View source for Habenula

{{Short description|Small bilateral neuronal structure in the brain of vertebrates}}
{{Infobox brain
| Name            = Habenula
| Latin           =
| Image           = Epithalamus.png
| Caption         = Medial aspect of [[human brain]] showing location of the  habenula in front of the [[pineal gland|pineal gland or body]] in the [[epithalamus]] shown in red The [[habenular commissure]] is labelled shown connecting the habenula.
| Image2          = Brainstem and thalamus ja ja 135.png
| Caption2        = Habenula shown in blue just in front of the [[pineal gland]] shown in red
| IsPartOf        =
| Components      =
| Artery          =
| Vein            =
}}
The '''habenula'''  (diminutive of Latin {{Lang|la|habena}} meaning [[rein]]) is a small bilateral [[Nucleus (neuroanatomy)|neuronal structure]] in the [[brain]] of vertebrates, that has also been called a microstructure since it is no bigger than a pea. The naming as little rein describes its elongated shape in the [[epithalamus]], where it borders the [[third ventricle]], and lies in front of the [[pineal gland]].<ref name="Antolin-Fontes">{{cite journal |last1=Antolin-Fontes |first1=B |last2=Ables |first2=JL |last3=Görlich |first3=A |last4=Ibañez-Tallon |first4=I |title=The habenulo-interpeduncular pathway in nicotine aversion and withdrawal. |journal=Neuropharmacology |date=September 2015 |volume=96 |issue=Pt B |pages=213–22 |doi=10.1016/j.neuropharm.2014.11.019 |pmid=25476971|pmc=4452453 }}</ref>
Although it is a microstructure each habenular nucleus is divided into two distinct regions of nuclei, a medial habenula (MHb), and a lateral habenula (LHb) both having different neuronal populations, inputs, and outputs.<ref name="Antunes">{{cite journal |last1=Antunes |first1=GF |last2=Campos |first2=ACP |last3=Martins |first3=DO |last4=Gouveia |first4=FV |last5=Rangel Junior |first5=MJ |last6=Pagano |first6=RL |last7=Martinez |first7=RCR |title=Unravelling the Role of Habenula Subnuclei on Avoidance Response: Focus on Activation and Neuroinflammation. |journal=International Journal of Molecular Sciences |date=27 June 2023 |volume=24 |issue=13 |page=10693 |doi=10.3390/ijms241310693 |doi-access=free |pmid=37445871|pmc=10342060 }}</ref><ref name="Boulos">{{cite journal |last1=Boulos |first1=LJ |last2=Darcq |first2=E |last3=Kieffer |first3=BL |title=Translating the Habenula-From Rodents to Humans. |journal=Biological Psychiatry |date=15 February 2017 |volume=81 |issue=4 |pages=296–305 |doi=10.1016/j.biopsych.2016.06.003 |pmid=27527822|pmc=5143215 }}</ref> The medial habenula can be subdivided into five subnuclei, the lateral habenula into four subnuclei.<ref name="Ables2023" /> Research has shown morphological complexity in  the MHb and LHb. Different inputs to the MHb are discriminated between the different subnuclei.<ref name="Juárez-Leal">{{cite journal |last1=Juárez-Leal |first1=I |last2=Carretero-Rodríguez |first2=E |last3=Almagro-García |first3=F |last4=Martínez |first4=S |last5=Echevarría |first5=D |last6=Puelles |first6=E |title=Stria medullaris innervation follows the transcriptomic division of the habenula. |journal=Scientific Reports |date=16 June 2022 |volume=12 |issue=1 |pages=10118 |doi=10.1038/s41598-022-14328-1 |pmid=35710872|pmc=9203815 |bibcode=2022NatSR..1210118J }}</ref> In the two regions of nuclei there is a difference in [[gene expression]] giving different functions to each.<ref name="Viswanath">{{cite journal |last1=Viswanath |first1=H |last2=Carter |first2=AQ |last3=Baldwin |first3=PR |last4=Molfese |first4=DL |last5=Salas |first5=R |title=The medial habenula: still neglected. |journal=Frontiers in Human Neuroscience |date=2013 |volume=7 |pages=931 |doi=10.3389/fnhum.2013.00931 |doi-access=free |pmid=24478666|pmc=3894476 }}</ref>
The habenula is a conserved structure across vertebrates. In mammals it is highly symmetric, and in [[fish]], [[amphibian]]s and [[reptile]]s it is highly asymmetric in size, molecular composition, and connections.<ref name="Antolin-Fontes"/> The habenular nuclei are a major component in the [[limbic system]] pathways.<ref name="Antolin-Fontes" /> The [[fasciculus retroflexus]] pathway between the habenula and the [[interpeduncular nucleus]] is one of the first major [[nerve tract]]s to form in the developing brain.<ref name="Antolin-Fontes" />
The habenula is a central structure that connects forebrain regions to midbrain regions, and acts as a hub or node for the integration of emotional and sensory processing.<ref name="Antunes"/> It integrates information from the limbic system, sensory and [[basal ganglia]] to guide appropriate and effective responses.<ref name="Juárez-Leal" /> The habenula is involved in the regulation of monoamine neurotransmitters notably dopamine and serotonin.<ref name="Antunes" /><ref name="Boulos" />  Both of these neurotransmitters are strongly associated with anxiety disorders, and avoidance behaviours.<ref name="Antunes" /> The functions of the habenula are also involved in motivation, emotion, learning, and [[nociception|pain]].<ref name="Antunes"/> The MHb plays an important role in depression, stress, memory, and nicotine withdrawal, as well as a role in cocaine, methamphetamine and alcohol addiction.<ref name="Viswanath" /> The MHb shows a high level of [[nicotinic acetylcholine receptor]]s (nAChRs), that are involved in  many forms of [[addiction]]. Previously their expression was only noted in other structures associated with addiction. Their expression in the MHb  has become a later focus of research.<ref name="Viswanath" />
==Anatomy==
Each habenular nucleus has two divisions, a medial habenular nucleus (MHb), and a lateral habenular nucleus (LHb). Studies have shown that the medial habenula can be subdivided into five subnuclei, and the lateral habenula into four subnuclei.<ref name="Ables2023">{{cite journal |last1=Ables |first1=JL |last2=Park |first2=K |last3=Ibañez-Tallon |first3=I |title=Understanding the habenula: A major node in circuits regulating emotion and motivation. |journal=Pharmacological Research |date=April 2023 |volume=190 |pages=106734 |doi=10.1016/j.phrs.2023.106734 |pmid=36933754|doi-access=free |pmc=11081310 }}</ref> The right and left habenular nuclei are connected to each other by the [[habenular commissure]]. The [[pineal gland]] is attached to the brain in this region.<ref name="Guglielmotti Cristino 2006">{{cite journal |last1=Guglielmotti |first1=Vittorio |last2=Cristino |first2=Luigia |year=2006 |title=The interplay between the pineal complex and the habenular nuclei in lower vertebrates in the context of the evolution of cerebral asymmetry |journal=Brain Research Bulletin |volume=69 |issue=5 |pages=475–488 |doi=10.1016/j.brainresbull.2006.03.010 |pmid=16647576 |s2cid=24786037 |issn=0361-9230}}</ref> The medial habenula (MHb) receives connections from posterior [[septum pellucidum]] and [[diagonal band of Broca]]; the lateral habenula receives afferents from the lateral [[hypothalamus]], [[nucleus accumbens]], [[internal globus pallidus]], [[ventral pallidum]], and diagonal band of Broca.<ref name="Geisler" /> As a whole, this complexly interconnected region is part of the [[dorsal diencephalic conduction system]] (DDCS), responsible for relaying information from the limbic system to the [[midbrain]], [[hindbrain]], and [[Forebrain|medial forebrain]].<ref>{{cite journal |last1=Beretta |first1=Carlo Antonio |last2=Dross |first2=Nicolas |last3=Gutierrez-Triana |first3=Jose Arturo |last4=Ryu |first4=Soojin |last5=Carl |first5=Matthias |date=2012-01-01 |title=Habenula circuit development: past, present, and future |journal= Frontiers in Neuroscience|volume=6 |pages=51 |doi=10.3389/fnins.2012.00051 |pmc=3332237 |pmid=22536170|doi-access=free }}</ref><ref>{{cite journal |last1=Bianco |first1=Isaac H. |last2=Wilson |first2=Stephen W. |date=2009-04-12 |title=The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain |journal=Philosophical Transactions of the Royal Society of London B: Biological Sciences |language=en |volume=364 |issue=1519 |pages=1005–1020 |doi=10.1098/rstb.2008.0213 |issn=0962-8436 |pmc=2666075 |pmid=19064356}}</ref>
===Lateral habenula===
The primary input regions to the lateral habenula (LHb) are the lateral [[preoptic area]] (bringing input from the [[hippocampus]] and lateral septum), the ventral [[pallidum]] (bringing input from the [[nucleus accumbens]] and mediodorsal nucleus of the [[thalamus]]), the lateral [[hypothalamus]], the medial habenula, and the internal segment of the [[globus pallidus]] (bringing input from other [[basal ganglia]] structures).<ref name="Geisler">{{cite journal | vauthors = Geisler S, Trimble M | title = The lateral habenula: no longer neglected | journal = CNS Spectrums | volume = 13 | issue = 6 | pages = 484–9 | date = June 2008 | pmid = 18567972 | doi = 10.1017/S1092852900016710 | s2cid = 37331212 }}</ref>
Neurons in the lateral habenula are 'reward-negative' as they are activated by stimuli associated with unpleasant events, the absence of the reward or the presence of punishment especially when this is unpredictable.<ref>{{cite journal | vauthors = Matsumoto M, Hikosaka O | title = Representation of negative motivational value in the primate lateral habenula | journal = Nature Neuroscience | volume = 12 | issue = 1 | pages = 77–84 | date = January 2009 | pmid = 19043410 | pmc = 2737828 | doi = 10.1038/nn.2233 }}</ref> Reward information to the lateral habenula comes from the internal part of the globus pallidus.<ref>{{cite journal | vauthors = Hong S, Hikosaka O | title = The globus pallidus sends reward-related signals to the lateral habenula | journal = Neuron | volume = 60 | issue = 4 | pages = 720–9 | date = November 2008 | pmid = 19038227 | pmc = 2638585 | doi = 10.1016/j.neuron.2008.09.035 }}</ref>
The outputs of the lateral habenula target dopaminergic regions ([[substantia nigra]] [[pars compacta]] and the [[ventral tegmental area]]), serotonergic regions ([[Median raphe nucleus|median raphe]] and [[dorsal raphe nucleus|dorsal raphe nuclei]]), and a cholinergic region (the [[laterodorsal tegmental nucleus]]).<ref name="Geisler" /> This output inhibits dopamine neurons in substantia nigra pars compacta and the ventral tegmental area, with activation in the lateral habenula linking to deactivation in them, and vice versa, deactivation in the lateral habenula with their activation.<ref name = "Matsumoto_2007">{{cite journal | vauthors = Matsumoto M, Hikosaka O | title = Lateral habenula as a source of negative reward signals in dopamine neurons | journal = Nature | volume = 447 | issue = 7148 | pages = 1111–5 | date = June 2007 | pmid = 17522629 | doi = 10.1038/nature05860 | url = https://zenodo.org/record/1233303 | bibcode = 2007Natur.447.1111M | s2cid = 4418279 }}</ref> The lateral habenula functions to oppose the action of the laterodorsal tegmental nucleus in the acquisition of [[avoidance response]]s but not the processing of avoidance later on when it is a memory, motivation or its execution.<ref>{{cite journal | vauthors = Shumake J, Ilango A, Scheich H, Wetzel W, Ohl FW | title = Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area | journal = The Journal of Neuroscience | volume = 30 | issue = 17 | pages = 5876–83 | date = April 2010 | pmid = 20427648 | pmc = 6632612 | doi = 10.1523/JNEUROSCI.3604-09.2010 }}</ref> Research suggests that lateral habenula may play a crucial role in decision making.<ref name="pmid24270185">{{cite journal | vauthors = Stopper CM, Floresco SB | title = What's better for me? Fundamental role for lateral habenula in promoting subjective decision biases | journal = Nature Neuroscience | volume = 17 | issue = 1 | pages = 33–5 | date = January 2014 | pmid = 24270185 | pmc = 4974073 | doi = 10.1038/nn.3587}}
*{{cite press release |date=November 24, 2013 |title=Scientists find brain region that helps you make up your mind |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2013/11/131124200554.htm}}</ref>
There has also shown to be an association with aberrant LHb activity and depression.<ref name="Yang">{{cite journal |vauthors=Yang Y, Wang H, Hu J, Hu H |title=Lateral habenula in the pathophysiology of depression |journal=Curr Opin Neurobiol |volume=48 |issue= |pages=90–96 |date=February 2018 |pmid=29175713 |doi=10.1016/j.conb.2017.10.024 |url=|doi-access=free }}</ref>
===Medial habenula===
The medial habenula (MHb) receives connections from the posterior [[septum pellucidum]] and [[diagonal band of Broca]].<ref name="Geisler" /> Input to the medial habenula comes from a variety of regions and carries a number of different chemicals. Most neuronal projections to the MHb come from the [[septal area]].<ref name="Juárez-Leal" /> Input regions include [[septal nuclei]] (the nucleus fimbrialis septi and the nucleus triangularis septi); [[dopaminergic]] inputs from the interfascicular nucleus of the ventral tegmental area, noradrenergic inputs from the [[locus ceruleus]], and [[GABAergic]] inputs from the [[diagonal band of Broca]]. The medial habenula sends outputs of [[glutamate]], [[substance P]] and [[acetylcholine]] to the [[periaqueductal gray]] via the [[interpeduncular nucleus]] as well as to the pineal gland.<ref>{{cite journal | vauthors = Lecourtier L, Kelly PH | title = A conductor hidden in the orchestra? Role of the habenular complex in monoamine transmission and cognition | journal = Neuroscience and Biobehavioral Reviews | volume = 31 | issue = 5 | pages = 658–72 | date = January 2007 | pmid = 17379307 | doi = 10.1016/j.neubiorev.2007.01.004 | s2cid = 12856377 }}</ref><ref>{{cite journal | vauthors = Antolin-Fontes B, Ables JL, Görlich A, Ibañez-Tallon I | title = The habenulo-interpeduncular pathway in nicotine aversion and withdrawal | journal = Neuropharmacology | volume = 96 | issue = Pt B | pages = 213–22 | date = September 2015 | pmid = 25476971 | pmc = 4452453 | doi = 10.1016/j.neuropharm.2014.11.019 }}</ref>
===Asymmetry===
Asymmetry in the habenula was first noted in 1883 by Nikolaus Goronowitsch.<ref name="Guglielmotti Cristino 2006" /> Various species exhibit left-right asymmetric differentiation of habenular neurons. In many [[fish]]es and [[amphibian]]s, the habenula on one side is significantly larger and better organized into distinct nuclei in the dorsal diencephalon than its smaller pair. The sidedness of such differentiation (whether the left or the right is more developed) varies with the species. In [[bird]]s and [[mammal]]s, however, both habenulae are more symmetrical (although not entirely) and consist of a medial and a lateral nucleus on each side which is in fish and amphibians equivalent to dorsal habenula and the ventral habenula, respectively.<ref>{{cite journal | vauthors = Hüsken U, Stickney HL, Gestri G, Bianco IH, Faro A, Young RM, Roussigne M, Hawkins TA, Beretta CA, Brinkmann I, Paolini A, Jacinto R, Albadri S, Dreosti E, Tsalavouta M, Schwarz Q, Cavodeassi F, Barth AK, Wen L, Zhang B, Blader P, Yaksi E, Poggi L, Zigman M, Lin S, Wilson SW, Carl M | title = Tcf7l2 is required for left-right asymmetric differentiation of habenular neurons | journal = Current Biology | volume = 24 | issue = 19 | pages = 2217–27 | date = October 2014 | pmid = 25201686 | pmc = 4194317 | doi = 10.1016/j.cub.2014.08.006 | bibcode = 2014CBio...24.2217H }}</ref><ref name="Geisler" /><ref name=":1a">{{Cite journal|last1=Hu|first1=Hailan|last2=Cui|first2=Yihui|last3=Yang|first3=Yan|date=April 2020|title=Circuits and functions of the lateral habenula in health and in disease|url=https://www.nature.com/articles/s41583-020-0292-4|journal=Nature Reviews Neuroscience|language=en|volume=21|issue=5|pages=277–295|doi=10.1038/s41583-020-0292-4|pmid=32269316|s2cid=215411587 |issn=1471-0048}}</ref>
===Olfactory coding===
In some [[fish]] ([[lamprey]]s and [[teleosts]]), [[mitral cell]] (principal olfactory neurons) axons project exclusively to the right hemisphere of the habenula in an asymmetric manner. It is reported that the dorsal habenula (DHb) are functionally asymmetric with predominantly odor responses in the right hemisphere. It was also shown that DHb neurons are spontaneously active even in the absence of olfactory stimulation. These spontaneously-active DHb neurons are organized into functional clusters which were proposed to govern olfactory responses.<ref>{{cite journal | vauthors = Jetti SK, Vendrell-Llopis N, Yaksi E | title = Spontaneous activity governs olfactory representations in spatially organized habenular microcircuits | journal = Current Biology | volume = 24 | issue = 4 | pages = 434–9 | date = February 2014 | pmid = 24508164 | doi = 10.1016/j.cub.2014.01.015 | doi-access = free | bibcode = 2014CBio...24..434J }}</ref>
==Functions==
These nuclei are hypothesized to be involved in regulation of monoamines, such as [[dopamine]] and [[serotonin]].<ref>{{cite journal |last1=Stephenson-Jones |first1=Marcus |last2=Floros |first2=Orestis |last3=Robertson |first3=Brita |last4=Grillner |first4=Sten |year=2011 |title=Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=109 |issue=3 |pages=E164–E173 |doi=10.1073/pnas.1119348109 |doi-access=free |pmc=3271889 |pmid=22203996}}</ref><ref name=":2">{{cite journal |last1=Boulos |first1=Laura-Joy |last2=Darcq |first2=Emmanuel |last3=Kieffer |first3=Brigitte Lina |title=Translating the Habenula—From Rodents to Humans |journal=Biological Psychiatry |volume=81 |issue=4 |pages=296–305 |doi=10.1016/j.biopsych.2016.06.003|pmid=27527822 |pmc=5143215 |date=2017-02-15 }}</ref>
The habenular nuclei are involved in pain processing, reproductive behavior, nutrition, [[Circadian rhythm|sleep-wake cycles]], stress responses, and learning. Recent demonstrations using [[fMRI]]<ref>{{cite journal | vauthors = Ullsperger M, von Cramon DY | title = Error monitoring using external feedback: specific roles of the habenular complex, the reward system, and the cingulate motor area revealed by functional magnetic resonance imaging | journal = The Journal of Neuroscience | volume = 23 | issue = 10 | pages = 4308–14 | date = May 2003 | pmid = 12764119 | pmc = 6741115 | doi = 10.1523/JNEUROSCI.23-10-04308.2003 }}</ref> and single unit electrophysiology<ref name = "Matsumoto_2007" /> have closely linked the function of the lateral habenula with reward processing, in particular with regard to encoding negative feedback or negative rewards. Matsumoto and Hikosaka suggested in 2007 that this reward and reward-negative information in the brain might "be elaborated through the interplay among the lateral habenula, the basal ganglia, and monoaminergic (dopaminergic and serotonergic) systems" and that the lateral habenula may play a pivotal role in this "integrative function".<ref name = "Matsumoto_2007" /> Then, Bromberg-Martin et al. (2011) highlighted that neurons in the lateral habenula signal positive and negative information-prediction errors in addition to positive and negative reward-prediction errors.<ref>{{cite journal | vauthors = Bromberg-Martin ES, Hikosaka O | title = Lateral habenula neurons signal errors in the prediction of reward information | journal = Nature Neuroscience | volume = 14 | issue = 9 | pages = 1209–16 | date = August 2011 | pmid = 21857659 | pmc = 3164948 | doi = 10.1038/nn.2902 }}</ref>
==Depression==
Both the medial and lateral habenula show reduced volume in those with [[Major depressive disorder|depression]]. Neuron cell numbers were also reduced on the right side.<ref name="Ranft"/> Such changes are not seen in those with [[schizophrenia]].<ref name="Ranft">{{cite journal | vauthors = Ranft K, Dobrowolny H, Krell D, Bielau H, Bogerts B, Bernstein HG | title = Evidence for structural abnormalities of the human habenular complex in affective disorders but not in schizophrenia | journal = Psychological Medicine | volume = 40 | issue = 4 | pages = 557–67 | date = April 2010 | pmid = 19671211 | doi = 10.1017/S0033291709990821 | s2cid = 11799795 }}</ref> [[Deep brain stimulation]] of the major afferent bundle (i.e., stria medullaris thalami) of the lateral habenula has been used for treatment of depression where it is severe, protracted and therapy-resistant.<ref>{{cite journal | vauthors = Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, Henn FA, Meyer-Lindenberg A | title = Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient | journal = Biological Psychiatry | volume = 67 | issue = 2 | pages = e9–e11 | date = January 2010 | pmid = 19846068 | doi = 10.1016/j.biopsych.2009.08.027 | s2cid = 43590983 }}</ref><ref>{{cite journal | vauthors = Juckel G, Uhl I, Padberg F, Brüne M, Winter C | title = Psychosurgery and deep brain stimulation as ultima ratio treatment for refractory depression | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 259 | issue = 1 | pages = 1–7 | date = February 2009 | pmid = 19137233 | doi = 10.1007/s00406-008-0826-7 | s2cid = 27076192 }}</ref>
[[NMDA receptor|N-Methyl-D-aspartate (NMDA) receptor]]-dependent [[bursting|burst firing]] in the lateral habenula has been associated with depression in animal studies,<ref>{{cite journal | vauthors = Howe WM, Kenny PJ | title = Burst firing sets the stage for depression | journal = [[Nature (journal)|Nature]] | volume = 554 | issue = 7692 | pages = 304–305 | date = February 2018 | pmid = 29446408 | doi = 10.1038/d41586-018-01588-z | bibcode = 2018Natur.554..304H | doi-access = free }}</ref> and it has been shown that the general anesthetic [[ketamine]] blocks this firing by acting as a [[receptor antagonist]].<ref name="YangCui2018">{{cite journal | vauthors = Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H | title = Ketamine blocks bursting in the lateral habenula to rapidly relieve depression | journal = Nature | volume = 554 | issue = 7692 | pages = 317–322 | date = February 2018 | pmid = 29446381 | doi = 10.1038/nature25509 | bibcode = 2018Natur.554..317Y | s2cid = 3334820 }}</ref>  Ketamine has been the subject of numerous studies after having shown fast-acting antidepressant effects in humans (in a 0.5&nbsp;mg/bw kg dose).<ref>{{cite journal | vauthors = Serafini G, Howland RH, Rovedi F, Girardi P, Amore M | title = The role of ketamine in treatment-resistant depression: a systematic review | journal = Current Neuropharmacology | volume = 12 | issue = 5 | pages = 444–61 | date = September 2014 | pmid = 25426012 | pmc = 4243034 | doi = 10.2174/1570159X12666140619204251 | df = dmy-all }}</ref>
== Motivation and addiction ==
Recent exploration of the habenular nuclei has begun to associate the structure with an organism's current mood, feeling of motivation, and reward recognition.<ref name=":3">{{Cite journal|last1=Fakhoury|first1=Marc|last2=López|first2=Domínguez|title=The Role of Habenula in Motivation and Reward|journal=Advances in Neuroscience}}</ref> Previously, the LHb has been identified as an "anti-reward" signal, but recent research suggests that the LHb helps identify preference, helping the brain to discriminate between potential actions and subsequent motivation decisions.<ref name="Stopper">{{cite journal|last1=Stopper|first1=Colin M|last2=Floresco|first2=Stan B|title=What's better for me? Fundamental role for lateral habenula in promoting subjective decision biases|journal=Nature Neuroscience|date=24 November 2013|volume=17|issue=1|pages=33–35|doi=10.1038/nn.3587|pmid=24270185|pmc=4974073}}</ref> In a study using a [[Pavlovian conditioning]] model, results showed an increase in the habenula response.<ref name=":5">{{Cite journal|last1=Lawson|first1=Rebecca P.|last2=Seymour|first2=Ben|last3=Loh|first3=Eleanor|last4=Lutti|first4=Antoine|last5=Dolan|first5=Raymond J.|last6=Dayan|first6=Peter|last7=Weiskopf|first7=Nikolaus|last8=Roiser|first8=Jonathan P.|date=2014-08-12|title=The habenula encodes negative motivational value associated with primary punishment in humans|journal=Proceedings of the National Academy of Sciences|language=en|volume=111|issue=32|pages=11858–11863|doi=10.1073/pnas.1323586111|issn=0027-8424|pmc=4136587|pmid=25071182|bibcode=2014PNAS..11111858L|doi-access=free}}</ref> This increase coincided with conditioned stimuli associated with more aversive punishments (i.e. electric shock).<ref name=":5" /> Therefore, researchers speculate that inhibition or damage to the LHb resulting in a failure to process such information may lead to random motivation behavior.<ref name="Stopper" /><ref name=":5" />
LHb is especially important in understanding the reward and motivation relationship as it relates to addictive behaviors.<ref name=":3" /> The LHb inhibits [[dopaminergic]] neurons, decreasing the release of dopamine.<ref name=":4">{{Cite journal|last1=Hikosaka|first1=Okihide|last2=Sesack|first2=Susan R.|last3=Lecourtier|first3=Lucas|last4=Shepard|first4=Paul D.|date=2008-11-12|title=Habenula: Crossroad between the Basal Ganglia and the Limbic System|journal=Journal of Neuroscience|volume=28|issue=46|pages=11825–11829|doi=10.1523/jneurosci.3463-08.2008|pmid=19005047|pmc=2613689}}</ref> It was determined by several animal studies that receiving a reward coincided with elevated dopamine levels, but once the learned association was learned by the animal, dopamine levels remain elevated, only decreasing when the reward is removed.<ref name=":1a" /><ref name=":2" /><ref name=":3" /><ref name=":4" /> Therefore, dopamine levels only increase with unpredicted rewards and with a "positive prediction error".<ref name=":1a" /> Moreover, it was determined that removal of an anticipated award activated LHb, inhibited dopamine levels.<ref name=":1a" /> This finding helps explain why addictive drugs are associated with elevated dopamine levels.<ref name=":1a" />
=== Nicotine and nAChRs ===
According to the [[National Institute on Drug Abuse]], one in five [[preventable deaths]] in the United States is caused by [[Tobacco smoking|tobacco]] use.<ref name=":6">{{Cite news|url=https://www.drugabuse.gov/drugs-abuse/tobacco-nicotine|title=Tobacco/Nicotine|last=Abuse|first=National Institute on Drug|date=2014-12-16|language=en-US|access-date=2016-11-22}}</ref> [[Nicotine]] is the addictive drug found in most tobacco products and is easily absorbed by the bloodstream of the body.<ref name=":6" /> Despite common misconceptions regarding the relaxing effects of tobacco and nicotine use, behavioral testing in animals has demonstrated nicotine to have an anxiogenic effect.<ref>{{Cite journal|last1=Casarrubea|first1=Maurizio|last2=Davies|first2=Caitlin|last3=Faulisi|first3=Fabiana|last4=Pierucci|first4=Massimo|last5=Colangeli|first5=Roberto|last6=Partridge|first6=Lucy|last7=Chambers|first7=Stephanie|last8=Cassar|first8=Daniel|last9=Valentino|first9=Mario|date=2015-01-01|title=Acute nicotine induces anxiety and disrupts temporal pattern organization of rat exploratory behavior in hole-board: a potential role for the lateral habenula|journal=Frontiers in Cellular Neuroscience|pages=197|doi=10.3389/fncel.2015.00197|pmc=4450172|pmid=26082682|volume=9|doi-access=free}}</ref> [[Nicotinic acetylcholine receptor]]s (nAChRs) have been identified as the primary site for nicotine activity and regulate consequent cellular polarization.<ref name=":7">{{Cite journal|last1=Zuo|first1=Wanhong|last2=Xiao|first2=Cheng|last3=Gao|first3=Ming|last4=Hopf|first4=F. Woodward|last5=Krnjević|first5=Krešimir|last6=McIntosh|first6=J. Michael|last7=Fu|first7=Rao|last8=Wu|first8=Jie|last9=Bekker|first9=Alex|date=2016-09-06|title=Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms|journal=Scientific Reports|language=en|volume=6|doi=10.1038/srep32937|issn=2045-2322|pmc=5011770|pmid=27596561|page=32937|bibcode=2016NatSR...632937Z}}</ref> nAChRs are made up a number of α and β subunits and are found in both the LHb and MHb, where research suggests they may play a key role in addiction and withdrawal behaviors.<ref name=":7" /><ref>{{Cite journal|last1=Dao|first1=Dang Q.|last2=Perez|first2=Erika E.|last3=Teng|first3=Yanfen|last4=Dani|first4=John A.|last5=De Biasi|first5=Mariella|date=2014-03-19|title=Nicotine Enhances Excitability of Medial Habenular Neurons via Facilitation of Neurokinin Signaling|journal=Journal of Neuroscience|volume=34|issue=12|pages=4273–4284|doi=10.1523/jneurosci.2736-13.2014|pmid=24647947|pmc=3960468}}</ref>
==History==
The habenular is a well conserved structure that appeared in vertebrates more than 360 million years ago.<ref name="Ables2023" /> The habenular commissure was described for the first time in 1555 by [[Andreas Vesalius]]<ref name="Turliuc Turliuc Cucu Dumitrescu 2015 pp. 88–100">{{cite journal |last1=Turliuc |first1=Dana |last2=Turliuc |first2=Șerban |last3=Cucu |first3=Andrei |last4=Dumitrescu |first4=Gabriela |last5=Costea |first5=Claudia |date=2015-11-19 |title=An entire universe of the Roman world's architecture found in the human skull |journal=Journal of the History of the Neurosciences |volume=26 |issue=1 |pages=88–100 |doi=10.1080/0964704x.2015.1099382 |pmid=26584250 |s2cid=21254791 |issn=0964-704X}}</ref> and the habenula nuclei in 1872 by [[Theodor Meynert|Theodor Hermann Meynert]].<ref name="Turliuc Turliuc Cucu Dumitrescu 2016 pp. 127–133">{{cite journal |last1=Turliuc |first1=Dana |last2=Turliuc |first2=Şerban |last3=Cucu |first3=Andrei |last4=Dumitrescu |first4=Gabriela Florenţa |last5=Cărăuleanu |first5=Alexandru |last6=Buzdugă |first6=Cătălin |last7=Tamaş |first7=Camelia |last8=Sava |first8=Anca |last9=Costea |first9=Claudia Florida |year=2016 |title=A review of analogies between some neuroanatomical terms and roman household objects |journal=Annals of Anatomy - Anatomischer Anzeiger |volume=204 |pages=127–133 |doi=10.1016/j.aanat.2015.07.001 |pmid=26337365 |issn=0940-9602}}</ref>
== References ==
{{Reflist}}
== External links ==
* {{BrainMaps|Habenula}}
* [https://www.neuinfo.org/mynif/search.php?q=Habenula&t=data&s=cover&b=0&r=20 NIF Search - Habenula] {{Webarchive|url=https://web.archive.org/web/20160304060146/https://www.neuinfo.org/mynif/search.php?q=Habenula&t=data&s=cover&b=0&r=20 |date=2016-03-04 }} via the [[Neuroscience Information Framework]]
* [https://web.archive.org/web/20080504165606/http://isc.temple.edu/neuroanatomy/lab/atlas/pdhn/ Neuroanatomy lab sectional atlas]
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{{Diencephalon}}
{{Olfactory system}}
{{Authority control}}
[[Category:Habenula| ]]