DOCSLIB.ORG

Influence of Chrna5 on Habenulopeduncular Neurotransmission By

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Influence of Chrna5 on Habenulopeduncular Neurotransmission By Influence of Chrna5 on Habenulopeduncular Neurotransmission by Sanghavy Sivakumaran A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Physiology University of Toronto © Copyright by Sanghavy Sivakumaran 2020 ii Influence of Chrna5 on Habenulopeduncular Neurotransmission Sanghavy Sivakumaran Master of Science Department of Physiology University of Toronto 2020 Abstract The habenulopeduncular pathway is known to modulate aversion behaviours, which are tightly associated with Chrna5 gene expression. Chrna5 encodes the α5 nicotinic receptor subunit, which is highly expressed in the interpeduncular nucleus but remains pharmacologically intractable. Here we investigate the impact of this subunit using wild-type and Chrna5-deleted mice. We optogenetically activated the habenulopeduncular pathway; thought to co-release acetylcholine and glutamate, to probe the electrophysiological role of α5 in interpeduncular neurons in acute brain slice. Optogenetic stimulation of this pathway yielded heterogenous responses in wild-type and Chrna5 deleted mice. Unexpectedly, the absence of the Chrna5 gene led to stronger light evoked glutamatergic and GABAergic neurotransmission. These light evoked glutamatergic responses were acutely attenuated by nicotinic antagonists in Chrna5 deleted mice. Intriguingly, our optogenetic experiments did not evoke a distinct cholinergic current in either genotype. This work provides insight into the action of Chrna5 on habenulopeduncular circuitry and raises new mechanistic questions. iii Acknowledgments I would like to sincerely thank my supervisor Dr. Evelyn Lambe for her incredible support of me and my work in her lab. She continuously provided inquisitive insights and guidance for navigating my research project. Her encouragement, patience, support and advice have proven to be invaluable in helping me learn to approach difficult research questions. I am incredibly appreciative of the encouraging research environment and wonderful mentorship she provided. Evelyn consistently encouraged me to present my research at multiple conferences, allowed for TA opportunities and helped curate a very thorough and rewarding research and learning experience through my master’s program. I am incredibly grateful for my time in the Lambe lab and the valuable skills I have learned from Evelyn and her lab. I would also like to thank my supervisory committee members, Dr. Amy Ramsey and Dr. Junchul Kim, for their feedback, questions and support for my ever-evolving project. Both Dr. Ramsey and Dr. Kim have assessed my work thoroughly and consistently provided novel insights. Thank you to Dr. Steve Prescott, Dr. Bernard Le Foll, Dr. Richard Horner and Dr. Amy Ramsey for their feedback and insights as part of my thesis defense committee. Thank you to the former and current members of the Lambe lab, including: Dr. Daniel Sparks, Sridevi Venkatesan, Saige Power, Katheron Intson, Janice McNabb, Jennifer (Tianhui) Chen, Kevin (Yupeng) Liu and Steve (Ha-Seul) Jeoung for your advice, encouragement, feedback and insights. I am incredibly grateful to have such wonderful lab-mates and have greatly enjoyed working with you all! Finally, thank you to my family and loved ones for their encouragement and support throughout my research journey. iv Table of Contents Acknowledgments.......................................................................................................................... iii Table of Contents ........................................................................................................................... iv List of Tables ................................................................................................................................. vi List of Figures ............................................................................................................................... vii List of Appendices ....................................................................................................................... viii List of Abbreviations ..................................................................................................................... ix Chapter 1 ..........................................................................................................................................1 General Introduction ...................................................................................................................1 1.1 The interpeduncular nucleus ................................................................................................2 1.1.1 Functional role .........................................................................................................2 1.1.2 Anatomy and connectivity .......................................................................................3 1.1.3 Distribution of neurophysiological components ......................................................5 1.2 The habenula and fasciculus retroflexus ..............................................................................7 1.2.1 Functional role .........................................................................................................7 1.2.2 Anatomy and connectivity .......................................................................................8 1.2.3 Distribution of neurophysiological components ....................................................10 1.3 Nicotinic cholinergic receptors ..........................................................................................11 1.3.1 Nicotinic versus muscarinic cholinergic receptors ................................................11 1.3.2 Structure and conductance of nAChRs ..................................................................12 1.3.3 Mechanisms of nAChR characterization ...............................................................13 1.4 Mammalian implications of nAChR α5 .............................................................................15 1.4.1 Function and distribution of nAChR α5 in the human brain .................................15 1.4.2 Function and distribution of nAChR α5 in rodent models.....................................16 1.5 Modulation of habenulopeduncular signalling ..................................................................19 1.5.1 Habenula versus IPN regarding nAChR α5 modulated signalling ........................19 v 1.5.2 Habenulopeduncular co-release mechanisms ........................................................20 1.5.3 Habenulopeduncular physiological relevance .......................................................21 1.6 Thesis Objective.................................................................................................................22 Chapter 2 .......................................................................................................................................24 Methods for opto-physiological characterization of Chrna5 modulation of habenulopeduncular neurotransmission ....................................................................................24 Chapter 3 .......................................................................................................................................28 Results for characterization of habenulopeduncular neurotransmission modulated by Chrna5 ......................................................................................................................................28 Chapter 4 .......................................................................................................................................42 Discussion .................................................................................................................................42 4.1. Summary of findings..........................................................................................................47 4.2. Future Work .......................................................................................................................47 4.3. Conclusions ........................................................................................................................48 Bibliography ..................................................................................................................................50 Appendices .....................................................................................................................................60 Copyright Acknowledgements.......................................................................................................62 vi List of Tables Table 1: Electrophysiological properties of α5WT-ChAT and α5KO-ChAT cells………………30 vii List of Figures Figure 1.1: Summary IPN sub-nuclei and IPN afferent/efferent connections…………………......4 Figure 1.2: Summary of in situ hybridization of the genes encoding the nicotinic cholinergic receptor subunits in coronal rostral IPN sections of an adult mouse brain…………………………6 Figure 1.3: Summary of how the FR and habenular sub-nuclei innervates the IPN as well as the afferent/efferent connections mediating habenular signalling………………………………..……9 Figure 1.4: Summary of in situ hybridization of the genes encoding signalling associated proteins in the habenula of an adult mouse brain………………………………………………………..…11 Figure 1.5: Summary of Chrna5 in situ hybridization in coronal sections of an adult mouse brain………………………………………………………………………………………...……18 Figure 1: Optogenetic stimulation to characterize habenulopeduncular signalling………………29
Load more

Recommended publications
  • Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed Hipscs To
    Hindawi Publishing Corporation Stem Cells International Volume 2013, Article ID 784629, 25 pages http://dx.doi.org/10.1155/2013/784629 Research Article Microarray-Based Comparisons of Ion Channel Expression Patterns: Human Keratinocytes to Reprogrammed hiPSCs to Differentiated Neuronal and Cardiac Progeny Leonhard Linta,1 Marianne Stockmann,1 Qiong Lin,2 André Lechel,3 Christian Proepper,1 Tobias M. Boeckers,1 Alexander Kleger,3 and Stefan Liebau1 1 InstituteforAnatomyCellBiology,UlmUniversity,Albert-EinsteinAllee11,89081Ulm,Germany 2 Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen, Pauwelstrasse 30, 52074 Aachen, Germany 3 Department of Internal Medicine I, Ulm University, Albert-Einstein Allee 11, 89081 Ulm, Germany Correspondence should be addressed to Alexander Kleger; [email protected] and Stefan Liebau; [email protected] Received 31 January 2013; Accepted 6 March 2013 Academic Editor: Michael Levin Copyright © 2013 Leonhard Linta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ion channels are involved in a large variety of cellular processes including stem cell differentiation. Numerous families of ion channels are present in the organism which can be distinguished by means of, for example, ion selectivity, gating mechanism, composition, or cell biological function. To characterize the distinct expression of this group of ion channels we have compared the mRNA expression levels of ion channel genes between human keratinocyte-derived induced pluripotent stem cells (hiPSCs) and their somatic cell source, keratinocytes from plucked human hair. This comparison revealed that 26% of the analyzed probes showed an upregulation of ion channels in hiPSCs while just 6% were downregulated.
    [Show full text]
  • Identification of Key Genes and Pathways Involved in Response To
    Deng et al. Biol Res (2018) 51:25 https://doi.org/10.1186/s40659-018-0174-7 Biological Research RESEARCH ARTICLE Open Access Identifcation of key genes and pathways involved in response to pain in goat and sheep by transcriptome sequencing Xiuling Deng1,2†, Dong Wang3†, Shenyuan Wang1, Haisheng Wang2 and Huanmin Zhou1* Abstract Purpose: This aim of this study was to investigate the key genes and pathways involved in the response to pain in goat and sheep by transcriptome sequencing. Methods: Chronic pain was induced with the injection of the complete Freund’s adjuvant (CFA) in sheep and goats. The animals were divided into four groups: CFA-treated sheep, control sheep, CFA-treated goat, and control goat groups (n 3 in each group). The dorsal root ganglions of these animals were isolated and used for the construction of a cDNA= library and transcriptome sequencing. Diferentially expressed genes (DEGs) were identifed in CFA-induced sheep and goats and gene ontology (GO) enrichment analysis was performed. Results: In total, 1748 and 2441 DEGs were identifed in CFA-treated goat and sheep, respectively. The DEGs identi- fed in CFA-treated goats, such as C-C motif chemokine ligand 27 (CCL27), glutamate receptor 2 (GRIA2), and sodium voltage-gated channel alpha subunit 3 (SCN3A), were mainly enriched in GO functions associated with N-methyl- D-aspartate (NMDA) receptor, infammatory response, and immune response. The DEGs identifed in CFA-treated sheep, such as gamma-aminobutyric acid (GABA)-related DEGs (gamma-aminobutyric acid type A receptor gamma 3 subunit [GABRG3], GABRB2, and GABRB1), SCN9A, and transient receptor potential cation channel subfamily V member 1 (TRPV1), were mainly enriched in GO functions related to neuroactive ligand-receptor interaction, NMDA receptor, and defense response.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence
    G C A T T A C G G C A T genes Article Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence Lingjun Zuo 1, Rolando Garcia-Milian 2, Xiaoyun Guo 1,3,4,*, Chunlong Zhong 5,*, Yunlong Tan 6, Zhiren Wang 6, Jijun Wang 3, Xiaoping Wang 7, Longli Kang 8, Lu Lu 9,10, Xiangning Chen 11,12, Chiang-Shan R. Li 1 and Xingguang Luo 1,6,* 1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] (L.Z.); [email protected] (C.-S.R.L.) 2 Curriculum & Research Support Department, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT 06510, USA; [email protected] 3 Shanghai Mental Health Center, Shanghai 200030, China; [email protected] 4 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA 5 Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 6 Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing 100096, China; [email protected] (Y.T.); [email protected] (Z.W.) 7 Department of Neurology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, Shanghai 200080, China; [email protected] 8 Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xianyang, Shanxi 712082, China; [email protected] 9 Provincial Key Laboratory for Inflammation and Molecular Drug Target, Medical
    [Show full text]
  • Alcohol, Smoking and Opioid Addiction Cielito C
    Reyes-Gibby et al. BMC Systems Biology (2015) 9:25 DOI 10.1186/s12918-015-0167-x METHODOLOGY ARTICLE Open Access Gene network analysis shows immune- signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction Cielito C. Reyes-Gibby1*, Christine Yuan1†, Jian Wang2†, Sai-Ching J. Yeung1 and Sanjay Shete2 Abstract Background: Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Results: Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Conlusions: Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction.
    [Show full text]
  • Role of Non-Coding Genetic Risk Variation in CHRNA5-CHRNA3-CHRNAB4 Cluster on Chromosome 15Q21
    Role of Non-Coding Genetic Risk Variation in CHRNA5-CHRNA3-CHRNAB4 Cluster on chromosome 15q21 in Addiction, Lung Cancer, Learning and Memory By Sonya Kostova Belimezova M.S. (M.D.) Sofia Medical University, Bulgaria A dissertation submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Integrative Physiology 2017 ii This thesis entitled: “Role of Non-Coding Genetic Risk Variation in CHRNA5-CHRNA3- CHRNAB4 Cluster on chromosome 15q21 in Addiction, Lung Cancer, Learning and Memory” Written by Sonya Kostova Belimezova has been approved for the Department of Integrative Physiology __________________________ (Dr. Marissa A. Ehringer, Ph.D.) ___________________________ (Dr. Jerry A. Stitzel, Ph.D.) ___________________________ (Dr. Robert Spencer, Ph.D.) ____________________________ (Dr. Michael C. Stallings, Ph.D.) ____________________________ (Dr. Christopher Lowry, Ph.D.) Date: _________ The final copy of this thesis has been examined by the signatories, and we find that both the content and form meet acceptable presentation standards of scholarly work in the above-mentioned discipline. IACUC protocol # 1510.02 iii Belimezova, Sonya Kostova (Ph.D., Integrative Physiology) Role of Non-Coding Genetic Risk Variation in CHRNA5-CHRNA3-CHRNAB4 Cluster on chromosome 15q21 in Addiction, Lung Cancer, Learning and Memory Thesis directed by Associate Professor Marissa A. Ehringer Modern large-scale genetic approaches like GWAS have allowed
    [Show full text]
  • Retrograde Inhibition by a Specific Subset of Interpeduncular Α5 Nicotinic Neurons Regulates Nicotine Preference
    Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference Jessica L. Ablesa,b,c, Andreas Görlicha,1, Beatriz Antolin-Fontesa,2,CuidongWanga, Sylvia M. Lipforda, Michael H. Riada, Jing Rend,e,3,FeiHud,e,4,MinminLuod,e,PaulJ.Kennyc, Nathaniel Heintza,f,5, and Ines Ibañez-Tallona,5 aLaboratory of Molecular Biology, The Rockefeller University, New York, NY 10065; bDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; cDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dNational Institute of Biological Sciences, Beijing 102206, China; eSchool of Life Sciences, Tsinghua University, Beijing 100084, China; and fHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Contributed by Nathaniel Heintz, October 23, 2017 (sent for review October 5, 2017; reviewed by Jean-Pierre Changeux and Lorna W. Role) Repeated exposure to drugs of abuse can produce adaptive changes nicotine withdrawal, and optical activation of IPN GABAergic cells that lead to the establishment of dependence. It has been shown that is sufficient to produce a withdrawal syndrome, while blockade of allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene GABAergic cells in the IPN reduced symptoms of withdrawal (17). CHRNA5 is associated with higher risk of tobacco dependence. In the Taken together these studies highlight the critical role of α5in brain, α5-containing nAChRs are expressed at very high levels in the regulating behavioral responses to nicotine. Here we characterize two subpopulations of GABAergic interpeduncular nucleus (IPN). Here we identified two nonoverlapping Amigo1 Epyc α + α Amigo1 α Epyc neurons in the IPN that express α5: α5- and α5- neu- 5 cell populations ( 5- and 5- ) in mouse IPN that respond α Amigo1 α Epyc differentially to nicotine.
    [Show full text]
  • Retrograde Inhibition by a Specific Subset of Interpeduncular Α5 Nicotinic Neurons Regulates Nicotine Preference
    Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference Jessica L. Ablesa,b,c, Andreas Görlicha,1, Beatriz Antolin-Fontesa,2,CuidongWanga, Sylvia M. Lipforda, Michael H. Riada, Jing Rend,e,3,FeiHud,e,4,MinminLuod,e,PaulJ.Kennyc, Nathaniel Heintza,f,5, and Ines Ibañez-Tallona,5 aLaboratory of Molecular Biology, The Rockefeller University, New York, NY 10065; bDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; cDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dNational Institute of Biological Sciences, Beijing 102206, China; eSchool of Life Sciences, Tsinghua University, Beijing 100084, China; and fHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Contributed by Nathaniel Heintz, October 23, 2017 (sent for review October 5, 2017; reviewed by Jean-Pierre Changeux and Lorna W. Role) Repeated exposure to drugs of abuse can produce adaptive changes nicotine withdrawal, and optical activation of IPN GABAergic cells that lead to the establishment of dependence. It has been shown that is sufficient to produce a withdrawal syndrome, while blockade of allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene GABAergic cells in the IPN reduced symptoms of withdrawal (17). CHRNA5 is associated with higher risk of tobacco dependence. In the Taken together these studies highlight the critical role of α5in brain, α5-containing nAChRs are expressed at very high levels in the regulating behavioral responses to nicotine. Here we characterize two subpopulations of GABAergic interpeduncular nucleus (IPN). Here we identified two nonoverlapping Amigo1 Epyc α + α Amigo1 α Epyc neurons in the IPN that express α5: α5- and α5- neu- 5 cell populations ( 5- and 5- ) in mouse IPN that respond α Amigo1 α Epyc differentially to nicotine.
    [Show full text]
  • Datasheet: VPA00527 Product Details
    Datasheet: VPA00527 Description: RABBIT ANTI CHRNA5 Specificity: CHRNA5 Format: Purified Product Type: PrecisionAb™ Polyclonal Isotype: Polyclonal IgG Quantity: 100 µl Product Details Applications This product has been reported to work in the following applications. This information is derived from testing within our laboratories, peer-reviewed publications or personal communications from the originators. Please refer to references indicated for further information. For general protocol recommendations, please visit www.bio-rad-antibodies.com/protocols. Yes No Not Determined Suggested Dilution Western Blotting 1/1000 PrecisionAb antibodies have been extensively validated for the western blot application. The antibody has been validated at the suggested dilution. Where this product has not been tested for use in a particular technique this does not necessarily exclude its use in such procedures. Further optimization may be required dependant on sample type. Target Species Human Species Cross Reacts with: Rat Reactivity N.B. Antibody reactivity and working conditions may vary between species. Product Form Purified IgG - liquid Preparation Rabbit polyclonal antibody prepared by affinity chromatography on Protein A Buffer Solution Phosphate buffered saline Preservative 0.09% Sodium Azide (NaN3) Stabilisers 2% Sucrose Immunogen Synthetic peptide directed towards the middle region of human CHRNA5 External Database Links UniProt: P30532 Related reagents Entrez Gene: 1138 CHRNA5 Related reagents Synonyms NACHRA5 Page 1 of 2 Specificity Rabbit anti Human CHRNA5 antibody recognizes CHRNA5 also known as neuronal acetylcholine receptor subunit alpha-5, Cholinergic receptor, neuronal nicotinic, alpha polypeptide-5, or neuronal nicotinic acetylcholine receptor, alpha5 subunit. The protein encoded by the CHRNA5 gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses.
    [Show full text]
  • Nicotinic Receptors Atlas in the Adult Human Lung
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.29.176750; this version posted August 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Nicotinic receptors atlas in the adult human lung 2 3 Zania Diabasana1, Jeanne-Marie Perotin1,2, Randa Belgacemi1, Julien Ancel1,2, Pauline 4 Mulette1,2, Gonzague Delepine3, Philippe Gosset4, Uwe Maskos5, Myriam Polette1,6, Gaëtan 5 Deslée1,2, Valérian Dormoy1 6 7 1University of Reims Champagne-Ardenne, Inserm, P3Cell UMR-S1250, SFR CAP-SANTE, 8 51092 Reims, France 9 2CHU of Reims, Hôpital Maison Blanche, Department of respiratory diseases, 51092 Reims, 10 France 11 3CHU of Reims, Hôpital Maison Blanche, Department of thoracic surgery, 51092 Reims, 12 France 13 4University of Lille, CNRS UMR9017, Inserm U1019, CHRU Lille, Pasteur Institute of Lille, 14 CIIL - Center for Infection and Immunity of Lille, 59000 Lille, France 15 5Pasteur Institute of Paris, Integrative Neurobiology of Cholinergic Systems, CNRS UMR 16 3571, Paris, France. 17 6CHU Reims, Hôpital Maison Blanche, Department of biopathology, 51092 Reims, France 18 19 Correspondence to: 20 Dr Valérian Dormoy 21 Inserm UMR-S 1250 22 University of Reims Champagne-Ardenne 23 CHU Maison Blanche 24 45 rue Cognacq-Jay 25 51092 Reims 26 Phone +33 (0)3 10 73 62 28; Fax +33 (0)3 26 06 58 61 27 e-mail: [email protected] 28 29 Short title: lung nicotinic receptors 30 31 32 33 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.29.176750; this version posted August 13, 2020.
    [Show full text]
  • Neural Circuits and Nicotinic Acetylcholine Receptors Mediate the Cholinergic Regulation of Midbrain Dopaminergic Neurons and Nicotine Dependence
    www.nature.com/aps REVIEW ARTICLE OPEN Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence Cheng Xiao1,2, Chun-yi Zhou1,2, Jin-hong Jiang1,2 and Cui Yin1,2 Midbrain dopaminergic (DA) neurons are governed by an endogenous cholinergic system, originated in the mesopontine nuclei. Nicotine hijacks nicotinic acetylcholine receptors (nAChRs) and interferes with physiological function of the cholinergic system. In this review, we describe the anatomical organization of the cholinergic system and the key nAChR subtypes mediating cholinergic regulation of DA transmission and nicotine reward and dependence, in an effort to identify potential targets for smoking intervention. Cholinergic modulation of midbrain DA systems relies on topographic organization of mesopontine cholinergic projections, and activation of nAChRs in midbrain DA neurons. Previous studies have revealed that α4, α6, and β2 subunit- containing nAChRs expressed in midbrain DA neurons and their terminals in the striatum regulate firings of midbrain DA neurons and activity-dependent dopamine release in the striatum. These nAChRs undergo modification upon chronic nicotine exposure. Clinical investigation has demonstrated that partial agonists of these receptors elevate the success rate of smoking cessation relative to placebo. However, further investigations are required to refine the drug targets to mitigate unpleasant side-effects. Keywords: midbrain DA neurons; mesopontine; cholinergic neurons; nicotinic acetylcholine receptors; neural circuits; nicotine reward and dependence; smoking intervention Acta Pharmacologica Sinica (2020) 41:1–9; https://doi.org/10.1038/s41401-019-0299-4 INTRODUCTION modified by chronic exposure to nicotine, and the subtypes of Cigarette smoking causes the most preventable diseases nAChRs implicated in nicotine dependence.
    [Show full text]
  • An Observational and Genome-Wide by Environment Interaction Study in UK Biobank
    Translational Psychiatry www.nature.com/tp ARTICLE OPEN Traumatic events during childhood and its risks to substance use in adulthood: an observational and genome-wide by environment interaction study in UK Biobank 1,2 1,2 1 1 1 1 1 1 1 Shiqiang Cheng , Yan Wen , Li Liu✉ , Bolun Cheng , Chujun Liang , Jing Ye , Xiaomeng Chu , Yao Yao , Yumeng Jia , Om Prakash Kafle1 and Feng Zhang 1 © The Author(s) 2021 We aimed to explore the underlying genetic mechanisms of traumatic events during childhood affecting the risks of adult substance use in present study. Using UK Biobank cohort, linear regression model was first applied to assess the relationships between cigarette smoking and alcohol drinking in adults with traumatic events during childhood, including felt hated by family member (41,648–111,465), felt loved (46,394–124,481) and sexually molested (47,598–127,766). Using traumatic events as exposure variables, genome-wide by environment interaction study was then performed by PLINK 2.0 to identify cigarette smoking and alcohol drinking associated genes interacting with traumatic events during childhood. We found that the frequency of cigarette smoking was significantly associated with felt hated by family member (coefficient = 0.42, P < 1.0 × 10–9), felt loved (coefficient = −0.31, P < 1.0 × 10–9) and sexually molested (coefficient = 0.46, P < 1.0 × 10–9). We also observed weaker associations of alcohol drinking with felt hated by family member (coefficient = 0.08, P = 3.10 × 10–6) and felt loved (coefficient = −0.06, P = 3.15 × 10–7). GWEIS identified multiple candidate loci interacting with traumatic events, such as CTNNA3 (rs189142060, P = 4.23 × 10–8) between felt hated by family member and the frequency of cigarette smoking, GABRG3 (rs117020886, P = 2.77 × 10–8) between felt hated by family member and the frequency of alcohol drinking.
    [Show full text]