Abstract: Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

压力动态过程中负性情绪在外侧缰核的"输入-输出"特异性整合

[1]AizawaH, KobayashiM, TanakaS, et al., 2012. Molecular characterization of the subnuclei in rat habenula. J Comp Neurol, 520(18):4051-4066.

[2]AlagapanS, ChoiKS, HeisigS, et al., 2023. Cingulate dynamics track depression recovery with deep brain stimulation. Nature, 622(7981):130-138.

[3]AmoR, FredesF, KinoshitaM, et al., 2014. The habenulo-raphe serotonergic circuit encodes an aversive expectation value essential for adaptive active avoidance of danger. Neuron, 84(5):1034-1048.

[4]AndalmanAS, BurnsVM, Lovett-BarronM, et al., 2019. Neuronal dynamics regulating brain and behavioral state transitions. Cell, 177(4):970-985.e20.

[5]BarkerDJ, Miranda-BarrientosJ, ZhangSL, et al., 2017. Lateral preoptic control of the lateral habenula through convergent glutamate and GABA transmission. Cell Rep, 21(7):1757-1769.

[6]BenekareddyM, StachniakTJ, BrunsA, et al., 2018. Identification of a corticohabenular circuit regulating socially directed behavior. Biol Psychiatry, 83(7):607-617.

[7]BernardR, VehRW, 2012. Individual neurons in the rat lateral habenular complex project mostly to the dopaminergic ventral tegmental area or to the serotonergic raphe nuclei. J Comp Neurol, 520(11):2545-2558.

[8]Caldecott-HazardS, MazziottaJ, PhelpsM, 1988. Cerebral correlates of depressed behavior in rats, visualized using 14C-2-deoxyglucose autoradiography. J Neurosci, 8(6):1951-1961.

[9]CalvigioniD, FuzikJ, le MerreP, et al., 2023. Esr1⁺ hypothalamic-habenula neurons shape aversive states. Nat Neurosci, 26(7):1245-1255.

[10]CerniauskasI, WintererJ, de JongJW, et al., 2019. Chronic stress induces activity, synaptic, and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors. Neuron, 104(5):899-915.e8.

[11]ChangSY, KimU, 2004. Ionic mechanism of long-lasting discharges of action potentials triggered by membrane hyperpolarization in the medial lateral habenula. J Neurosci, 24(9):2172-2181.

[12]CoffeyKR, MarxRE, VoEK, et al., 2020. Chemogenetic inhibition of lateral habenula projections to the dorsal raphe nucleus reduces passive coping and perseverative reward seeking in rats. Neuropsychopharmacology, 45(7):1115-1124.

[13]ColeEJ, StimpsonKH, BentzleyBS, et al., 2020. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry, 177(8):716-726.

[14]ColeEJ, PhillipsAL, BentzleyBS, et al., 2022. Stanford neuro

[15]modulation therapy (SNT): a double-blind randomized controlled trial. Am J Psychiatry, 179(2):132-141.

[16]CuiYH, YangY, NiZY, et al., 2018a. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature, 554(7692):323-327.

[17]CuiYH, YangY, DongYY, et al., 2018b. Decoding depression: insights from glial and ketamine regulation of neuronal burst firing in lateral habenula. Cold Spring Harb Symp Quant Biol, 83:141-150.

[18]CuiYH, HuSH, HuHL, 2019. Lateral habenular burst firing as a target of the rapid antidepressant effects of ketamine. Trends Neurosci, 42(3):179-191.

[19]FagetL, OsakadaF, DuanJY, et al., 2016. Afferent inputs to neurotransmitter-defined cell types in the ventral tegmental area. Cell Rep, 15(12):2796-2808.

[20]FagetL, ZellV, SouterE, et al., 2018. Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum. Nat Commun, 9:849.

[21]FoxMD, BucknerRL, WhiteMP, et al., 2012. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry, 72(7):595-603.

[22]GonçalvesL, SegoC, MetzgerM, 2012. Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat. J Comp Neurol, 520(6):1278-1300.

[23]HashikawaY, HashikawaK, RossiMA, et al., 2020. Transcriptional and spatial resolution of cell types in the mammalian habenula. Neuron, 106(5):743-758.e5.

[24]HerkenhamM, NautaWJH, 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(1):123-145.

[25]HerkenhamM, NautaWJH, 1979. Efferent connections of the habenular nuclei in the rat. J Comp Neurol, 187(1):19-47.

[26]HikosakaO, 2010. The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci, 11(7):503-513.

[27]HongS, HikosakaO, 2008. The globus pallidus sends reward-related signals to the lateral habenula. Neuron, 60(4):720-729.

[28]HongS, JhouTC, SmithM, et al., 2011. Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci, 31(32):11457-11471.

[29]HuHL, CuiYH, YangY, 2020. Circuits and functions of the lateral habenula in health and in disease. Nat Rev Neurosci, 21(5):277-295.

[30]HuangL, XiY, PengYF, et al., 2019. A visual circuit related to habenula underlies the antidepressive effects of light therapy. Neuron, 102(1):128-142.e8.

[31]IpCK, RezitisJ, QiY, et al., 2023. Critical role of lateral habenula circuits in the control of stress-induced palatable food consumption. Neuron, 111(16):2583-2600.e6.

[32]JhouTC, FieldsHL, BaxterMG, et al., 2009a. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron, 61(5):786-800.

[33]JhouTC, GeislerS, MarinelliM, et al., 2009b. 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(6):566-596.

[34]KnowlandD, LilascharoenV, PaciaCP, et al., 2017. Distinct ventral pallidal neural populations mediate separate symptoms of depression. Cell, 170(2):284-297.e18.

[35]LammelS, LimBK, RanC, et al., 2012. Input-specific control of reward and aversion in the ventral tegmental area. Nature, 491(7423):212-217.

[36]LammelS, SteinbergEE, FöldyC, et al., 2015. Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons. Neuron, 85(2):429-438.

[37]LazaridisI, TzortziO, WeglageM, et al., 2019. A hypothalamus-habenula circuit controls aversion. Mol Psychiatry, 24(9):1351-1368.

[38]LeccaS, PelosiA, TchenioA, et al., 2016. Rescue of GABA_B and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med, 22(3):254-261.

[39]LeccaS, MeyeFJ, TruselM, et al., 2017. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. eLife, 6:e30697.

[40]LeccaS, CongiuM, RoyonL, et al., 2023. A neural substrate for negative affect dictates female parental behavior. Neuron, 111(7):1094-1103.e8.

[41]LiB, PirizJ, MirrioneM, et al., 2011. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature, 470(7335):535-539.

[42]LiH, VentoPJ, Parrilla-CarreroJ, et al., 2019a. Three rostromedial tegmental afferents drive triply dissociable aspects of punishment learning and aversive valence encoding. Neuron, 104(5):987-999.e4.

[43]LiH, PullmannD, JhouTC, 2019b. Valence-encoding in the lateral habenula arises from the entopeduncular region. eLife, 8:e41223.

[44]LiH, PullmannD, ChoJY, et al., 2019c. Generality and opponency of rostromedial tegmental (RMTg) roles in valence processing. eLife, 8:e41542.

[45]LiK, ZhouT, LiaoLJ, et al., 2013. βCaMKII in lateral habenula mediates core symptoms of depression. Science, 341(6149):1016-1020.

[46]LinS, HuangL, LuoZC, et al., 2022. The ATP level in the medial prefrontal cortex regulates depressive-like behavior via the medial prefrontal cortex-lateral habenula pathway. Biol Psychiatry, 92(3):179-192.

[47]LiuH, RastogiA, NarainP, et al., 2021. Blunted diurnal firing in lateral habenula projections to dorsal raphe nucleus and delayed photoentrainment in stress-susceptible mice. PLoS Biol, 19(3):e3000709.

[48]MalezieuxM, KleinAS, GogollaN, 2023. Neural circuits for emotion. Annu Rev Neurosci, 46:211-231.

[49]MathisVP, WilliamsM, FillingerC, et al., 2021. Networks of habenula-projecting cortical neurons regulate cocaine seeking. Sci Adv, 7(45):eabj2225.

[50]MatsumotoM, HikosakaO, 2007. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature, 447(7148):1111-1115.

[51]MatsumotoM, HikosakaO, 2009. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci, 12(1):77-84.

[52]McEwenBS, 1998. Protective and damaging effects of stress mediators. N Engl J Med, 338(3):171-179.

[53]McEwenBS, BowlesNP, GrayJD, et al., 2015. Mechanisms of stress in the brain. Nat Neurosci, 18(10):1353-1363.

[54]MetzgerM, SouzaR, LimaLB, et al., 2021. Habenular connections with the dopaminergic and serotonergic system and their role in stress-related psychiatric disorders. Eur J Neurosci, 53(1):65-88.

[55]MeyeFJ, Soiza-ReillyM, SmitT, et al., 2016. Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse. Nat Neurosci, 19(8):1019-1024.

[56]MorrisJS, SmithKA, CowenPJ, et al., 1999. Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion. NeuroImage, 10(2):163-172.

[57]OmelchenkoN, BellR, SesackSR, 2009. Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. Eur J Neurosci, 30(7):1239-1250.

[58]ParekhPK, JohnsonSB, ListonC, 2022. Synaptic mechanisms regulating mood state transitions in depression. Annu Rev Neurosci, 45:581-601.

[59]ProulxCD, HikosakaO, MalinowR, 2014. Reward processing by the lateral habenula in normal and depressive behaviors. Nat Neurosci, 17(9):1146-1152.

[60]ProulxCD, AronsonS, MilivojevicD, et al., 2018. A neural pathway controlling motivation to exert effort. Proc Natl Acad Sci USA, 115(22):5792-5797.

[61]QuinaLA, TempestL, NgL, et al., 2015. Efferent pathways of the mouse lateral habenula. J Comp Neurol, 523(1):32-60.

[62]Riva-PosseP, CrowellAL, WrightK, et al., 2020. Rapid antidepressant effects of deep brain stimulation and their relation to surgical protocol. Biol Psychiatry, 88(8):e37-e39.

[63]RootDH, Mejias-AponteCA, QiJ, et al., 2014a. Role of glutamatergic projections from ventral tegmental area to lateral habenula in aversive conditioning. J Neurosci, 34(42):13906-13910.

[64]RootDH, Mejias-AponteCA, ZhangSL, et al., 2014b. Single rodent mesohabenular axons release glutamate and GABA. Nat Neurosci, 17(11):1543-1551.

[65]RootDH, BarkerDJ, EstrinDJ, et al., 2020. Distinct signaling by ventral tegmental area glutamate, GABA, and combinatorial glutamate-GABA neurons in motivated behavior. Cell Rep, 32(9):108094.

[66]RossiMA, BasiriML, LiuYJ, et al., 2021. Transcriptional and functional divergence in lateral hypothalamic glutamate neurons projecting to the lateral habenula and ventral tegmental area. Neuron, 109(23):3823-3837.e6.

[67]RussoSJ, NestlerEJ, 2013. The brain reward circuitry in mood disorders. Nat Rev Neurosci, 14(9):609-625.

[68]SartoriusA, KieningKL, KirschP, et al., 2010. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry, 67(2):e9-e11.

[69]SegoC, GonçalvesL, LimaL, et al., 2014. Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat. J Comp Neurol, 522(7):1454-1484.

[70]SeoJS, ZhongP, LiuA, et al., 2018. Elevation of p11 in lateral habenula mediates depression-like behavior. Mol Psychiatry, 23(5):1113-1119.

[71]ShabelSJ, ProulxCD, TriasA, et al., 2012. Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron, 74(3):475-481.

[72]ShabelSJ, WangCY, MonkB, et al., 2019. Stress transforms lateral habenula reward responses into punishment signals. Proc Natl Acad Sci USA, 116(25):12488-12493.

[73]SpixTA, NanivadekarS, ToongN, et al., 2021. Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation. Science, 374(6564):201-206.

[74]StamatakisAM, StuberGD, 2012. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci, 15(8):1105-1107.

[75]StamatakisAM, JenningsJH, UngRL, et al., 2013. A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Neuron, 80(4):1039-1053.

[76]StamatakisAM, van SwietenM, BasiriML, et al., 2016. Lateral hypothalamic area glutamatergic neurons and their projections to the lateral habenula regulate feeding and reward. J Neurosci, 36(2):302-311.

[77]Stephenson-JonesM, FlorosO, RobertsonB, et al., 2012. Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. Proc Natl Acad Sci USA, 109(3):E164-E173.

[78]Stephenson-JonesM, YuK, AhrensS, et al., 2016. A basal ganglia circuit for evaluating action outcomes. Nature, 539(7628):289-293.

[79]Stephenson-JonesM, Bravo-RiveraC, AhrensS, et al., 2020. Opposing contributions of GABAergic and glutamatergic ventral pallidal neurons to motivational behaviors. Neuron, 105(5):921-933.e5.

[80]St. Laurent R, Martinez Damonte V, Tsuda AC, et al., 2020. Periaqueductal gray and rostromedial tegmental inhibitory afferents to VTA have distinct synaptic plasticity and opiate sensitivity. Neuron, 106(4):624-636.e4.

[81]SylwestrakEL, JoY, VesunaS, et al., 2022. Cell-type-specific population dynamics of diverse reward computations. Cell, 185(19):3568-3587.e27.

[82]SzőnyiA, ZichóK, BarthAM, et al., 2019. Median raphe controls acquisition of negative experience in the mouse. Science, 366(6469):eaay8746.

[83]TakahashiA, Durand-de CuttoliR, FlaniganME, et al., 2022. Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice. Nat Commun, 13:4039.

[84]TianJ, UchidaN, 2015. Habenula lesions reveal that multiple mechanisms underlie dopamine prediction errors. Neuron, 87(6):1304-1316.

[85]TooleyJ, MarconiL, AlipioJB, et al., 2018. Glutamatergic ventral pallidal neurons modulate activity of the habenula-tegmental circuitry and constrain reward seeking. Biol Psychiatry, 83(12):1012-1023.

[86]TruselM, Nuno-PerezA, LeccaS, et al., 2019. Punishment-predictive cues guide avoidance through potentiation of hypothalamus-to-habenula synapses. Neuron, 102(1):120-127.e4.

[87]VentoPJ, BurnhamNW, RowleyCS, et al., 2017. Learning from one’s mistakes: a dual role for the rostromedial tegmental nucleus in the encoding and expression of punished reward seeking. Biol Psychiatry, 81(12):1041-1049.

[88]WallaceML, HuangKW, HochbaumD, et al., 2020. Anatomical and single-cell transcriptional profiling of the murine habenular complex. Elife, 9:e51271.

[89]WangDQ, LiY, FengQR, et al., 2017. Learning shapes the aversion and reward responses of lateral habenula neurons. eLife, 6:e23045.

[90]WangMR, LiPJ, LiZW, et al., 2023. Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula. Nat Commun, 14:1880.

[91]WangXY, XuX, ChenR, et al., 2023. The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain. Cell Rep, 42(10):113170.

[92]WangZY, CaiXD, QiuRR, et al., 2021. Case report: lateral habenula deep brain stimulation for treatment-resistant depression. Front Psychiatry, 11:616501.

[93]WardenMR, SelimbeyogluA, MirzabekovJJ, et al., 2012. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature, 492(7429):428-432.

[94]WeissT, VehRW, 2011. Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices. Neuroscience, 172:74-93.

[95]WilcoxKS, GutnickMJ, ChristophGR, 1988. Electrophysiological properties of neurons in the lateral habenula nucleus: an in vitro study. J Neurophysiol, 59(1):212-225.

[96]WilliamsNR, SudheimerKD, BentzleyBS, et al., 2018. High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain, 141(3):e18.

[97]WintersND, KondevV, LoombaN, et al., 2023. Opposing retrograde and astrocyte-dependent endocannabinoid signaling mechanisms regulate lateral habenula synaptic transmission. Cell Rep, 42(3):112159.

[98]WirtshafterD, AsinKE, PitzerMR, 1994. Dopamine agonists and stress produce different patterns of Fos-like immunoreactivity in the lateral habenula. Brain Res, 633(1-2):21-26.

[99]YangHB, YangJH, XiW, et al., 2016. Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear. Nat Neurosci, 19(2):283-289.

[100]YangSH, YangE, LeeJ, et al., 2023. Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice. Nat Commun, 14:2435.

[101]YangY, CuiYH, SangKN, et al., 2018. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 554(7692):317-322.

[102]YooJH, ZellV, Gutierrez-ReedN, et al., 2016. Ventral tegmental area glutamate neurons co-release GABA and promote positive reinforcement. Nat Commun, 7:13697.

[103]ZahmDS, RootDH, 2017. Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol Biochem Behav, 162:3-21.

[104]ZhangCC, ZhangYY, LuoHC, et al., 2022. Bilateral Habenula deep brain stimulation for treatment-resistant depression: clinical findings and electrophysiological features. Transl Psychiatry, 12:52.

[105]ZhangGW, ShenL, ZhongW, et al., 2018. Transforming sensory cues into aversive emotion via septal-habenular pathway. Neuron, 99(5):1016-1028.e5.

[106]ZhangH, LiK, ChenHS, et al., 2018. Dorsal raphe projection inhibits the excitatory inputs on lateral habenula and alleviates depressive behaviors in rats. Brain Struct Funct, 223(5):2243-2258.

[107]ZhangYQ, MaLY, ZhangXY, et al., 2023. Deep brain stimulation in the lateral habenula reverses local neuronal hyperactivity and ameliorates depression-like behaviors in rats. Neurobiol Dis, 180:106069.

[108]ZhengZW, GuoC, LiM, et al., 2022. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron, 110(8):1400-1415.e6.

[109]ZhouL, LiuMZ, LiQ, et al., 2017. Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Rep, 20(8):1991-1993.

[110]ZhouWJ, JinY, MengQ, et al., 2019. A neural circuit for comorbid depressive symptoms in chronic pain. Nat Neurosci, 22(10):1649-1658.