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Optogentic Neuromodulation in Animal Models Of Optogenetic Neuromodulation in a Rodent Model of Depression Inaugural-Dissertation zur Erlangung der Doktorwürde der Fakultät für Biologie der Albert–Ludwigs–Universität Freiburg im Breisgau vorgelegt von Lisa-Marie Pfeiffer aus Kassel Freiburg im Breisgau September 2019 Angefertigt in der Abteilung für Stereotaktische und Funktionelle Neurochirur- gie des Universitätsklinikums Freiburg unter der Leitung von Prof. Dr. med. Volker A. Coenen und PD Dr. Máté D. Döbrössy. Dekan der Fakultät für Biologie: Prof. Dr. Wolfgang Driever Promotionsvorsitzender: Prof. Dr. Andreas Hiltbrunner Betreuer der Arbeit: Prof. Dr. med. Volker A. Coenen Betreuer der biologischen Fakultät: Prof. Dr. Wolfgang Driever Referent: Prof. Dr. Wolfgang Driever Koreferentin: Prof. Dr. Ilka Diester Drittprüferin: Prof. Dr. Carola Haas Datum der mündlichen Prüfung: 28.11.2019 To Mom and Dad. “Rabbit’s clever," said Pooh thoughtfully. "Yes," said Piglet, "Rabbit’s clever." "And he has Brain." "Yes," said Piglet, "Rabbit has Brain." There was a long silence. "I suppose," said Pooh, "that that’s why he never understands anything.” — A.A. Milne, Winnie-the-Pooh I Contents Contents List of TablesVI List of Figures VII ErklärungIX AbstractX Deutsche Zusammenfassung XII 1 Introduction1 1.1 Neuromodulation in psychiatric diseases . .1 1.2 Major Depression . .2 1.2.1 The Neurobiology of Depression . .3 1.2.1.1 (Epi-) Genetics and Environmental Factors . .4 1.2.1.2 Monoamine Deficiency Theory . .5 1.2.1.3 Stress Hypothesis . .6 1.2.1.4 Dysbalanced Neurotrophins and Neurogenesis . .7 1.2.1.5 Inflammation Theory . .8 1.2.1.6 Gut Microbiota Theory . .8 1.2.1.7 Dysregulation of the Reward Circuitry . .9 1.2.2 The Neuroanatomy of the Reward Circuitry . 12 1.2.3 Therapy for Major Depression . 14 1.2.3.1 Pharmacotherapy . 15 1.2.3.2 Psychotherapy . 17 1.2.3.3 Electroconvulsive Therapy . 17 1.2.3.4 Transcranial Magnetic Stimulation . 18 1.2.3.5 Vagus Nerve Stimulation . 18 1.2.3.6 Deep Brain Stimulation . 18 1.3 Animal models of Depression . 20 1.3.1 The Chronic Mild Unpredictable Stress Protocol . 20 1.3.2 Learned Helplessness . 21 1.3.3 Early Life Stress . 21 1.3.4 Olfactory Bulbectomy . 22 1.3.5 Genetically Modified Rodents . 22 1.3.6 Selectively Bred Animals - The Flinder’s Sensitive Line Rat . 24 II Contents 1.3.7 Testing Depressive-like Phenotype . 26 1.3.7.1 Forced Swim and Tail Suspension Test . 26 1.3.7.2 Open-space Swimming Test . 26 1.3.7.3 Sucrose Preference Test . 27 1.3.7.4 Others . 27 1.4 Optogenetics . 28 1.4.1 Microbial Opsins . 28 1.4.2 Opsin Targeting Strategies . 30 1.4.2.1 Targeting with Viruses . 30 1.4.2.2 Projection Targeting . 31 1.4.2.3 Transgenic Animal Targeting . 31 1.4.2.4 The Long Evans TH::Cre Rat and the Cre/loxP Re- combination System . 32 1.4.3 Light Delivery . 34 1.4.3.1 Light Requirements . 34 1.4.3.2 Light Sources . 35 1.4.3.3 Optical Properties of Brain Tissue . 36 1.4.4 Validation/Readouts . 37 1.4.5 Optogenetics and Major Depression . 38 2 Aims 41 3 Materials and Methods 42 3.1 Chemicals and Equipment . 42 3.1.1 Solutions for Immunohistochemistry . 42 3.1.2 Antibodies . 43 3.1.3 Substances Applied to the Animals . 43 3.1.4 Viruses for Optogenetics . 44 3.1.5 Kits used for Molecular Analysis . 44 3.1.6 Primer . 45 3.1.7 Mastermix for PCR........................ 45 3.2 Animals . 46 3.2.1 Breeding and Genotyping of Long EvansTH::Cre Rats . 46 3.3 Establishment of the Virus Injection . 48 3.3.1 Stereotactic Surgery - Virus Injection . 48 3.3.2 Immunohistochemistry . 50 3.3.2.1 Transcardial Perfusion . 51 III Contents 3.3.2.2 Immunofluorescent Stainings . 51 3.3.2.3 Microscopical Analysis - Epifluorescent Microscopy . 52 3.4 Behavioural Characterization of Long Evans vs. Sprague Dawley Rats 52 3.4.1 Sucrose Preference Test . 53 3.4.2 Ultrasonic Vocalization . 53 3.4.3 Double-H Maze . 53 3.4.4 Forced Swim Test . 55 3.4.5 Elevated Plus Maze . 56 3.4.6 Open Field Test . 56 3.5 Establishment of the Chronic Mild Unpredictable Stress Protocol . 57 3.5.1 Weight Measurements . 59 3.5.2 Corticosterone Measurements . 60 3.5.3 Sucrose Preference Test - New Protocol . 62 3.5.4 Social Interaction Test . 62 3.5.5 Object Recognition Test . 64 3.6 Optogenetic Stimulation of the Medial Forebrain Bundle in the Flinder’s Sensitive Line Rat Depression Model - 6-OHDA Lesioned vs. Unle- sioned Rats . 64 3.6.1 Stereotactic Surgery - 6-OHDA-Lesion . 65 3.6.2 Stereotactic Surgery - Virus Injection and Cannula Implantation 66 3.6.3 Laser Set Up and Light Parameters . 67 3.6.4 Behaviour Testing . 68 3.6.4.1 Activity measurements . 68 3.6.5 Immunohistochemistry . 68 3.6.6 Microscopical Analysis . 69 3.7 Dopamine-specific Optogenetic Stimulation of the Medial Forebrain Bundle in a Stress-induced Rat Depression Model . 70 3.7.1 Stereotactic Surgery - Virus Injection and Cannula Implantation 71 3.7.2 Chronic Mild Unpredictable Stress (CMUS) Protocol . 71 3.7.3 Behaviour Testing . 74 3.7.3.1 Open Space Swimming Test . 74 3.7.4 Immunohistochemistry and Microscopy . 75 3.8 Final Analysis and Statistics . 75 4 Results 76 4.1 Establishment of the Virus Injection . 76 IV Contents 4.2 Behavioural Characterization of Long Evans vs. Sprague Dawley Rats 78 4.2.1LE andSD Rats Differ in Weight But Not in Weight Growth Dynamics . 78 4.2.2SD Rats Show a Decreased Exploratory Behaviour Compared toLERats ............................ 80 4.2.3SD Rats Show Deficits in Spatial Learning Compared toLE Rats . 82 4.2.4 No Strain and Gender Differences are Detected in EPM and FST................................ 84 4.2.5 Sucrose Preference is Equally Pronounced in Both Strains . 86 4.2.6LE Males Emit Less Calls in the High Band Compared toSD Males . 87 4.3 Establishment of the CMUS Protocol . 88 4.3.1 CMUS Had no Significant Effect on the Weight of the Animals 89 4.3.2 Levels of FCM Increased Significantly in Both Groups After CMUS............................... 89 4.3.3 CMUS Did Not Have an Effect on the Rats Performance in EPM, SPT,OF, SIT, FST and USV.............. 90 4.3.4 Rats That Underwent CMUS Spent Significantly Less Time with Novel Objects . 93 4.4 Optogenetic Stimulation of the Medial Forebrain Bundle in the Flinder’s Sensitive Line Rat Depression Model - 6-OHDA Lesioned vs. Unle- sioned Rats . 94 4.4.1 Mean Transfection Rate of VTA DA neurons Was Low . 95 4.4.2 Amphetamine-induced Activity Was Decreased in Lesioned Rats 97 4.4.3 Optogenetic Stimulation Increased Homecage-Activity . 98 4.4.4 Testing of a Depressive-like Phenotype Did Not Show Signi- ficant Differences Between Groups . 99 4.4.5 Social Behaviour as Measured in the social interaction test (SIT) Did Not Differ Between Groups . 100 4.4.6 No Differences Were Seen in the Animals’ Exploratory Behaviour102 4.5 Dopamine-specific Optogenetic Stimulation of the Medial Forebrain Bundle in a Stress-induced Rat Depression Model . 102 4.5.1 The Applied Virus Injection Parameters Led to a Transfection Rate of over 50 % . 103 V Contents 4.5.2 The Weight Development in Stressed Animals Was Slightly Decreased . 105 4.5.3 Corticosterone Levels Decreased over the Length of the Ex- periment . 105 4.5.4 Optogenetic Stimulation Did not Lead to an Increase in Home- Cage-Activity . 106 4.5.5 Anxiety-Behaviour was Decreased in dopamine (DA)-Stim An- imals . 107 4.5.6 DA-Stim Rats Spent Less Time in the Center Zone of theOF Compared to CTRL Rats . 107 4.5.7 Social Behaviour is Increased in DA-Stim Rats . 108 4.5.8 Stimulation Rescued the Depressive-like Phenotype in the OSST109 4.5.9 Immobility, Sucrose Consumption and USVs Did Not Differ Between Groups . 110 5 Discussion 113 5.1 Establishment of optogenetics . 114 5.2 The Long Evans TH::Cre Rat . 117 5.3 The CMUS Protocol . 118 5.4 Optogenetic Stimulation of the MFB in the FSL Depression Model - 6-OHDA Lesioned vs. Unlesioned Rats . 120 5.4.1 The FSL rat . 120 5.4.2 Optogenetic Stimulation of the MFB in the FSL Depression Model - Discussion of Results . 121 5.5 DA-specific Optogenetic Stimulation of the MFB in the CMUS-induced Depression Model . 123 5.6 Conclusions . 129 5.6.1 Potential Mechanism of Action of the Optogenetic Stimulation of the MFB . 129 5.7 Outlook . 131 5.7.1 Application of Optogenetics in Humans . 132 Bibliography 134 Acknowledgements 171 List of Publications 173 VI List of Tables List of Tables 1.1 Diagnostic Criteria for Major Depression . .3 1.2 Selectively Bred Depression Models . 25 1.3 Viral Promoters in AAVs for Specific Optogenetic Targeting . 31 1.4 Optogenetic studies in Depression . 40 3.1 Solutions for Histology . 42 3.2 Primary Antibodies . 43 3.3 Secondary Antibodies . 43 3.4 Substances Applied to the Animals . 44 3.5 Viruses for Optogenetics . 44 3.6 Kits for Molecular Analysis.
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