Transcriptomic-anatomic analysis of the mouse habenula uncovers a high molecular heterogeneity among neurons in the lateral complex, while gene expression in the medial complex largely obeys subnuclear boundaries

详细信息    查看全文

• 作者：Franziska Wagner ; Leon French ; Rüdiger W. Veh
• 关键词：Lateral habenular complex (LHb) ; Medial habenular complex (MHb) ; Monaminergic systems ; Non ; reward system ; Neuron types ; Marker proteins ; Autism
• 刊名：Brain Structure and Function
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：221
• 期：1
• 页码：39-58
• 全文大小：5,397 KB
• 参考文献：Aizawa H, Kobayashi M, Tanaka SC, Fukai T, Okamoto H (2012) Molecular characterization of the subnuclei in rat habenula. J Comp Neurol 520:4051–4066CrossRef PubMed
  Allen Institute for Brain Science (2012) Technical white paper: In situ hybridization data production. Mouse Brain Atlas. http://​help.​brain.​map.​org/​download/​attachments/​2818169/​ABADataProductio​nProcessespdf?​version=​1&​modificationDate​=​1319477154403 . 2:1–22
  Allen Institute for Brain Science (2014) Mouse Brain Atlas. http://​mouse.​brain-map.​org
  Amo R, Aizawa H, Takahoko M, Kobayashi M, Takahashi R, Aoki T, Okamoto H (2010) Identification of the zebrafish ventral habenula as a homolog of the mammalian lateral habenula. J Neurosci 30:1566–1574CrossRef PubMed
  Andres KH, von Düring M, Veh RW (1999) Subnuclear organization of the rat habenular complexes. J Comp Neurol 407:130–150CrossRef PubMed
  Basu SN, Kollu R, Banerjee-Basu S (2009) AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37 (Database issue):D832-836. http://​autism.​mindspec.​org/​autdb (25.07.2014)
  Berthold M, Collin M, Sejlitz T, Meister B, Lind P (2003) Cloning of a novel orphan G protein-coupled receptor (GPCR-2037): in situ hybridization reveals high mRNA expression in rat brain restricted to neurons of the habenular complex. Mol Brain Res 120:22–29CrossRef PubMed
  Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77CrossRef PubMed
  Brinschwitz K, Dittgen A, Madai VI, Lommel R, Geisler S, Veh RW (2010) Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168:463–476CrossRef PubMed
  Broms JC, Tingström A (2013) Immunohistochemical characterization of GPR151, an orphan receptor specifically expressed in habenula neurons 3403 2013 Neuroscience Meeting Planner San Diego, CA, Society for Neuroscience (2013 Online)
  Chastrette N, Pfaff DW, Gibbs RB (1991) Effects of daytime and nighttime stress on Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, the habenula, and the posterior paraventricular nucleus of the thalamus. Brain Res 563:339–344CrossRef PubMed
  Christoph GR, Leonzio RJ, Wilcox KS (1986) Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmentum area of the rat. J Neurosci 6:613–619PubMed
  Cook EH, Leventhal BL (1996) The serotonin system in autism. Curr Opin Pediatr 8:348–354CrossRef PubMed
  De Biasi M, Dani JA (2011) Reward, Addiction, Withdrawal to Nicotine. Annu Rev Neurosci 34:105–130PubMedCentral CrossRef PubMed
  De Jong TR, Measor KT, Chauke M, Harris BN, Saltzman W (2010) Brief pup exposure induces Fos-expession in the lateral habenula and serotonergic caudal dorsal raphe nucleus of paternally experienced male california mice (peromyscus californicus). Neurosci 169:1094–1104CrossRef
  Eden E, Lipson D, Yogev S, Yakhini Z (2007) Discovering Motifs in Ranked Lists of DNA sequences. PLoS Comput Biol 3(3):e39PubMedCentral CrossRef PubMed
  Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z (2009) GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10:48PubMedCentral CrossRef PubMed
  Feng G, Mellor RH, Bernstein M, Keller-Peck C, Nguyen QT, Wallace M, Nerbonne JM, Lichtman JW, Sanes JR (2000) Imaging neuronal subsets neurotechnique in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51CrossRef PubMed
  Geisler S, Zahm DS (2005) Afferents of the ventral tegmental area in the rat—anatomical substratum for integrative functions. J Comp Neurol 490:270–294CrossRef PubMed
  Geisler S, Andres KH, Veh RW (2003) Morphologic and cytochemical criteria for the identification and delineation of individual subnuclei within the lateral habenular complex of the rat. J Comp Neurol 458:78–97CrossRef PubMed
  Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743PubMedCentral CrossRef PubMed
  Goncalves L, Sego C, Metzger M (2012) Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat. J Comp Neurol 520:1278–1300CrossRef PubMed
  Görlich A, Antolin-Fontes B, Ables JL, Frahm S, Slimak MA, Dougherty JD, Ibanez-Tallon I (2013) Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons. Proc Natl Acad Sci USA 110:17077–17082PubMedCentral CrossRef PubMed
  Herkenham M, Nauta WJH (1977) Afferent connections of the habenular nuclei in the rat. A horseradish peroxidase study, with a note on the fiber-of-passage problem. J Comp Neurol 173:123–146CrossRef PubMed
  Ignatov A, Hermans-Borgmeyer I, Schaller HC (2004) Cloning and characterization of a novel G-protein-coupled receptor with homology to galanin receptors. Neuropharmacol 46:1114–1120CrossRef
  Jhou T, Geisler S, Marinelli M, Degarmo BA, Zahm DS (2009) The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and Substantia Nigra Compacta. J Comp Neurol 513:566–596PubMedCentral CrossRef PubMed
  Ji H, Shepard PD (2007) Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA-A receptor-mediated mechanism. J Neurosci 27:6923–6930CrossRef PubMed
  Kasukawa Masumoto K-H, Nikaido I, Nagano M, Uno KD, Tsujino K, Hanashima C, Shigeyoshi Y, Ueda HR (2011) Quantitative expression profile of distinct functional regions in the adult mouse brain. Plos One. doi:10.​1371/​journal.​pone.​0023228 PubMedCentral PubMed
  Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier M-J, Barrot M (2010) Gamma-aminobutyric acid cells with cocaine-induced delte-FosB in the ventral tegmental area innervate mesolimbic neurons. Biol Psychiatry 67:88–92CrossRef PubMed
  Kobayashi Y, Sano Y, Vannoni E, Goto H, Suzuki H, Oba A, Kawasaki H, Kanba S, Lipp H-P, Murphy NP, Wolfer DP, Itohara S (2013) Genetic dissection of medial habenula –interpeduncular nucleus pathway function in mice. Front Behav Neursci 7:1–20
  Kowski AB, Veh RW, Weiss T (2009) Dopaminergic activation excites rat lateral habenular neurons in vivo. Neurosci 161:1154–1165CrossRef
  Lammel S, Ion DI, Roeper J, Malenka RC (2011) Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70:855–862PubMedCentral CrossRef PubMed
  Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176CrossRef PubMed
  Li B, Piriz J, Mirrione M, Chung C-H, Proulx CD, Schulz D, Henn F, Malinow R (2011) Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:535–539PubMedCentral CrossRef PubMed
  Li X, Zou H, Brown WT (2012) Transcripts associated with autism spectrum disorder. Brain Res Bull 88:543–552CrossRef PubMed
  Maroteaux M, Mameli M (2012) Cocaine evokes projection-specific synaptic plasticity of lateral habenula neurons. J Neurosci 32:12641–12646CrossRef PubMed
  Matsumoto M, Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447:1111–1115CrossRef PubMed
  Matsuo A, Matsumoto S-I, Nagano M, Masumoto K-H, Takasaki J, Matsumoto M, Kobori M, Katoh M, Shigeyoshi Y (2005) Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system. Biochem Biophys Res Commun 331:363–369CrossRef PubMed
  Ng L, Pathak S, Kuan L, Lau C, Dong HW, Sodt A, Dang C, Avants B, Yushkevich P, Gee J, Haynor D, Lein E, Jones A, Hawrylycz M (2007) Genomic scale neuroinformatics for 3-D gene expression mapping in the mouse brain. IEEE/ACM Trans Comp Biol Bioinform 4(3):382–393CrossRef
  Ng L, Bernard A, Lau C, Overly CC, Dong H-W, Kuan C, Pathak S, Sunkin SM, Dang C, Bohland JW, Bokil H, Mitra PP, Puelles L, Hohmann J, Anderson DJ, Lein ES, Jones AR, Hawrylycz M (2009) An anatomic gene expression atlas of the adult mouse brain. Nat Neurosci 12:356–362CrossRef PubMed
  Notomi T, Shigemoto R (2004) Immunohistochemical localization of I-h channel subunits, HCN1-4, in the rat brain. J Comp Neurol 471:241–276CrossRef PubMed
  Omelchenko N, Bell R, Sesack SR (2009) Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci 30:1239–1250PubMedCentral CrossRef PubMed
  Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego
  Poller WC, Bernard R, Derst C, Weiss T, Madai VI, Veh RW (2011) Lateral habenular neurons projecting to reward-processing nonoaminergic nuclei express hyperpolarization activated cyclic nucleotide-gated cation channels. Neurosci 193:205–216CrossRef
  Quina LA, Wang S, Ng L, Turner EE (2009) Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. J Neurosci 29:14309–14322PubMedCentral CrossRef PubMed
  Roeper J (2013) Dissecting the diversity of midbrain dopamine neurons. Trends Neurosci 36:336–342CrossRef PubMed
  Sandyk R (1992) Pineal and habenula calcification in schizophrenia. Int J Neurosci 67:19–30CrossRef PubMed
  Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, Henn FA, Meyer-Lindenberg A (2010) Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 67:e9–e11CrossRef PubMed
  Schain RJ, Freedman DX (1961) Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 58:315–320CrossRef PubMed
  Schultz W (1998) Predictive reward signal of dopamine neurons. J Neurophysiol 80:1–27PubMed
  Scott MM, Wylie CJ, Lerch JK, Murphy R, Lobur K, Herlitze S, Jiang W, Conlon RA, Strowbridge BW, Deneris ES (2005) A genetic approach to access serotonin neurons for in vivo and in vitro studies. Proc Natl Acad Sci USA 102:16472–16477PubMedCentral CrossRef PubMed
  Shepard PD, Holcomb HH, Gold JM (2006) The presence of absence: Habenular regulation of dopamine neurons and the encoding of negative outcomes. Schizophrenia Bull 32:417–421CrossRef
  Shinoda K, Tohyama M (1987) Analysis of the habenulopetal enkephalinergic system in the rat brain: an immunohistochemical study. J Comp Neurol 255:483–496CrossRef PubMed
  Sugino K, Hempel CM, Miller MN, Hattox AM, Shapiro P, Wu CZ, Huang ZJ, Nelson SB (2006) Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nat Neurosci 9:99–107CrossRef PubMed
  Sunkin SM, Ng L, Lau C, Dolbeare T, Gilbert TL, Thompson CL, Hawrylycz M, Dang C (2013) Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res 41:D996–D1008PubMedCentral CrossRef PubMed
  Sutton S, Lee G, Kuei C, Nepomuceno D, Liu C, Bonventure P, Lovenberg T (2013) GPR139 mRNA is expressed in the habenular system of the rat and mouse 3405, Neuroscience Meeting Planner San Diego, CA, Society for Neuroscience, (2013 Online)
  van Kerkhof LW, Damsteegt R, Trezza V, Voorn P, Vanderschuren LJMJ (2013) Functional integrity of the habenula is necessary for social play behaviour in rats. Eur J Neurosci 38:3465–3475CrossRef PubMed
  Visscher PM, Brown MA, McCarthy MI, Jang J (2012) Five years of GWAS discovery. Amer J Hum Genetics 90:7–24CrossRef
  Wagner F, Stroh T, Veh RW (2014) Correlating habenular subnuclei in rat and mouse by using topographic, morphological, and cytochemical criteria. J Comp Neurol 522:2650–2662CrossRef PubMed
  Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, and Parkinson H (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Research 42:D1001-D1006. http://​www.​genome.​gov/​page.​cfm?​pageid=​26525384#searchForm
  Wirtshafter D, Asin KE, Pitzer MR (1994) Dopamine Agonists and Stress Produce Different Patterns of Fos-Like Immunoreactivity in the Lateral Habenula. Brain Res 633:21–26CrossRef PubMed
  Wise R (2004) Dopamine, learning and motivation. Nature Rev 5:1–12CrossRef
  Xu LM, Li JR, Huang Y, Zhao M, Tang X and Wei L (2012) AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic Acids Res 40: D1016-1022. http://​autismkb.​cbi.​pku.​edu.​cn/​ (25.07.2014; syndromic, non-syndromic and core dataset)
  Zhang R, Oorschot DE (2006) Total number of neurons in the habenular nuclei of the rat epithalamus: a stereological study. J Anat 208:577–585PubMedCentral CrossRef PubMed
  
• 作者单位：Franziska Wagner (1)
  Leon French (2)
  Rüdiger W. Veh (1)
  
  1. Institut für Zell- und Neurobiologie, Centrum 2, Charité-Universitätsmedizin Berlin, Philippstrasse 12, D-10115, Berlin, Germany
  2. Rotman Research Institute, University of Toronto, 3560 Bathurst Street, Toronto, M6A 2E1, Canada
  
• 刊物主题：Neurosciences; Cell Biology; Neurology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1863-2661

文摘

The mammalian habenula with its medial and lateral complexes has gained much interest in recent years, while knowledge on the detailed biological functions of these nuclei is still scarce. Novel strategies to differentiate and identify habenular cell types are required. Such attempts have largely failed, most likely due to the lack of appropriate molecular markers. One important tool to approach this dilemma is available in form of the Allen Brain Atlas (ABA), which provides detailed expression patterns of many genes in the mouse brain. In the present report, ABA tools in combination with visual inspection of ISH images were used to detect transcripts, which are strongly expressed in medial (MHb) and lateral (LHb) habenular complexes. Against our expectations, most transcripts were differentially distributed throughout the LHb, disregarding boundaries of subnuclear areas. Nine distinct distribution patterns were recognized. Yet, several transcripts could not be attributed to one of these, suggesting a high diversity of neuron types in the LHb. In the MHb, in contrast, many transcripts tended to obey subnuclear boundaries. The differential distribution of others like Adcyap1, Chrna3, or Trp53i11 suggests the presence of a novel subfield adjacent to the region of the MHbVm, which now is termed intermediate field of the ventral MHb. In addition, the localizations of Amigo2, Adcyap1, and a couple of other transcripts suggest a lateral extension of the MHb, which is here, termed HbX area. Apparently, this area is composed of intermingled MHb and LHb neurons and may allow functional interaction between the both habenular complexes. Keywords Lateral habenular complex (LHb) Medial habenular complex (MHb) Monaminergic systems Non-reward system Neuron types Marker proteins Autism