Habenula

Abstract

The habenula is a diencephalic brain region that has attracted growing interest over the past decade because of its role in reward‐related behaviours and potential involvement in neuropsychiatric disorders in which reward processes are perturbed. The habenula exerts remarkable control over major dopaminergic and serotonergic neurotransmitter systems and has been implicated in a plethora of complex behavioural processes. It has been hypothesised that the habenula integrates information regarding rewarding and aversive stimuli and participates in the selection of behavioural strategies to maximise rewarding outcomes. Habenular activity is highly responsive to drugs of abuse and alterations in its activity may contribute to the negative emotional states during periods of drug abstinence that may precipitate the emergence of compulsive drug seeking behaviours. Thus, the habenula appears today as a hot topic in the neuroscience field in regard to its proper role such as to its potential implication in several pathologies like addiction.

Key Concepts

  • The habenula is a well‐conserved structure, divided in a medial and a lateral part, controlling the monoaminergic centres of the brain.
  • The medial and the lateral habenula, even if they belong to a same complex (the habenular complex or habenula), present important differences in term of connectivity and neurochemical markers.
  • The habenula location allows it to convey information from the telencephalon to the midbrain regions, regarding the rewarding properties such as the emotional aspect of a situation.
  • It is now well described that drug of abuse, such as nicotine and cocaine, induce important alterations of the medial and lateral habenula activity respectively.
  • Drug‐induced alteration of the habenular nuclei may lead to severe negative states and participate to withdrawal symptoms, such as depression.

Keywords: habenular complex; reward; aversion; substance use disorders; lateral habenula; medial habenula; reward‐related behaviors; monoamines; addiction

Figure 1. (a) The main inputs (green) of the habenular complex, passing through the stria medullairs (sm), are the medial part of prefrontal cortex (PFCm), the entopeduncular nucleus (EPN), septum (Sep), lateral hypothalamus (LH) and suprachiasmatic nucleus (SCN). This complex sends axons, via the fasciculus retroflexus (fr), to different midbrain areas (orange) such as the rostromedial tegmentum (RMTg), ventral tegmental area (VTA), substantia nigra (SN), the raphe and the interpeduncular nucleus (IPN). (b) The lateral (LHb) and medial (MHb) habenula subnuclei show a very different pattern of connections; almost all the MHb inputs arise in the septum [septofimbrial nucleus, medial septum and triangular septal nucleus (TSN)] and the nucleus of diagonal band (NDB), and MHb neurons project almost exclusively to the IPN via the fr. Inputs to the LHb arise in the PFCm, the EPN, LH and SCN but also in the lateral preoptic area (LPOA) and the ventral pallidum (VP). Then, the major LHb outputs, via the FR, are the monoaminergic centres of the midbrain such as the VTA, the SN and the raphe nuclei but also the GABAergic neurons of the RMTg. Reproduced with permission from https://www.sciencedirect.com/science/article/pii/S0149763418301209?via%3Dihub. © Elsevier.
close

References

Aizawa H, Amo R and Okamoto H (2011) Phylogeny and ontogeny of the habenular structure. Frontiers in Neuroscience 5: 138.

Aizawa H, Kobayashi M, Tanaka S, Fukai T and Okamoto H (2012) Molecular characterization of the subnuclei in rat habenula. The Journal of Comparative Neurology 520: 4051–4066.

Amo R, Aizawa H, Takahoko M, et al. (2010) Identification of the zebrafish ventral habenula as a homolog of the mammalian lateral habenula. The Journal of Neuroscience 30: 1566–1574.

Antolin‐Fontes B, Ables JL, Görlich A and Ibañez‐Tallon I (2015) The habenulo‐interpeduncular pathway in nicotine aversion and withdrawal. Neuropharmacology 96: 213–222.

Araki M, McGeer PL and McGeer EG (1984) Retrograde HRP tracing combined with a pharmacohistochemical method for GABA transaminase for the identification of presumptive GABAergic projections to the habenula. Brain Research 304: 271–277.

Baker PM, Oh SE, Kidder KS and Mizumori SJY (2015) Ongoing behavioral state information signaled in the lateral habenula guides choice flexibility in freely moving rats. Frontiers in Behavioral Neuroscience 9: 295.

Barker DJ, Miranda‐Barrientos J, Zhang S, et al. (2017) Lateral preoptic control of the lateral habenula through convergent glutamate and GABA transmission. Cell Reports 21: 1757–1769.

Brinschwitz K, Dittgen A, Madai VI, et al. (2010) Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168: 463–476.

Chastrette N, Pfaff DW and 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 Research 563: 339–344.

Christensen T, Jensen L, Bouzinova EV and Wiborg O (2013) Molecular profiling of the lateral habenula in a rat model of depression. PLoS ONE 8: e80666.

Concha ML and Wilson SW (2001) Asymmetry in the epithalamus of vertebrates. Journal of Anatomy 199: 63–84.

Craig AD (2003) Distribution of trigeminothalamic and spinothalamic lamina I terminations in the cat. Somatosensory & Motor Research 20: 209–222.

Darcq E, Befort K, Koebel P, et al. (2012) RSK2 signaling in medial habenula contributes to acute morphine analgesia. Neuropsychopharmacology, The Official Publication of the American College of Neuropsychopharmacology 37: 1288–1296.

Díaz E, Bravo D, Rojas X and Concha ML (2011) Morphologic and immunohistochemical organization of the human habenular complex. The Journal of Comparative Neurology 519: 3727–3747.

Fowler CD and Kenny PJ (2012) Habenular signaling in nicotine reinforcement. Neuropsychopharmacology, The Official Publication of the American College of Neuropsychopharmacology 37: 306–307.

Fowler CD, Lu Q, Johnson PM, Marks MJ and Kenny PJ (2011) Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471: 597–601.

Fowler CD, Tuesta L and Kenny PJ (2013) Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice. Psychopharmacology (Berl.).

Gardon O, Faget L, Chu Sin Chung P, et al. (2014) Expression of mu opioid receptor in dorsal diencephalic conduction system: new insights for the medial habenula. Neuroscience 277: 595–609.

Geisler S and Trimble M (2008) The lateral habenula: no longer neglected. CNS Spectrums 13: 484–489.

Golden SA, Heshmati M, Flanigan M, et al. (2016) Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534: 688–692.

Gottesfeld Z (1983) Origin and distribution of noradrenergic innervation in the habenula: a neurochemical study. Brain Research 275: 299–304.

Herkenham M and Nauta WJ (1977) Afferent connections of the habenular nuclei in the rat: a horseradish peroxidase study, with a note on the fiber‐of‐passage problem. The Journal of Comparative Neurology 173: 123–146.

Herkenham M and Nauta WJ (1979) Efferent connections of the habenular nuclei in the rat. The Journal of Comparative Neurology 187: 19–47.

Herzog E, Gilchrist J, Gras C, et al. (2004) Localization of VGLUT3, the vesicular glutamate transporter type 3, in the rat brain. Neuroscience 123: 983–1002.

Hikosaka O (2010) The habenula: from stress evasion to value‐based decision‐making. Nature Reviews Neuroscience 11: 503–513.

Howe WM and Kenny PJ (2018) Burst firing sets the stage for depression. Nature 554: 304–305.

Hsu Y‐WA, Wang SD, Wang S, et al. (2014) Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement. The Journal of Neuroscience 34: 11366–11384.

Jhou TC, Good CH, Rowley CS, et al. (2013) Cocaine drives aversive conditioning via delayed activation of dopamine‐responsive habenular and midbrain pathways. The Journal of Neuroscience 33: 7501–7512.

van Kerkhof LWM, Damsteegt R, Trezza V, Voorn P and Vanderschuren LJMJ (2013) Functional integrity of the habenula is necessary for social play behaviour in rats. European Journal of Neuroscience 38: 3465–3475.

Kim U and Chang S‐Y (2005) Dendritic morphology, local circuitry, and intrinsic electrophysiology of neurons in the rat medial and lateral habenular nuclei of the epithalamus. The Journal of Comparative Neurology 483: 236–250.

Kobayashi Y, Sano Y, Vannoni E, et al. (2013) Genetic dissection of medial habenula‐interpeduncular nucleus pathway function in mice. Frontiers in Behavioral Neuroscience 7: 17.

Li K, Zhou T, Liao L, et al. (2013) βCaMKII in lateral habenula mediates core symptoms of depression. Science 341: 1016–1020.

Margeta‐Mitrovic M, Mitrovic I, Riley RC, Jan LY and Basbaum AI (1999) Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. The Journal of Comparative Neurology 405: 299–321.

Mathis V and Lecourtier L (2017) Role of the lateral habenula in memory through online processing of information. Pharmacology Biochemistry and Behavior 162: 69–78.

Matsumoto M and Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447: 1111–1115.

Matsumoto M and Hikosaka O (2009) Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459: 837–841.

Mechling AE, Arefin T, Lee H‐L, et al. (2016) Deletion of the mu opioid receptor gene in mice reshapes the reward‐aversion connectome. Proceedings of the National Academy of Sciences of the United States of America 113: 11603–11608.

Meye FJ, Lecca S, Valentinova K and Mameli M (2013) Synaptic and cellular profile of neurons in the lateral habenula. Frontiers in Human Neuroscience 7.

Mizumori SJY and Baker PM (2017) The lateral habenula and adaptive behaviors. Trends in Neurosciences 40 (8): 481–493.

Molas S, Zhao‐Shea R, Liu L, et al. (2017a) A circuit‐based mechanism underlying familiarity signaling and the preference for novelty. Nature Neuroscience 20: 1260–1268.

Molas S, DeGroot SR, Zhao‐Shea R and Tapper AR (2017b) Anxiety and nicotine dependence: emerging role of the habenulo‐interpeduncular axis. Trends in Pharmacological Sciences 38: 169–180.

Okamoto H and Aizawa H (2013) Fear and anxiety regulation by conserved affective circuits. Neuron 78: 411–413.

Okamoto H, Agetsuma M and Aizawa H (2012) Genetic dissection of the zebrafish habenula, a possible switching board for selection of behavioral strategy to cope with fear and anxiety. Developmental Neurobiology 72: 386–394.

Petralia RS, Wang YX, Niedzielski AS and Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71: 949–976.

Qin C and Luo M (2009) Neurochemical phenotypes of the afferent and efferent projections of the mouse medial habenula. Neuroscience 161: 827–837.

Ren J, Qin C, Hu F, et al. (2011) Habenula ‘cholinergic’ neurons corelease glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes. Neuron 69: 445–452.

Rivera C, Voipio J, Payne JA, et al. (1999) The K+/Cl− co‐transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397: 251–255.

Rønnekleiv OK and Møller M (1979) Brain‐pineal nervous connections in the rat: an ultrastructure study following habenular lesion. Experimental Brain Research 37: 551–562.

Root DH, Mejias‐Aponte CA, Qi J and Morales M (2014) Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. The Journal of Neuroscience 34: 13906–13910.

Root DH, Hoffman AF, Good CH, et al. (2015) Norepinephrine activates dopamine D4 receptors in the rat lateral habenula. The Journal of Neuroscience 35: 3460–3469.

Salas R, Sturm R, Boulter J and De Biasi M (2009) Nicotinic receptors in the habenulo‐interpeduncular system are necessary for nicotine withdrawal in mice. The Journal of Neuroscience 29: 3014–3018.

Sartorius A and Henn FA (2007) Deep brain stimulation of the lateral habenula in treatment resistant major depression. Medical Hypotheses 69: 1305–1308.

Sartorius A, Kiening KL, Kirsch P, et al. (2010) Remission of major depression under deep brain stimulation of the lateral habenula in a therapy‐refractory patient. Biological Psychiatry 67: e9–e11.

Semba K and Fibiger HC (1992) Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro‐ and antero‐grade transport and immunohistochemical study. The Journal of Comparative Neurology 323: 387–410.

Shabel SJ, Proulx CD, Trias A, Murphy RT and Malinow R (2012) Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron 74: 475–481.

Shabel SJ, Proulx CD, Piriz J and Malinow R (2014) GABA/glutamate co‐release controls habenula output and is modified by antidepressant treatment. Science 345: 1494–1498.

Shepard PD, Holcomb HH and Gold JM (2005) Schizophrenia in translation: the presence of absence: habenular regulation of dopamine neurons and the encoding of negative outcomes. Schizophrenia Bulletin 32: 417–421.

Shih P‐Y, Engle SE, Oh G, et al. (2014) Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. The Journal of Neuroscience 34: 9789–9802.

Ślimak MA, Ables JL, Frahm S, et al. (2014) Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption. Frontiers in Human Neuroscience 8: 12.

Stephenson‐Jones M, Yu K, Ahrens S, et al. (2016) A basal ganglia circuit for evaluating action outcomes. Nature 539: 289–293.

Stopper CM and Floresco SB (2013) What's better for me? Fundamental role for lateral habenula in promoting subjective decision biases. Nat. Neurosci. 17: 33–35.

Su Z‐I, Santoostaroam A, Wenzel J and Ettenberg A (2013) On the persistence of cocaine‐induced place preferences and aversions in rats. Psychopharmacology (Berl.) 229: 115–123.

Sutherland RJ (1982) The dorsal diencephalic conduction system: a review of the anatomy and functions of the habenular complex. Neuroscience & Biobehavioral Reviews 6: 1–13.

Viswanath H, Carter AQ, Baldwin PR, Molfese DL and Salas R (2013) The medial habenula: still neglected. Frontiers in Human Neuroscience 7: 931.

Wagner F, Bernard R, Derst C, French L and Veh RW (2016) Microarray analysis of transcripts with elevated expressions in the rat medial or lateral habenula suggest fast GABAergic excitation in the medial habenula and habenular involvement in the regulation of feeding and energy balance. Brain Structure and Function 221 (9): 4663–4689.

Wang D‐G, Gong N, Luo B and Xu T‐L (2006) Absence of GABA type A signaling in adult medial habenular neurons. Neuroscience 141: 133–141.

Weiss T and Veh RW (2011) Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices. Neuroscience 172: 74–93.

Yamaguchi T, Danjo T, Pastan I, Hikida T and Nakanishi S (2013) Distinct roles of segregated transmission of the septo‐habenular pathway in anxiety and fear. Neuron 78: 537–544.

Yang Y, Cui Y, Sang K, et al. (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554: 317–322.

Zahm DS (2006) The evolving theory of basal forebrain functional—anatomical ‘macrosystems.’. Neuroscience & Biobehavioral Reviews 30: 148–172.

Zhang J, Tan L, Ren Y, et al. (2016a) Presynaptic excitation via GABAB receptors in habenula cholinergic neurons regulates fear memory expression. Cell 166: 716–728.

Zhang L, Hernández VS, Vázquez‐Juárez E, Chay FK and Barrio RA (2016b) Thirst is associated with suppression of habenula output and active stress coping: is there a role for a non‐canonical vasopressin‐glutamate pathway? Frontiers in Neural Circuits 10: 13.

Further Reading

Bianco IH and Wilson SW (2009) The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philosophical Transactions of the Royal Society B 364: 1005–1020.

Hörtnagl H, Tasan RO, Wieselthaler A, et al. (2013) Patterns of mRNA and protein expression for 12 GABAA receptor subunits in the mouse brain. Neuroscience 236: 345–372.

Pirker S, Schwarzer C, Wieselthaler A, Sieghart W and Sperk G (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101: 815–850.

Sperlágh B, Maglóczky Z, Vizi ES and Freund TF (1998) The triangular septal nucleus as the major source of ATP release in the rat habenula: a combined neurochemical and morphological study. Neuroscience 86: 1195–1207.

Villalón A, Sepúlveda M, Guerrero N, et al. (2012) Evolutionary plasticity of habenular asymmetry with a conserved efferent connectivity pattern. PLoS ONE 7: e35329.

Yañez J and Anadon R (1994) Afferent and efferent connections of the habenula in the larval sea lamprey (Petromyzon marinus L.): an experimental study. The Journal of Comparative Neurology 345: 148–160.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Mathis, Victor, and Kenny, Paul J(Oct 2018) Habenula. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028063]