Advances in Molecular and Circuitry Mechanisms of Depressive Disorder—A Focus on Lateral Habenula

  • Hailan HuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1180)


Depression is a devastating disorder with a combination of diverse symptoms such as low self-esteem, lack of motivation, anhedonia, loss of appetite, low energy, and discomfort without a clear cause. Depression has been suggested to be the result of maladaptive changes in specific brain circuits. Recently, the lateral habenula (LHb) has emerged as a key brain region in the pathophysiology of depression. Increasing evidence from rodent, nonhuman primate, and human studies indicates that the aberrant activity of the LHb is associated with depressive symptoms such as helplessness, anhedonia, and excessive negative focus. Revealing the molecular, cellular, and circuit properties of the LHb will help explain how abnormalities in LHb activity are linked to depressive disorders and shed light on developing novel strategies for depression treatment.


Depression Lateral habenula LHb circuits Novel antidepressant treatments 



This chapter was modified from the paper reported by our group in “current opinion in neurobiology” journal (Yang, Y. et al. (2018) Lateral habenula in the pathophysiology of depression. Curr. Opin. Neurobiol. 48, 90–96). The related contents are reused with permission.

This work was supported by the Natural Science Foundation of China (#91432108, #31225010 and #81527901) and 111 projects to H.H.

Conflict of Interest Statement

Nothing declared.


  1. Aizawa H, Amo R, Okamoto H (2011) Phylogeny and ontogeny of the habenular structure. Front Neurosci 5:138PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aizawa H, Cui WP, Tanaka K, Okamoto H (2013) Hyperactivation of the habenula as a link between depression and sleep disturbance. Front Hum Neurosci 7Google Scholar
  3. Aizawa H, Kobayashi M, Tanaka S, Fukai T, Okamoto H (2012) Molecular characterization of the subnuclei in rat habenula. J Comp Neurol 520:4051–4066PubMedCrossRefGoogle Scholar
  4. Baker PM, Mizumori SJY (2017) Control of behavioral flexibility by the lateral habenula. Pharmacol Biochem Behav 162:62–68CrossRefGoogle Scholar
  5. Brown PL, Palacorolla H, Brady D, Riegger K, Elmer GI, Shepard PD (2017) Habenula-induced inhibition of midbrain dopamine neurons is diminished by lesions of the rostromedial tegmental nucleus. J Neurosci 37:217–225PubMedPubMedCentralCrossRefGoogle Scholar
  6. Caldecott-Hazard S, Mazziotta J, Phelps M (1988) Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci 8:1951–1961PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, Takayanagi R, Ozawa K, Tanaka K, Aizawa H (2014) glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci 34:16273–16285PubMedPubMedCentralCrossRefGoogle Scholar
  8. Gao DM, Jeaugey L, Pollak P, Benabid AL (1990) Intensity-dependent nociceptive responses from presumed dopaminergic-neurons of the substantia-nigra, pars compacta in the rat and their modification by lateral habenula inputs. Brain Res 529:315–319PubMedCrossRefGoogle Scholar
  9. Golden SA, Heshmati M, Flanigan M, Christoffel DJ, Guise K, Pfau ML, Aleyasin H, Menard C, Zhang H, Hodes GE et al (2016) Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534:688–692PubMedPubMedCentralCrossRefGoogle Scholar
  10. Haber SN, Groenewegen HJ, Grove EA, Nauta WJH (1985) Efferent connections of the ventral pallidum—evidence of a dual striato pallidofugal pathway. J Comp Neurol 235:322–335PubMedCrossRefPubMedCentralGoogle Scholar
  11. Herkenham M (1979) The afferent and efferent connections of the ventromedial thalamic nucleus in the rat. J Comp Neurol 183:487–517PubMedCrossRefPubMedCentralGoogle Scholar
  12. Herkenham M, Nauta WJ (1979) Efferent connections of the habenular nuclei in the rat. J Comp Neurol 187:19–47PubMedCrossRefPubMedCentralGoogle Scholar
  13. Hikosaka O (2010) The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 11:503–513PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hikosaka O, Sesack SR, Lecourtier L, Shepard PD (2008) Habenula: crossroad between the basal ganglia and the limbic system. J Neurosci 28:11825–11829PubMedPubMedCentralCrossRefGoogle Scholar
  15. Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O (2011) Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci 31:11457–11471PubMedPubMedCentralCrossRefGoogle Scholar
  16. Jhou TC, 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 513:566–596PubMedPubMedCentralCrossRefGoogle Scholar
  17. Kaufling J, Veinante P, Pawlowski SA, Freund-Mercier MJ, Barrot M (2009) Afferents to the GABAergic tail of the ventral tegmental area in the rat. J Comp Neurol 513:597–621PubMedCrossRefPubMedCentralGoogle Scholar
  18. Knowland D, Lilascharoen V, Pacia CP, Shin S, Wang EH, Lim BK (2017) Distinct ventral pallidal neural populations mediate separate symptoms of depression. Cell 170(284–297):e18Google Scholar
  19. Kowski AB, Geisler S, Krauss M, Veh RW (2008) Differential projections from subfields in the lateral preoptic area to the lateral habenular complex of the rat. J Comp Neurol 507:1465–1478PubMedCrossRefPubMedCentralGoogle Scholar
  20. Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212–217PubMedPubMedCentralCrossRefGoogle Scholar
  21. Lammel S, Steinberg EE, Foldy C, Wall NR, Beier K, Luo LQ, Malenka RC (2015) Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons. Neuron 85:429–438PubMedPubMedCentralCrossRefGoogle Scholar
  22. Lawson RP, Nord CL, Seymour B, Thomas DL, Dayan P, Pilling S, Roiser JP (2017) Disrupted habenula function in major depression. Mol Psychiatry 22:202–208PubMedCrossRefPubMedCentralGoogle Scholar
  23. Lawson RP, Seymour B, Loh E, Lutti A, Dolan RJ, Dayan P, Weiskopf N, Roiser JP (2014) The habenula encodes negative motivational value associated with primary punishment in humans. Proc Natl Acad Sci USA 111:11858–11863PubMedCrossRefPubMedCentralGoogle Scholar
  24. Lecca S, Pelosi A, Tchenio A, Moutkine I, Lujan R, Herve D, Mameli M (2016) Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med 22:254–261PubMedCrossRefPubMedCentralGoogle Scholar
  25. Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, Burdakov D, Georges F, Mameli M (2017) Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife 6Google Scholar
  26. Li JC, Li Y, Zhang BL, Shen XF, Zhao H (2016) Why depression and pain often coexist and mutually reinforce: role of the lateral habenula. Exp Neurol 284:106–113PubMedCrossRefPubMedCentralGoogle Scholar
  27. Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011) Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:535–539PubMedPubMedCentralCrossRefGoogle Scholar
  28. Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, Malinow R, Yates JR 3rd, Hu H (2013) betaCaMKII in lateral habenula mediates core symptoms of depression. Science 341:1016–1020PubMedPubMedCentralCrossRefGoogle Scholar
  29. Matsumoto M, Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447:1111PubMedCrossRefPubMedCentralGoogle Scholar
  30. Matsumoto M, Hikosaka O (2009) Representation of negative motivational value in the primate lateral habenula. Nat Neurosci 12:77–84PubMedCrossRefGoogle Scholar
  31. Matthews-Felton T, Corodimas KP, Rosenblatt JS, Morrell JI (1995) Lateral habenula neurons are necessary for the hormonal onset of maternal behavior and for the display of postpartum estrus in naturally parturient female rats. Behav Neurosci 109:1172–1188PubMedCrossRefGoogle Scholar
  32. Mendoza J (2017) Circadian neurons in the lateral habenula: clocking motivated behaviors. Pharmacol Biochem Behav 162:55–61CrossRefGoogle Scholar
  33. Meye FJ, Trusel M, Soiza-Reilly M, Mameli M (2017) Neural circuit adaptations during drug withdrawal—spotlight on the lateral habenula. Pharmacol Biochem Behav 162:87–93CrossRefGoogle Scholar
  34. Morris JS, Smith KA, Cowen PJ, Friston KJ, Dolan RJ (1999) Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion. Neuroimage 10:163–172PubMedCrossRefGoogle Scholar
  35. Omelchenko N, Bell R, Sesack SR (2009) Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci 30:1239–1250PubMedPubMedCentralCrossRefGoogle Scholar
  36. Ostergaard SD (2014) Mood disorders and antidepressants. Stahl’s essential psychopharmacology. Acta Psychiatr Scand 130:74–75CrossRefGoogle Scholar
  37. Park MR (1987) Monosynaptic inhibitory postsynaptic potentials from lateral habenula recorded in dorsal raphe neurons. Brain Res Bull 19:581–586PubMedCrossRefGoogle Scholar
  38. Park H, Rhee J, Park K, Han JS, Malinow R, Chung C (2017a) Exposure to stressors facilitates long-term synaptic potentiation in the lateral habenula. J Neurosci 37:6021–6030PubMedPubMedCentralCrossRefGoogle Scholar
  39. Park H, Rhee J, Lee S, Chung C (2017b) Selectively impaired endocannabinoid-dependent long-term depression in the lateral habenula in an animal model of depression. Cell Rep 20:289–296PubMedCrossRefPubMedCentralGoogle Scholar
  40. Proulx CD, Hikosaka O, Malinow R (2014) Reward processing by the lateral habenula in normal and depressive behaviors. Nat Neurosci 17:1146–1152PubMedPubMedCentralCrossRefGoogle Scholar
  41. Root DH, Mejias-Aponte CA, Zhang S, Wang HL, Hoffman AF, Lupica CR, Morales M (2014) Single rodent mesohabenular axons release glutamate and GABA. Nat Neurosci 17:1543–1551PubMedPubMedCentralCrossRefGoogle Scholar
  42. Sartorius A, Henn FA (2007) Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses 69:1305–1308PubMedCrossRefPubMedCentralGoogle Scholar
  43. 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–e11PubMedCrossRefPubMedCentralGoogle Scholar
  44. Sego C, Goncalves L, Lima L, Furigo IC, Donato J Jr, Metzger M (2014) Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat. J Comp Neurol 522:1454–1484PubMedCrossRefPubMedCentralGoogle Scholar
  45. Shabel SJ, Proulx CD, Trias A, Murphy RT, Malinow R (2012) Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron 74:475–481PubMedPubMedCentralCrossRefGoogle Scholar
  46. Shabel SJ, Proulx CD, Piriz J, Malinow R (2014) Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345:1494–1498PubMedPubMedCentralCrossRefGoogle Scholar
  47. Shumake J, Gonzalez-Lima F (2003) Brain systems underlying susceptibility to helplessness and depression. Behav Cogn Neurosci Rev 2:198–221PubMedCrossRefGoogle Scholar
  48. Shumake J, Gonzalez-Lima F (2013) Functional opposition between habenula metabolism and the brain reward system. Front Hum Neurosci 7:662PubMedPubMedCentralCrossRefGoogle Scholar
  49. Shumake J, Edwards E, Gonzalez-Lima F (2003) Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Res 963:274–281PubMedCrossRefGoogle Scholar
  50. Smith KS, Tindell AJ, Aldridge JW, Berridge KC (2009) Ventral pallidum roles in reward and motivation. Behav Brain Res 196:155–167PubMedCrossRefPubMedCentralGoogle Scholar
  51. Stamatakis AM, Stuber GD (2012) Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15:1105–1107PubMedPubMedCentralCrossRefGoogle Scholar
  52. Stamatakis AM, Jennings JH, Ung RL, Blair GA, Weinberg RJ, Neve RL, Boyce F, Mattis J, Ramakrishnan C, Deisseroth K et al (2013) A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Neuron 80:1039–1053PubMedCrossRefPubMedCentralGoogle Scholar
  53. Stamatakis AM, Van Swieten M, Basiri ML, Blair GA, Kantak P, Stuber GD (2016) Lateral hypothalamic area glutamatergic neurons and their projections to the lateral habenula regulate feeding and reward. J Neurosci 36:302–311PubMedPubMedCentralCrossRefGoogle Scholar
  54. Stephenson-Jones M, Yu K, Ahrens S, Tucciarone JM, van Huijstee AN, Mejia LA, Penzo MA, Tai LH, Wilbrecht L, Li B (2016) A basal ganglia circuit for evaluating action outcomes. Nature 539:289–293PubMedPubMedCentralCrossRefGoogle Scholar
  55. Stuber GD, Stamatakis AM, Kantak PA (2015) Considerations when using cre-driver rodent lines for studying ventral tegmental area circuitry. Neuron 85:439–445PubMedPubMedCentralCrossRefGoogle Scholar
  56. Taylor SR, Badurek S, Dileone RJ, Nashmi R, Minichiello L, Picciotto MR (2014) GABAergic and glutamatergic efferents of the mouse ventral tegmental area. J Comp Neurol 522:3308–3334PubMedPubMedCentralCrossRefGoogle Scholar
  57. Tian J, Uchida N (2015) Habenula lesions reveal that multiple mechanisms underlie dopamine prediction errors. Neuron 87:1304–1316PubMedPubMedCentralCrossRefGoogle Scholar
  58. Valentinova K, Mameli M (2016) mGluR-LTD at excitatory and inhibitory synapses in the lateral habenula tunes neuronal output. Cell Rep 16:2298–2307PubMedPubMedCentralCrossRefGoogle Scholar
  59. Varga V, Kocsis B, Sharp T (2003) Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus. Eur J Neurosci 17:280–286PubMedCrossRefPubMedCentralGoogle Scholar
  60. Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM, Frank LM, Deisseroth K (2012) A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492:428–432PubMedPubMedCentralCrossRefGoogle Scholar
  61. Wirtshafter D, Asin KE, Pitzer MR (1994) Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula. Brain Res 633:21–26PubMedCrossRefGoogle Scholar
  62. Yang LM, Hu B, Xia YH, Zhang BL, Zhao H (2008) Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res 188:84–90PubMedCrossRefGoogle Scholar
  63. Ye L, Allen WE, Thompson KR, Tian Q, Hsueh B, Ramakrishnan C, Wang AC, Jennings JH, Adhikari A, Halpern CH et al (2016) Wiring and molecular features of prefrontal ensembles representing distinct experiences. Cell 165:1776–1788PubMedPubMedCentralCrossRefGoogle Scholar
  64. Yetnikoff L, Cheng AY, Lavezzi HN, Parsley KP, Zahm DS (2015) Sources of input to the rostromedial tegmental nucleus, ventral tegmental area, and lateral habenula compared: a study in rat. J Comp Neurol 523:2426–2456PubMedPubMedCentralCrossRefGoogle Scholar
  65. Yoo JH, Zell V, Gutierrez-Reed N, Wu J, Ressler R, Shenasa MA, Johnson AB, Fife KH, Faget L, Hnasko TS (2016) Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement. Nat Commun 7:13697PubMedPubMedCentralCrossRefGoogle Scholar
  66. Zahm DS, Root DH (2017) Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol Biochem Behav 162:3–21CrossRefGoogle Scholar
  67. Zhang LM, Hernandez VS, Vazquez-Juarez E, Chay FK, Barrio RA (2016) Thirst is associated with suppression of habenula output and active stress coping: is there a role for a non-canonical vasopressin-glutamate pathway? Front Neural Circuits 10Google Scholar
  68. Zhou L, Liu MZ, Li Q, Deng J, Mu D, Sun YG (2017) Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Rep 18:3018–3032PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Center for Neuroscience and Department of Psychiatry of First Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
  2. 2.Interdisciplinary Institute of Neuroscience and Technology, Qiushi Academy for Advanced Studies, Zhejiang UniversityHangzhouChina
  3. 3.NHC and CAMS Key Laboratory of Medical NeurobiologyMental Health Center, Zhejiang UniversityHangzhouChina

Personalised recommendations