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Effects of Psychosocial Stress on Retinal Neurodegeneration

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Effects of Psychosocial Stress on Retinal Neurodegeneration Effects of Psychosocial Stress on Retinal Neurodegeneration Dissertation DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER FAKULTÄT FÜR BIOLOGIE UND VORKLINISCHE MEDIZIN DER UNIVERSITÄT REGENSBURG vorgelegt von Forkwa Kieran Tembei Aus ANGIE-KAMERUN 2012 Das Promotionsgesuch wurde eingereicht am: 09.10.2012 Die Arbeit wurde angeleitet von: Prof. Dr. med. Ernst R. Tamm Prüfungsausschuss: Vorsitzender: PD Dr. Stefan Reber 1. Gutachter: Prof. Dr. Ernst Tamm 2. Gutachter: Prof. Dr. Inga Neumann 3. Prüfer: Prof. Dr. Stephan Schneuwly MY FAMILY TABLE OF CONTENT ix Table of Content 1 INTRODUCTION ..................................... 1 1.1. Loss of vision due to retinal degeneration ______________________________ 1 1.2. Anatomy and physiology of the retina _________________________________ 2 1.2.1. Retinal structure................................................................................................................ 2 1.2.2. Visual phototransduction .................................................................................................. 4 1.2.3. Retinal degenerative diseases ........................................................................................... 5 1.3. Causes and pathways leading to photoreceptor degeneration ______________ 7 1.3.1. Causes of photoreceptor degeneration .............................................................................. 7 1.3.2. Pathways leading to photoreceptor degeneration ............................................................. 9 1.3.3. Photoreceptor demise in retinal degenerations ............................................................... 11 1.4. Research and therapeutic strategies for retinal degeneration _____________ 12 1.4.1. Animal and Experimental models .................................................................................. 13 1.4.2. Therapeutic strategies to promote photoreceptor survival .............................................. 14 1.5. Stress ___________________________________________________________ 14 1.5.1. Acute vs Chronic stress .................................................................................................. 15 1.5.2. Psychosocial stress ......................................................................................................... 16 1.5.3. Psychosocial stress in mice via chronic subordinate colony (CSC) housing .................. 17 1.6. Glucocortcoid synthesis, release and their effects _______________________ 17 1.6.1. The HPA axis and the release of GCs ............................................................................ 17 1.6.2. Glucocorticoid effects and modes of action. .................................................................. 19 1.6.3. The role of glucocorticoids in apoptosis and neuroprotection ........................................ 20 1.7. The Phosphatidylinositol 3-Akt kinase (PI3-Akt) pathway _______________ 22 2 AIM OF THE THESIS ........................... 23 3 MATERIALS AND METHODS ............. 25 3.1. Main materials and equipment. _____________________________________ 25 3.2. Animal Models ___________________________________________________ 26 3.2.1. Mice ................................................................................................................................ 26 3.2.2. CSC housing ................................................................................................................... 27 3.2.3. Short-term vs. Chronic CSC Housing ............................................................................ 27 3.3. Intravitreal and intraperitoneal injections _____________________________ 29 3.3.1. Materials and Reagents ................................................................................................... 29 3.3.2. Intravitreal injection ....................................................................................................... 30 3.3.1. Intraperitoneal (ip) injection ........................................................................................... 30 3.4. Animal surgery and blood sampling __________________________________ 31 3.4.1. Materials and Reagents ................................................................................................... 31 3.4.2. Adrenalectomy (ADX) ................................................................................................... 31 3.4.3. Dertermination of adrenal weight ................................................................................... 32 TABLE OF CONTENT x 3.4.4. Blood sampling ............................................................................................................... 32 3.5. Induction of retinal degeneration ____________________________________ 32 3.5.1. Light induced damage of photoreceptors........................................................................ 33 3.5.2. NMDA induced damage of RGC´s................................................................................. 33 3.6. Histology ________________________________________________________ 34 3.6.1. Paraffin sections ............................................................................................................. 34 3.6.2. TUNEL Labelling ........................................................................................................... 36 3.6.3. Preparation of semi-thin Sections ................................................................................... 39 3.7. Molecular Biology _________________________________________________ 43 3.7.1. Reagents, Materials and Equipment ............................................................................... 43 3.7.2. Genotyping of mice for Balb/c lineage ........................................................................... 44 3.7.3. RNA isolation from cells and tissue ............................................................................... 47 3.7.4. RT-PCR primer design ................................................................................................... 49 3.7.5. Quantitative Real-time PCR ........................................................................................... 50 3.8. Protein biochemistry techniques _____________________________________ 53 3.8.1. Reagents and materials ................................................................................................... 53 3.8.2. Protein isolation for Western Blot .................................................................................. 56 3.9. Determination of protein concentration through the BCA-Assay __________ 57 3.9.1. SDS PAGE ..................................................................................................................... 58 3.9.2. Western Blot analysis. .................................................................................................... 62 3.9.3. Protein quantification by ELISA .................................................................................... 63 3.10. Immunohistochemistry ____________________________________________ 64 3.10.2. Embedding and Cryosectioning ................................................................................. 64 3.10.3. Protocol immunohistochemistry ................................................................................ 65 3.10.4. Fluorescence microscopy ........................................................................................... 66 3.11. In vitro studies ____________________________________________________ 67 3.11.1. Reagents and materials for cell culture ...................................................................... 67 3.11.2. General cell culture procedures ................................................................................. 67 3.11.3. Isolation and culture of Müller cells .......................................................................... 68 3.11.4. Viability of 661 W cells after CORT treatment ......................................................... 69 3.11.5. CORT treatment of Müller and 661 W cells .............................................................. 71 3.12. Statistics _________________________________________________________ 71 4 RESULTS ................................................ 72 4.1. Ten hours CSC alters physiological parameters of stress in Balb/c mice ____ 72 4.1.1. Ten hours CSC causes body weight loss in Balb/c Mice ................................................ 72 4.1.2. Ten hours CSC causes a rise in CORT levels in Balb/c mice......................................... 73 4.1.3. Ten hours CSC causes mild increase of adrenal weight in Balb/c mice ......................... 73 4.2. Nineteen days CSC influences physiological parameters of stress in Balb/c mice 74 4.2.1. Nineteen days CSC affects body weight gain in Balb/c mice......................................... 75 4.2.2. CORT levels re-normalize following 19 days CSC in Balb/c mice ............................... 76 4.2.3. Nineteen days CSC causes adrenal hyperplasia in Balb/c mice ..................................... 76 4.3. Balb/c mice were genetically susceptible to light damage _________________ 78 TABLE OF CONTENT xi 4.4. Effects of short-term psychosocial stress on induced retina neurodegeneration 79 4.4.1. Prior short-term psychosocial stress decreased apoptosis in the retina........................... 79 4.4.2. Short-term psychosocial stress decreases free histone release following light damage.. 80 4.5. Effects of chronic psychosocial stress on induced retinal degeneration _____
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