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Evolution of Acetylcholine Receptors and Study of the Anatomy of the Mouse Brain Reward System

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Evolution of Acetylcholine Receptors and Study of the Anatomy of the Mouse Brain Reward System Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1472 Evolution of acetylcholine receptors and study of the anatomy of the mouse brain reward system JULIA E. PEDERSEN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0366-6 UPPSALA urn:nbn:se:uu:diva-353989 2018 Dissertation presented at Uppsala University to be publicly examined in Biomedicinskt centrum C4:301, Husargatan 3, Uppsala, Thursday, 6 September 2018 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: PhD Arnaud Chatonnet (Department of Animal Physiology and Livestock Systems, French National Institute for Agricultural Research, Montpeiller France). Abstract Pedersen, J. E. 2018. Evolution of acetylcholine receptors and study of the anatomy of the mouse brain reward system. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1472. 54 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0366-6. This thesis work is divided in two parts. In the first part, I make use of the transgenic TRPV1- Cre mouse line as a tool to investigate the midbrain ventral tegmental area (VTA). By using a ChR2-EYFP construct, detailed mapping of connectivity shows that TRPV1-Cre VTA neurons innervate many brain areas such as the prefrontal cortex (PFC), ventral pallidum, bed nucleus of stria terminalis and lateral habenula. Interestingly, a mainly excitatory subcircuit from the VTA to PFC in the TRPV1-Cre mouse was identified which suggests a fast modulatory mechanism of the PFC by a VTA subpopulation. These results are discussed in the light of behavioral and neurophysiological literature. In the second part, the evolution of the vertebrate acetylcholine (ACh) receptor gene families in relation to the whole genome duplications (WGDs), also called 1R and 2R, was investigated. The nicotinic ACh receptors (nAChRs) form a complex gene family, where the members have evolved with varying rates. Our analyses combined phylogeny, intron positions and chromosomal synteny in order to elucidate the nAChR evolution in relation to the vertebrate WGDs. We found that ten ancestral nAChR genes were present prior to the WGDs. 1R and 2R then expanded this set to 19 genes, of which 16 are present in mammals today. The teleost specific WGD, 3R, further expanded the repertoire into 31 genes, of which 27 genes are present in zebrafish. The muscarinic ACh receptors (mAChRs) on the other hand form a smaller receptor family. Using the same approach, our analyses show that there were two ancestral genes present prior to the WGDs, expanding to five genes following 1R and 2R. In zebrafish, all genes retained duplicates in 3R resulting in ten mAChR genes present today. Our analyses also showed that four mAChR teleost genes have gained introns, some up to six introns. The evolutionary analyses of the receptor gene families show that all vertebrate duplication events in the AChR families, except for two among the nAChR genes, occurred through 1R, 2R and 3R, displaying the substantial impact of the WGDs on the evolution of the AChR genes. Keywords: Ventral Tegmental Area, Mesocorticolimbic system, Glutamate, Optogenetics, Histology, Acetylcholine, Receptor, Muscarininc, Nicotinic, G protein-coupled receptor, Gene duplication, Tetraploidization, Synteny, Paralogon, Ohnolog, Zebrafish, Spotted gar Julia E. Pedersen, Department of Neuroscience, Pharmacology, Box 593, Uppsala University, SE-75124 Uppsala, Sweden. © Julia E. Pedersen 2018 ISSN 1651-6206 ISBN 978-91-513-0366-6 urn:nbn:se:uu:diva-353989 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-353989) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Pedersen, J.E. The connectivity of the TRPV1-Cre mouse line as a useful tool for exploring the function of a VTA subpopula- tion. Manuscript. II Pedersen J.E., Bergqvist C.A., Larhammar D. Evolution of ver- tebrate nicotinic acetylcholine receptors. Manuscript. III Pedersen J.E.*, Bergqvist C.A.*, Larhammar D. Evolution of the muscarinic acetylcholine receptors in vertebrates. Manu- script. * Authors contributed equally. Contents Introduction ..................................................................................................... 9 How to make a brain .................................................................................. 9 Part I: The brain reward system ............................................................... 10 Brain structure and function ................................................................ 10 The mesocorticolimbic system ............................................................ 12 Behaviors related to VTA circuit activity ............................................ 14 Novel VTA subcircuitries arising from the TRPV1-Cre VTA subpopulation ....................................................................................... 15 Part II: Evolution of receptor gene families in vertebrates ....................... 15 Vertebrate genome evolution ............................................................... 15 The nicotinic acetylcholine receptors .................................................. 20 The muscarinic acetylcholine receptors ............................................... 23 The evolution of the ACh receptor gene families ................................ 24 Aims .............................................................................................................. 26 Specific aims for each study ..................................................................... 26 Experimental procedures .............................................................................. 27 Part I ......................................................................................................... 27 Animals and ethical considerations ..................................................... 27 Optogenetics – virus injection and light stimulation ........................... 27 Immunohistochemical staining procedures ......................................... 27 Part II ........................................................................................................ 29 Amino acid sequence retrieval and multiple sequence alignment ....... 29 Phylogenetic analyses .......................................................................... 29 Conserved synteny and paralogon analysis of neighboring gene regions ................................................................................................. 29 Intron position analysis ........................................................................ 30 Results ........................................................................................................... 31 Paper I ...................................................................................................... 31 Paper II ..................................................................................................... 32 Paper III .................................................................................................... 34 Discussion ..................................................................................................... 36 The VTATRPV1-Cre population as a model for investigating VTA function (Paper I) ..................................................................................... 36 The evolution of the nAChR gene family and its expansion in the vertebrate WGDs (Paper II) ..................................................................... 37 All vertebrate mAChR genes originate from the vertebrate WGDs (Paper III) ................................................................................................. 39 The evolution of receptor gene families (Paper II and III) ....................... 40 Conclusions ................................................................................................... 41 Future perspectives ....................................................................................... 43 Acknowledgement ........................................................................................ 45 References ..................................................................................................... 46 Abbreviations ACh, acetylcholine mAChR, muscarinic acetylcholine re- AH, anterior hypothalamus ceptor Ahi, amygdalohippocampal area ML, maximum likelihood aLRT SH, approximate likelihood MnR, median raphe nucleus ratio test Shimodaira–Hasegawa Mya, million years ago AORe, ancestral ohnologs resolution NAc, nucleus accumbens BD, binding domain NAcC, nucleus accumbens core BNST, bed nucleus of stria terminalis nAChR, nicotinic acetylcholine re- CHRN, cholinergic receptor nicotinic ceptor CHRM, cholinergic receptor NAcSh, nucleus accumbens shell muscarinic NMJ, neuromuscular junction ChR2, channelrhodopsin-2 OMIM, online mendelian inheritance CLi, caudal linear nucleus of man Co, cortical amygdala PBP, parabrachial pigmented nuclei DAPI, 4',6-diamidino-2-phenylindole PFA, paraformaldehyde DAT, dopamine transporter PFC, prefrontal cortex DR, dorsal raphe PhyML, phylogenetic maximum like- ECD, extracellular domain lihood EL, extracellular loop PIF, parainterfascicular nucleus EYFP, enhanced yellow PO, preoptic area fluorescent protein PN, paranigral nuclei GAD, glutamic acid decarboxylase RLi, rostral linear nucleus GPCR, G protein-coupled receptor SN, substantia nigra HTR3, 5-hydroxytryptamine SUM, supramammillary nucleus receptor 3 TH,
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