ii) this overexpression can be significantly reduced when HABs are housed in enriched environment and (iii) a bilateral application of a CRHR1 antagonist in the BLA of SE HABs induced a significant anxiolytic effect. Subsequent pyrosequencing identified that enriched environment increased methylation at a CpG site in the promoter of Crhr1, which is located next to a transcription factor binding site (TFB) of the epigenetic transcription factor Yin Yang 1 (YY1), whose mRNA levels are indeed decreased in EE HABs. In silico analysis identified Nr4a1 and D3Ertd300e as critical co- transcription factors, whereas Nr4a1 seems to be regulated by the quantity of available glucocorticoid receptor (GR) and D3Ertd300e positively regulates YY1. Thus, we hypothesize that reduced corticosterone release decreases the availability and thus binding of corticosterone to GR in the BLA. This, in turn decreases the binding affinity of Nr4a1 to D3Ertd300e, which then cannot positively regulate YY1 to decrease or even prevent methylation at the identified CpG site of Crhr1. This would finally result in a differentially methylated region (DMR) with higher methylation levels in EE HABs, which underlies the observed gene expression differences. The identified DMR might therefore be used as a biomarker for high or pathological anxiety. This hypothesized mechanism highlights the possibility that even a rigid genetic predisposition modeling pathological anxiety might be rescued by an epigenetic process that seems to be triggered by beneficial environmental stimuli, thereby raising the exciting possibility for new treatment strategies, which can be utilized complementary to already existing ones. 1 Table of contents List of abbreviations .............................................................................................................. 4 1.1 Fear, anxiety and the stress response ............................................................................... 7 1.2 Maintenance of homeostasis ............................................................................................ 8 1.3 CRH system and the critical role of the amygdala ........................................................ 10 1.4 Epigenetics - the missing link in psychopathology? ..................................................... 14 1.5 From normal to pathological anxiety............................................................................. 17 1.6 Limitation of actual treatment strategies for pathological anxiety ................................ 20 1.7 The beneficial effects of enriched environment ............................................................ 21 1.8 High anxiety-related behavior mice - a mouse model of pathological anxiety. ............ 24 2 Aims of the thesis ............................................................................................................. 27 3 Material and Methods ....................................................................................................... 29 3.1 Animals and housing conditions.................................................................................... 29 3.2 Behavioral Testing ......................................................................................................... 30 3.3 in silico and molecular analyses .................................................................................... 37 3.4 Pharmacological manipulation: ..................................................................................... 48 3.5 Statistical analyses ......................................................................................................... 51 4. Results ............................................................................................................................. 53 4.1.1. Effect of EE on anxiety-related behavior .................................................................. 53 4.1.2. Effects of EE on exploratory behavior and locomotion ............................................ 58 4.1.3. Effects of EE on coping style and stress reactivity ................................................... 62 4.2 Variability and reproducibility of EE: a meta-analysis of beneficial effects ................ 63 4.2.2. Meta-analysis of locomotion ..................................................................................... 66 4.2.3 Meta-analysis of coping style ..................................................................................... 67 4.3 Impact of enrichment on “normal” anxiety-related behavior animals .......................... 67 4.4.2. Impact of EE on exploratory behavior ...................................................................... 73 4.3.3 Effect of environmental enrichment on coping style and anhedonia ......................... 74 4.4 Impact of environmental enrichment on anxiety-related behavior of outbred CD1 mice. ............................................................................................................................................. 75 4.5 Impact of duration on the effects elicited by environmental enrichment ...................... 76 4.5.2 Impact of prolonged enrichment on coping style ....................................................... 82 4.6 Comparison of the impact of environmental enrichment between NABs and HABs receiving either 4 or 10 weeks of EE. .................................................................................. 85 2 4.7 Contribution of maternal, pup and adolescent behavior to the anxiolytic effect elicited by environmental enrichment in HABs. .............................................................................. 86 4.7.1 Impact of maternal behavior on anxiety-related behavior during enrichment. .......... 86 4.7.2 Effect of EE on pup behavior ..................................................................................... 87 4.7.3 Impact of EE on adolescent behavior ......................................................................... 89 4.8 Identification of candidate genes related to anxiety-related behavior. .......................... 91 4.8.2 Western Blot ............................................................................................................... 93 4.9 Pharmacological validation of CRHR1 via an α-helical antagonist .............................. 94 4.10 Assessment of Crhr1 promoter methylation by pyrosequencing................................. 95 4.11 Identification of transcriptional regulators by in silico analysis.................................. 96 4.12 Modulation of behavior by epigenetic drugs ............................................................... 98 4.13 Evaluation of transgenerational effects ..................................................................... 101 5 Discussion and future experiments ................................................................................. 109 6 References .....................................................................................................................
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