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Gene Expression Profiling of the Habenula in Rats Exposed to Chronic Restraint Stress

  • Yoo, Hyeijung (Department of Anatomy, College of Medicine, Korea University) ;
  • Kim, Hyun Jung (Department of Anatomy, College of Medicine, Korea University) ;
  • Yang, Soo Hyun (Department of Anatomy, College of Medicine, Korea University) ;
  • Son, Gi Hoon (Department of Legal Medicine, College of Medicine, Korea University) ;
  • Gim, Jeong-An (Medical Science Research Center, College of Medicine, Korea University) ;
  • Lee, Hyun Woo (Department of Anatomy, College of Medicine, Korea University) ;
  • Kim, Hyun (Department of Anatomy, College of Medicine, Korea University)
  • 투고 : 2021.10.21
  • 심사 : 2022.02.07
  • 발행 : 2022.05.31

초록

Chronic stress contributes to the risk of developing depression; the habenula, a nucleus in epithalamus, is associated with many neuropsychiatric disorders. Using genome-wide gene expression analysis, we analyzed the transcriptome of the habenula in rats exposed to chronic restraint stress for 14 days. We identified 379 differentially expressed genes (DEGs) that were affected by chronic stress. These genes were enriched in neuroactive ligand-receptor interaction, the cAMP (cyclic adenosine monophosphate) signaling pathway, circadian entrainment, and synaptic signaling from the Kyoto Encyclopedia of Genes and Genomes pathway analysis and responded to corticosteroids, positive regulation of lipid transport, anterograde trans-synaptic signaling, and chemical synapse transmission from the Gene Ontology analysis. Based on protein-protein interaction network analysis of the DEGs, we identified neuroactive ligand-receptor interactions, circadian entrainment, and cholinergic synapse-related subclusters. Additionally, cell type and habenular regional expression of DEGs, evaluated using a recently published single-cell RNA sequencing study (GSE137478), strongly suggest that DEGs related to neuroactive ligand-receptor interaction and trans-synaptic signaling are highly enriched in medial habenular neurons. Taken together, our findings provide a valuable set of molecular targets that may play important roles in mediating the habenular response to stress and the onset of chronic stress-induced depressive behaviors.

키워드

과제정보

This research was supported by the Ministry of Science and ICT through the National Research Foundation of Korea (NRF-2017M3C7A1079692 to H.K., NRF-2017R1D1A1B06032730 to H.W.L., and NRF-2019M3C7A1032764 to G.H.S.).

참고문헌

  1. Aizawa, H., Kobayashi, M., Tanaka, S., Fukai, T., and Okamoto, H. (2012). Molecular characterization of the subnuclei in rat habenula. J. Comp. Neurol. 520, 4051-4066. https://doi.org/10.1002/cne.23167
  2. American Psychiatric Association (2013). Desk Reference to the Diagnostic Criteria from DSM-5 (Washington, DC: American Psychiatric Publishing).
  3. Andrus, B.M., Blizinsky, K., Vedell, P.T., Dennis, K., Shukla, P.K., Schaffer, D.J., Radulovic, J., Churchill, G.A., and Redei, E.E. (2012). Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models. Mol. Psychiatry 17, 49-61. https://doi.org/10.1038/mp.2010.119
  4. Bader, G.D. and Hogue, C.W. (2003). An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4, 2. https://doi.org/10.1186/1471-2105-4-2
  5. Bano-Otalora, B. and Piggins, H.D. (2017). Contributions of the lateral habenula to circadian timekeeping. Pharmacol. Biochem. Behav. 162, 46-54. https://doi.org/10.1016/j.pbb.2017.06.007
  6. Buynitsky, T. and Mostofsky, D.I. (2009). Restraint stress in biobehavioral research: recent developments. Neurosci. Biobehav. Rev. 33, 1089-1098. https://doi.org/10.1016/j.neubiorev.2009.05.004
  7. Cheon, M., Park, H., Rhim, H., and Chung, C. (2019). Actions of neuropeptide Y on synaptic transmission in the lateral habenula. Neuroscience 410, 183-190. https://doi.org/10.1016/j.neuroscience.2019.04.053
  8. Chiba, S., Numakawa, T., Ninomiya, M., Richards, M.C., Wakabayashi, C., and Kunugi, H. (2012). Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry 39, 112-119. https://doi.org/10.1016/j.pnpbp.2012.05.018
  9. Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., and Lin, C.Y. (2014). cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol. 8 Suppl 4, S11. https://doi.org/10.1186/1752-0509-8-S4-S11
  10. Christensen, T., Jensen, L., Bouzinova, E.V., and Wiborg, O. (2013). Molecular profiling of the lateral habenula in a rat model of depression. PLoS One 8, e80666. https://doi.org/10.1371/journal.pone.0080666
  11. Christiansen, S.L., Bouzinova, E.V., Fahrenkrug, J., and Wiborg, O. (2016). Altered expression pattern of clock genes in a rat model of depression. Int. J. Neuropsychopharmacol. 19, pyw061. https://doi.org/10.1093/ijnp/pyw061
  12. Cochran, D.M., Fallon, D., Hill, M., and Frazier, J.A. (2013). The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings. Harv. Rev. Psychiatry 21, 219-247. https://doi.org/10.1097/HRP.0b013e3182a75b7d
  13. Cui, Y., Yang, Y., Ni, Z., Dong, Y., Cai, G., Foncelle, A., Ma, S., Sang, K., Tang, S., Li, Y., et al. (2018). Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554, 323-327. https://doi.org/10.1038/nature25752
  14. Dableh, L.J., Yashpal, K., Rochford, J., and Henry, J.L. (2005). Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat. Eur. J. Pharmacol. 507, 99-105. https://doi.org/10.1016/j.ejphar.2004.11.024
  15. DePasquale, E.A.K., Schnell, D.J., Van Camp, P.J., Valiente-Alandi, I., Blaxall, B.C., Grimes, H.L., Singh, H., and Salomonis, N. (2019). DoubletDecon: deconvoluting doublets from single-cell RNA-sequencing data. Cell Rep. 29, 1718-1727.e8. https://doi.org/10.1016/j.celrep.2019.09.082
  16. Dulawa, S.C. and Janowsky, D.S. (2019). Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol. Psychiatry 24, 694-709. https://doi.org/10.1038/s41380-018-0219-x
  17. Fakhoury, M. (2017). The habenula in psychiatric disorders: more than three decades of translational investigation. Neurosci. Biobehav. Rev. 83, 721-735. https://doi.org/10.1016/j.neubiorev.2017.02.010
  18. Ge, F., Mu, P., Guo, R., Cai, L., Liu, Z., Dong, Y., and Huang, Y.H. (2021). Chronic sleep fragmentation enhances habenula cholinergic neural activity. Mol. Psychiatry 26, 941-954. https://doi.org/10.1038/s41380-019-0419-z
  19. Geracioti, T.D., Jr., Carpenter, L.L., Owens, M.J., Baker, D.G., Ekhator, N.N., Horn, P.S., Strawn, J.R., Sanacora, G., Kinkead, B., Price, L.H., et al. (2006). Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression. Am. J. Psychiatry 163, 637-643. https://doi.org/10.1176/appi.ajp.163.4.637
  20. Ghosal, S., Bang, E., Yue, W., Hare, B.D., Lepack, A.E., Girgenti, M.J., and Duman, R.S. (2018). Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol. Psychiatry 83, 29-37. https://doi.org/10.1016/j.biopsych.2017.06.017
  21. Gutierrez-Sacristan, A., Grosdidier, S., Valverde, O., Torrens, M., Bravo, A., Pinero, J., Sanz, F., and Furlong, L.I. (2015). PsyGeNET: a knowledge platform on psychiatric disorders and their genes. Bioinformatics 31, 3075-3077. https://doi.org/10.1093/bioinformatics/btv301
  22. Han, S., Yang, S.H., Kim, J.Y., Mo, S., Yang, E., Song, K.M., Ham, B.J., Mechawar, N., Turecki, G., Lee, H.W., et al. (2017). Down-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior. Sci. Rep. 7, 900. https://doi.org/10.1038/s41598-017-01088-6
  23. Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W.M., 3rd, Zheng, S., Butler, A., Lee, M.J., Wilk, A.J., Darby, C., Zager, M., et al. (2021). Integrated analysis of multimodal single-cell data. Cell 184, 3573-3587.e29. https://doi.org/10.1016/j.cell.2021.04.048
  24. Hashikawa, Y., Hashikawa, K., Rossi, M.A., Basiri, M.L., Liu, Y., Johnston, N.L., Ahmad, O.R., and Stuber, G.D. (2020). Transcriptional and spatial resolution of cell types in the mammalian habenula. Neuron 106, 743-758.e5. https://doi.org/10.1016/j.neuron.2020.03.011
  25. Hikosaka, O. (2010). The habenula: from stress evasion to value-based decision-making. Nat. Rev. Neurosci. 11, 503-513. https://doi.org/10.1038/nrn2866
  26. Hokfelt, T., Broberger, C., Xu, Z.Q., Sergeyev, V., Ubink, R., and Diez, M. (2000). Neuropeptides--an overview. Neuropharmacology 39, 1337-1356. https://doi.org/10.1016/S0028-3908(00)00010-1
  27. Hsu, Y.W., Morton, G., Guy, E.G., Wang, S.D., and Turner, E.E. (2016). Dorsal medial habenula regulation of mood-related behaviors and primary reinforcement by tachykinin-expressing habenula neurons. eNeuro 3, ENEURO.0109-16.2016.
  28. Hsu, Y.W., Wang, S.D., Wang, S., Morton, G., Zariwala, H.A., de la Iglesia, H.O., and Turner, E.E. (2014). Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement. J. Neurosci. 34, 11366-11384. https://doi.org/10.1523/JNEUROSCI.1861-14.2014
  29. Kim, S.M., Cho, S.Y., Kim, M.W., Roh, S.R., Shin, H.S., Suh, Y.H., Geum, D., and Lee, M.A. (2020). Genome-wide analysis identifies NURR1-controlled network of new synapse formation and cell cycle arrest in human neural stem cells. Mol. Cells 43, 551-571. https://doi.org/10.14348/molcells.2020.0071
  30. Kramer, M.S., Cutler, N., Feighner, J., Shrivastava, R., Carman, J., Sramek, J.J., Reines, S.A., Liu, G., Snavely, D., Wyatt-Knowles, E., et al. (1998). Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640-1645. https://doi.org/10.1126/science.281.5383.1640
  31. Lamont, E.W., Legault-Coutu, D., Cermakian, N., and Boivin, D.B. (2007). The role of circadian clock genes in mental disorders. Dialogues Clin. Neurosci. 9, 333-342. https://doi.org/10.31887/DCNS.2007.9.3/elamont
  32. Lee, H.W., Yang, S.H., Kim, J.Y., and Kim, H. (2019). The role of the medial habenula cholinergic system in addiction and emotion-associated behaviors. Front. Psychiatry 10, 100. https://doi.org/10.3389/fpsyt.2019.00100
  33. Lee, M.R., Sheskier, M.B., Farokhnia, M., Feng, N., Marenco, S., Lipska, B.K., and Leggio, L. (2018). Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: a human post-mortem study. Psychoneuroendocrinology 96, 143-147. https://doi.org/10.1016/j.psyneuen.2018.05.039
  34. Lee, S., Woo, J., Kim, Y.S., and Im, H.I. (2015). Integrated miRNA-mRNA analysis in the habenula nuclei of mice intravenously self-administering nicotine. Sci. Rep. 5, 12909. https://doi.org/10.1038/srep12909
  35. Li, J.Z., Bunney, B.G., Meng, F., Hagenauer, M.H., Walsh, D.M., Vawter, M.P., Evans, S.J., Choudary, P.V., Cartagena, P., Barchas, J.D., et al. (2013a). Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc. Natl. Acad. Sci. U. S. A. 110, 9950-9955. https://doi.org/10.1073/pnas.1305814110
  36. Li, K., Zhou, T., Liao, L., Yang, Z., Wong, C., Henn, F., Malinow, R., Yates, J.R., 3rd, and Hu, H. (2013b). βCaMKII in lateral habenula mediates core symptoms of depression. Science 341, 1016-1020. https://doi.org/10.1126/science.1240729
  37. Li, Y., Li, G., Li, J., Cai, X., Sun, Y., Zhang, B., and Zhao, H. (2021). Depression-like behavior is associated with lower Per2mRNA expression in the lateral habenula of rats. Genes Brain Behav. 20, e12702.
  38. Liao, W., Liu, Y., Huang, H., Xie, H., Gong, W., Liu, D., Tian, F., Huang, R., Yi, F., and Zhou, J. (2021). Intersectional analysis of chronic mild stress-induced lncRNA-mRNA interaction networks in rat hippocampus reveals potential anti-depression/anxiety drug targets. Neurobiol. Stress 15, 100347. https://doi.org/10.1016/j.ynstr.2021.100347
  39. Lin, L.C. and Sibille, E. (2013). Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? Front. Pharmacol. 4, 110. https://doi.org/10.3389/fphar.2013.00110
  40. McLaughlin, I., Dani, J.A., and De Biasi, M. (2017). The medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulation. J. Neurochem. 142 Suppl 2, 130-143. https://doi.org/10.1111/jnc.14008
  41. Meynen, G., Unmehopa, U.A., Hofman, M.A., Swaab, D.F., and Hoogendijk, W.J. (2007). Hypothalamic oxytocin mRNA expression and melancholic depression. Mol. Psychiatry 12, 118-119. https://doi.org/10.1038/sj.mp.4001911
  42. Morris, J.H., Kuchinsky, A., Ferrin, T.E., and Pico, A.R. (2014). enhancedGraphics: a Cytoscape app for enhanced node graphics. F1000Res. 3, 147. https://doi.org/10.12688/f1000research.4460.1
  43. Navarria, A., Wohleb, E.S., Voleti, B., Ota, K.T., Dutheil, S., Lepack, A.E., Dwyer, J.M., Fuchikami, M., Becker, A., Drago, F., et al. (2015). Rapid antidepressant actions of scopolamine: role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. Neurobiol. Dis. 82, 254-261. https://doi.org/10.1016/j.nbd.2015.06.012
  44. Nwokafor, C., Serova, L.I., Nahvi, R.J., McCloskey, J., and Sabban, E.L. (2020). Activation of NPY receptor subtype 1 by [D-His(26)]NPY is sufficient to prevent development of anxiety and depressive like effects in the single prolonged stress rodent model of PTSD. Neuropeptides 80, 102001. https://doi.org/10.1016/j.npep.2019.102001
  45. Ozsoy, S., Esel, E., and Kula, M. (2009). Serum oxytocin levels in patients with depression and the effects of gender and antidepressant treatment. Psychiatry Res. 169, 249-252. https://doi.org/10.1016/j.psychres.2008.06.034
  46. Purba, J.S., Hoogendijk, W.J., Hofman, M.A., and Swaab, D.F. (1996). Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiatry 53, 137-143. https://doi.org/10.1001/archpsyc.1996.01830020055007
  47. Quina, L.A., Wang, S., Ng, L., and Turner, E.E. (2009). Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. J. Neurosci. 29, 14309-14322. https://doi.org/10.1523/JNEUROSCI.2430-09.2009
  48. Raudvere, U., Kolberg, L., Kuzmin, I., Arak, T., Adler, P., Peterson, H., and Vilo, J. (2019). g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47(W1), W191-W198. https://doi.org/10.1093/nar/gkz369
  49. Redrobe, J.P., Dumont, Y., Fournier, A., and Quirion, R. (2002). The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 26, 615-624. https://doi.org/10.1016/S0893-133X(01)00403-1
  50. Saunders, A., Macosko, E.Z., Wysoker, A., Goldman, M., Krienen, F.M., de Rivera, H., Bien, E., Baum, M., Bortolin, L., Wang, S., et al. (2018). Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015-1030.e16. https://doi.org/10.1016/j.cell.2018.07.028
  51. Scantamburlo, G., Hansenne, M., Fuchs, S., Pitchot, W., Marechal, P., Pequeux, C., Ansseau, M., and Legros, J.J. (2007). Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrinology 32, 407-410. https://doi.org/10.1016/j.psyneuen.2007.01.009
  52. Seo, J.S., Zhong, P., Liu, A., Yan, Z., and Greengard, P. (2018). Elevation of p11 in lateral habenula mediates depression-like behavior. Mol. Psychiatry 23, 1113-1119. https://doi.org/10.1038/mp.2017.96
  53. Szklarczyk, D., Gable, A.L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N.T., Morris, J.H., Bork, P., et al. (2019). STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47(D1), D607-D613. https://doi.org/10.1093/nar/gky1131
  54. Wallace, M.L., Huang, K.W., Hochbaum, D., Hyun, M., Radeljic, G., and Sabatini, B.L. (2020). Anatomical and single-cell transcriptional profiling of the murine habenular complex. Elife 9, e51271. https://doi.org/10.7554/elife.51271
  55. Wishart, D.S., Knox, C., Guo, A.C., Shrivastava, S., Hassanali, M., Stothard, P., Chang, Z., and Woolsey, J. (2006). DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 34(Database issue), D668-D672. https://doi.org/10.1093/nar/gkj067
  56. Xu, P., Wang, K., Lu, C., Dong, L., Chen, Y., Wang, Q., Shi, Z., Yang, Y., Chen, S., and Liu, X. (2017). Effects of the chronic restraint stress induced depression on reward-related learning in rats. Behav. Brain Res. 321, 185-192. https://doi.org/10.1016/j.bbr.2016.12.045
  57. Yang, Y., Wang, H., Hu, J., and Hu, H. (2018). Lateral habenula in the pathophysiology of depression. Curr. Opin. Neurobiol. 48, 90-96. https://doi.org/10.1016/j.conb.2017.10.024
  58. Yi, J.H., Jeon, J., Kwon, H., Cho, E., Yun, J., Lee, Y.C., Ryu, J.H., Park, S.J., Cho, J.H., and Kim, D.H. (2020). Rubrofusarin attenuates chronic restraint stress-induced depressive symptoms. Int. J. Mol. Sci. 21, 3454. https://doi.org/10.3390/ijms21103454
  59. Yoo, H., Yang, S.H., Kim, J.Y., Yang, E., Park, H.S., Lee, S.J., Rhyu, I.J., Turecki, G., Lee, H.W., and Kim, H. (2021). Down-regulation of habenular calcium-dependent secretion activator 2 induces despair-like behavior. Sci. Rep. 11, 3700. https://doi.org/10.1038/s41598-021-83310-0
  60. Yu, G., Wang, L.G., Han, Y., and He, Q.Y. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284-287. https://doi.org/10.1089/omi.2011.0118
  61. Zeisel, A., Hochgerner, H., Lonnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., Haring, M., Braun, E., Borm, L.E., La Manno, G., et al. (2018). Molecular architecture of the mouse nervous system. Cell 174, 999-1014. e22. https://doi.org/10.1016/j.cell.2018.06.021
  62. Zelikowsky, M., Hui, M., Karigo, T., Choe, A., Yang, B., Blanco, M.R., Beadle, K., Gradinaru, V., Deverman, B.E., and Anderson, D.J. (2018). The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress. Cell 173, 1265-1279.e19. https://doi.org/10.1016/j.cell.2018.03.037