Synaptic potentiation onto habenula neurons in the learned helplessness model of depression
Open accessAbstract
The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Excitatory synapses onto lateral habenula cells have a high AMPAR-to-NMDAR ratio, indicating low NMDAR expression.
“Excitatory synapses onto LHb cells are characterized by a high ratio of AMPAR-to NMDAR-mediated synaptic responses [255], indicative of low levels of NMDAR expression.”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [255]
Lateral habenula neurons receive feed-forward and feedback GABAergic inhibition.
“LHb neurons also receive feed-forward and feedback GABAergic inhibition [253,255].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [255]
Increased probability of presynaptic glutamate release in the lateral habenula accompanies learned helplessness and chronic restraint stress.
“An increased probability of presynaptic glutamate release in the LHb accompanies learned helplessness and chronic restraint stress [255,260].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [255]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Short-Term Synaptic Plasticity
Zucker, R. S., & Regehr, W. G. (2002) · Annual Review of Physiology · doi:10.1146/annurev.physiol.64.092501.114547 · Cited by 5,068 · see citing works
Depression: a new animal model sensitive to antidepressant treatments
PORSOLT, R. D., LE PICHON, M., & JALFRE, M. (1977) · Nature · doi:10.1038/266730a0 · Cited by 4,451 · see citing works
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889 · cited 5× · see citing works
“Right, mean EPSP slope at indicated time points before, during and after DBS: (1) before (first pulse 1.”
BackgroundMethodInfluentialKrishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · see citing works
The mesolimbic dopamine reward circuit in depression
Nestler, E. J., & Carlezon, W. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.09.018 · Cited by 2,059 · see citing works
Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms
Pittenger, C., & Duman, R. S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301574 · Cited by 1,795 · see citing works
New approaches to antidepressant drug discovery: beyond monoamines
Berton, O., & Nestler, E. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1846 · Cited by 1,589 · see citing works
Lateral habenula as a source of negative reward signals in dopamine neurons
Matsumoto, M., & Hikosaka, O. (2007) · Nature · doi:10.1038/nature05860 · Cited by 1,292 · see citing works
Adult hippocampal neurogenesis in depression
Sahay, A., & Hen, R. (2007) · Nature Neuroscience · doi:10.1038/nn1969 · Cited by 1,206 · cited 2× · see citing works
“001; one-way ANOVA with repeated measures) and more extensive synaptic depression (20 Hz, F(1,22) 5 6.”
MethodThe habenula: from stress evasion to value-based decision-making
Hikosaka, O. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2866 · Cited by 955 · see citing works
Postsynaptic receptor trafficking underlying a form of associative learning
Rumpel, S., LeDoux, J., Zador, A., & Malinow, R. (2005) · Science · doi:10.1126/science.1103944 · Cited by 775 · see citing works
Self-citationJhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B., & Holland, P. C. (2009) · Neuron · doi:10.1016/j.neuron.2009.02.001 · Cited by 696 · see citing works
Sartorius, A., Kiening, K. L., Kirsch, P., von Gall, C. C., Haberkorn, U., Unterberg, A. W., Henn, F. A., & Meyer-Lindenberg, A. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.08.027 · Cited by 611 · cited 2× · see citing works
“Compared with WT animals, animals with cLH showed a faster synaptic depression (20 Hz, F(9,198) 5 2.”
BackgroundSelf-citationRepresentation of negative motivational value in the primate lateral habenula
Matsumoto, M., & Hikosaka, O. (2009) · Nature Neuroscience · doi:10.1038/nn.2233 · Cited by 547 · cited 2× · see citing works
“001 for both pulses compared with those in 1, Student’s t-test); and (3) after (first pulse 1.”
BackgroundTargeted electrode-based modulation of neural circuits for depression.
Mayberg, H. S. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38454 · Cited by 542 · see citing works
Glutamate Receptor Exocytosis and Spine Enlargement during Chemically Induced Long-Term Potentiation
Kopec, C. D., Li, B., Wei, W., Boehm, J., & Malinow, R. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3918-05.2006 · Cited by 486 · see citing works
Self-citationHigh-speed imaging reveals neurophysiological links to behavior in an animal model of depression
Airan, R. D., Meltzer, L. A., Roy, M., Gong, Y., Chen, H., & Deisseroth, K. (2007) · Science · doi:10.1126/science.1144400 · Cited by 396 · see citing works
Ji, H., & Shepard, P. D. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0958-07.2007 · Cited by 388 · see citing works
Afferents to the GABAergic tail of the ventral tegmental area in the rat
Kaufling, J., Veinante, P., Pawlowski, S. A., Freund‐Mercier, M., & Barrot, M. (2009) · Journal of Comparative Neurology · doi:10.1002/cne.21983 · Cited by 347 · see citing works
Learned helplessness and animal models of depression
Maier, S. F. (1984) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/s0278-5846(84)80032-9 · Cited by 309 · see citing works
Molecular studies of major depressive disorder: the epigenetic perspective
Mill, J. S., & Petronis, A. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001992 · Cited by 302 · see citing works
Covariation of activity in habenula and dorsal raphe nuclei following tryptophan depletion
Morris, J. S., Smith, K. A., Cowen, P. J., Friston, K. J., & Dolan, R. J. (1999) · NeuroImage · doi:10.1006/nimg.1999.0455 · Cited by 288 · see citing works
Lecourtier, L., & Kelly, P. H. (2007) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.01.004 · Cited by 283 · see citing works
Stress models of depression: forming genetically vulnerable strains
Henn, F. A., & Vollmayr, B. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2005.03.019 · Cited by 274 · see citing works
Self-citationDeep brain stimulation of the lateral habenula in treatment resistant major depression
Sartorius, A., & Henn, F. A. (2007) · Medical Hypotheses · doi:10.1016/j.mehy.2007.03.021 · Cited by 251 · see citing works
Self-citationLearned helplessness in the rat: improvements in validity and reliability
Vollmayr, B., & Henn, F. A. (2001) · Brain Research Protocols · doi:10.1016/s1385-299x(01)00067-8 · Cited by 238 · see citing works
Self-citationYang, L.-M., Hu, B., Xia, Y.-H., Zhang, B.-L., & Zhao, H. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.10.022 · Cited by 236 · see citing works
GluR1 Links Structural and Functional Plasticity at Excitatory Synapses
Kopec, C. D., Réal, É., Kessels, H. W. H. G., & Malinow, R. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3503-07.2007 · Cited by 220 · see citing works
Self-citationCaldecott-Hazard, S., Mazziotta, J. C., & Phelps, M. E. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-06-01951.1988 · Cited by 194 · see citing works
Amat, J., Sparks, P., Matus-Amat, P., Griggs, J., Watkins, L. R., & Maier, S. F. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02934-1 · Cited by 187 · see citing works
Winter, C., Vollmayr, B., Djodari-Irani, A., Klein, J., & Sartorius, A. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.07.034 · Cited by 145 · see citing works
Brain Systems Underlying Susceptibility to Helplessness and Depression
Shumake, J., & Gonzalez-Lima, F. (2003) · Behavioral and Cognitive Neuroscience Reviews · doi:10.1177/1534582303259057 · Cited by 135 · see citing works
The Effects of Tryptophan Depletion on Neural Responses to Emotional Words in Remitted Depression
Roiser, J. P., Levy, J., Fromm, S. J., Nugent, A. C., Talagala, S. L., Hasler, G., Henn, F. A., Sahakian, B. J., & Drevets, W. C. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.05.002 · Cited by 123 · see citing works
Self-citationSchulz, D., Mirrione, M. M., & Henn, F. A. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.11.003 · Cited by 40 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Neuronal circuits for fear and anxiety
Tovote, P., Fadok, J. P., & Lüthi, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3945 · Cited by 1,786 · see citing works
The role of medial prefrontal cortex in memory and decision making
Euston, D. R., Gruber, A. J., & McNaughton, B. L. (2012) · Neuron · doi:10.1016/j.neuron.2012.12.002 · Cited by 1,541 · see citing works
Input-specific control of reward and aversion in the ventral tegmental area
Lammel, S., Lim, B. K., Ran, C., Huang, K. W., Betley, M. J., Tye, K. M., Deisseroth, K., & Malenka, R. C. (2012) · Nature · doi:10.1038/nature11527 · Cited by 1,300 · see citing works
“Further elucidation of the detailed synaptic connectivity of LHb inputs to VTA may be particularly interesting in the context of the potential role of LHb in psychiatric disorders such as depression and schizophrenia 18, 35-37 .”
Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons
Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H.-C., Pomeranz, L., Christoffel, D. J., et al. (2013) · Nature · doi:10.1038/nature11713 · Cited by 1,156 · see citing works
Mechanisms of ketamine action as an antidepressant
Zanos, P., & Gould, T. D. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.255 · Cited by 1,127 · see citing works
Ketamine blocks bursting in the lateral habenula to rapidly relieve depression
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., & Hu, H. (2018) · Nature · doi:10.1038/nature25509 · Cited by 1,036 · see citing works
Engineering a memory with LTD and LTP
Nabavi, S., Fox, R., Proulx, C. D., Lin, J. Y., Tsien, R. Y., & Malinow, R. (2014) · Nature · doi:10.1038/nature13294 · Cited by 980 · see citing works
Self-citationReward and aversion in a heterogeneous midbrain dopamine system
Lammel, S., Lim, B. K., & Malenka, R. C. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.03.019 · Cited by 804 · see citing works
“The potential involvement of the LHb in depression (Li et al., 2011; Morris et al., 1999; Shumake and Gonzalez-Lima, 2003) and the specific synaptic connectivity of LHb inputs in the VTA (Hikosaka, 2010; Lammel et al.”
BackgroundSustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation
Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Alway, E. J., et al. (2019) · Science · doi:10.1126/science.aat8078 · Cited by 643 · see citing works
Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression
Cui, Y., Yang, Y., Ni, Z., Dong, Y., Cai, G., Foncelle, A., Ma, S., Sang, K., Tang, S., Li, Y., et al. (2018) · Nature · doi:10.1038/nature25752 · Cited by 597 · see citing works
Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance
Stamatakis, A. M., & Stuber, G. D. (2012) · Nature Neuroscience · doi:10.1038/nn.3145 · Cited by 564 · see citing works
The neurobiology of depression and antidepressant action
Willner, P., Scheel-Krüger, J., & Belzung, C. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.12.007 · Cited by 519 · see citing works
Experience-dependent modification of a central amygdala fear circuit
Li, H., Penzo, M. A., Taniguchi, H., Kopec, C. D., Huang, Z. J., & Li, B. (2013) · Nature Neuroscience · doi:10.1038/nn.3322 · Cited by 497 · see citing works
Self-citationAnimal models of major depression: drawbacks and challenges
Planchez, B., Surget, A., & Belzung, C. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-02084-y · Cited by 480 · see citing works
Circuits and functions of the lateral habenula in health and in disease
Hu, H., Cui, Y., & Yang, Y. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0292-4 · Cited by 471 · see citing works
Reward processing by the lateral habenula in normal and depressive behaviors
Proulx, C. D., Hikosaka, O., & Malinow, R. (2014) · Nature Neuroscience · doi:10.1038/nn.3779 · Cited by 461 · see citing works
Self-citationβCaMKII in Lateral Habenula Mediates Core Symptoms of Depression
Li, K., Zhou, T., Liao, L., Yang, Z., Wong, C., Henn, F., Malinow, R., Yates, J. R., & Hu, H. (2013) · Science · doi:10.1126/science.1240729 · Cited by 411 · see citing works
“Furthermore, synaptic activity and spike output of LHb neurons were enhanced in animal models of depression (14).”
Self-citationAnhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens
Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., & Malenka, R. C. (2012) · Nature · doi:10.1038/nature11160 · Cited by 368 · see citing works
Dysfunctional reward processing in depression
Admon, R., & Pizzagalli, D. A. (2015) · Current Opinion in Psychology · doi:10.1016/j.copsyc.2014.12.011 · Cited by 343 · see citing works
“More recently and specifically relevant to depression, lesions of the lateral habenula [30] and attenuation of midbrain-habenula signaling [31] were found to reduce depression-like behaviors in rat models of depression.”
BackgroundGABA/glutamate co-release controls habenula output and is modified by antidepressant treatment
Shabel, S. J., Proulx, C. D., Piriz, J., & Malinow, R. (2014) · Science · doi:10.1126/science.1250469 · Cited by 369 · see citing works
Self-citationSingle rodent mesohabenular axons release glutamate and GABA
Root, D. H., Mejias-Aponte, C. A., Zhang, S., Wang, H.-L., Hoffman, A. F., Lupica, C. R., & Morales, M. (2014) · Nature Neuroscience · doi:10.1038/nn.3823 · Cited by 349 · see citing works
“Bicuculline significantly attenuated mesohabenular light-evoked inhibition (paired t-test, t(5) = 3.”
MethodA neural circuit for comorbid depressive symptoms in chronic pain
Zhou, W., Jin, Y., Meng, Q., Zhu, X., Bai, T., Tian, Y., Mao, Y., Wang, L., Xie, W., Zhong, H., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0468-2 · Cited by 343 · see citing works
Shabel, S. J., Proulx, C. D., Trias, A., Murphy, R. T., & Malinow, R. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.037 · Cited by 334 · see citing works
“The LHb has been implicated in the pathophysiology of depression (Hikosaka, 2010; Li et al., 2011), potentially by reducing the output of brainstem aminergic neurons (Ferraro et al., 1996; Hikosaka, 2010; Ji and Shepard, 2007).”
BackgroundSelf-citationWiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences
Li, Y., Allen, W. E., Thompson, K. R., Tian, Q., Hsueh, B., Ramakrishnan, C., Wang, A.-C., Jennings, J. H., Adhikari, A., Halpern, C. H., et al. (2016) · Cell · doi:10.1016/j.cell.2016.05.010 · Cited by 326 · see citing works
“The second PC, by contrast, revealed a specific correlated group of DORpm (polymodal association cortex-related dorsal thalamus) regions, containing the lateral habenula (LHb), a key nucleus for aversive behaviors (Li et al., 2011, 2013).”
An excitatory synapse hypothesis of depression
Thompson, S. M., Kallarackal, A. J., Kvarta, M. D., Van Dyke, A. M., LeGates, T. A., & Cai, X. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.03.003 · Cited by 265 · see citing works
Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of Depression
Knowland, D., Lilascharoen, V., Pacia, C. P., Shin, S., Wang, E. H.-J., & Lim, B. K. (2017) · Cell · doi:10.1016/j.cell.2017.06.015 · Cited by 273 · see citing works
“Enhanced PV and PV Activity Defines Susceptibility to SDS Previous studies report increased cellular activity in the LHb and dopaminergic neurons in the VTA in animal models of depression (Chaudhury et al., 2013; Li et al., 2011).”
InfluentialLateral habenula in the pathophysiology of depression
Yang, Y., Wang, H., Hu, J., & Hu, H. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.10.024 · Cited by 254 · see citing works
“Current Opinion in Neurobiology 2018, 48:90–96 symptoms such as helplessness [15,16] and lack of pleasure (anhedonia) [17].”
BackgroundInfluentialDandekar, M. P., Fenoy, A. J., Carvalho, A. F., Soares, J. C., & Quevedo, J. (2018) · Molecular Psychiatry · doi:10.1038/mp.2018.2 · Cited by 264 · see citing works
“(2011)(84) UL, BP 80–100 150 300 7–28 Days continuously WH rats: reduces DLP in CUS model; increases DA/NA/5-HT in blood serum and hippocampus Li et al. (2011)(83) UL, BP 150, 300 130 40 ms FST: 1 h after and 1 h before swimming sessions LH: 1 h after baseline testing and 1 h before LH sessions Congenital LH rats: ant…”
MethodInfluentialHu, H. (2016) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-014106 · Cited by 253 · see citing works
Neuronal Dynamics Regulating Brain and Behavioral State Transitions
Andalman, A. S., Burns, V. M., Lovett-Barron, M., Broxton, M. J., Poole, B., Yang, S., Grosenick, L., Lerner, T. N., Chen, R., Benster, T., et al. (2019) · Cell · doi:10.1016/j.cell.2019.02.037 · Cited by 246 · see citing works
“Intriguingly, these modeling results are consistent with the potentiation of LHb synapses correlating with helplessness behaviors (Li et al., 2011) and with the raphe-to-LHb projection exerting causal effects on LHb excitability and depressive behaviors (Zhang et al.”
InfluentialBasal forebrain projections to the lateral habenula modulate aggression reward
Golden, S. A., Heshmati, M., Flanigan, M. E., Christoffel, D. J., Guise, K. G., Pfau, M. L., Aleyasin, H., Ménard, C., Zhang, H., Hodes, G. E., et al. (2016) · Nature · doi:10.1038/nature18601 · Cited by 241 · see citing works
Impaired reward prediction error encoding and striatal-midbrain connectivity in depression
Kumar, P., Goer, F., Murray, L., Dillon, D. G., Beltzer, M. L., Cohen, A. L., Brooks, N. H., & Pizzagalli, D. A. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0032-x · Cited by 219 · see citing works
“For instance, prior animal studies have reported elevated habenula metabolism [43] and enhanced excitatory inputs to VTA-projecting habenula neurons during learned helplessness [44], with the former reversed following antidepressant treatment [45].”
BackgroundCellular and molecular basis for stress-induced depression
Seo, J.-S., Wei, J., Qin, L., Kim, Y., Yan, Z., & Greengard, P. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.118 · Cited by 235 · see citing works
Belujon, P., & Grace, A. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.014 · Cited by 225 · see citing works
“Learned Helplessness Paradigm In the LH paradigm (16,17), inescapable stress occurred on day 1 in one chamber of a two-chamber shuttle box (Med Associates, St.”
Cerniauskas, I., Winterer, J., de Jong, J. W., Lukacsovich, D., Yang, H., Khan, F., Peck, J. R., Obayashi, S. K., Lilascharoen, V., Lim, B. K., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.09.005 · Cited by 187 · see citing works
“On the other hand, LHb neurons are mainly glutamatergic as demonstrated by extensive expression of vesicular glutamate transporter VGlut2 (Li et al., 2011; Lammel et al., 2012).”
BackgroundMethodResultInfluentialAmo, R., Fredes, F., Kinoshita, M., Aoki, R., Aizawa, H., Agetsuma, M., Aoki, T., Shiraki, T., Kakinuma, H., Matsuda, M., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.035 · Cited by 207 · see citing works
“…address: Institute of Science and Technology Austria, 3400 Klosterneuburg, Austria 9Present address: Tokyo Medical and Dental University, Medical Research Institute, Tokyo 113-8510, Japan 10Present address: The Institute of Scientific Research and Industrial Research, Osaka University, Mihogaoka…”
BackgroundDisrupted habenula function in major depression
Lawson, R. P., Nord, C. L., Seymour, B., Thomas, D. L., Dayan, P., Pilling, S., & Roiser, J. P. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.81 · Cited by 206 · see citing works
Epigenetics and the regulation of stress vulnerability and resilience
Zannas, A. S., & West, A. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2013.12.003 · Cited by 211 · see citing works
“…in neurons of the lateral habenula, which is a brain region strongly implicated in the regulation of stress-induced depressivelike behaviors via its ability to directly modulate the firing of dopaminergic and serotonergic neurons in brainstem nuclei (Hikosaka, 2010, Li et al., 2011).”
BackgroundA new control center for dopaminergic systems: pulling the VTA by the tail
Bourdy, R., & Barrot, M. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.06.007 · Cited by 208 · see citing works
Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb
Ma, S., Chen, M., Jiang, Y., Xiang, X., Wang, S., Wu, Z., Li, S., Cui, Y., Wang, J., Zhu, Y., et al. (2023) · Nature · doi:10.1038/s41586-023-06624-1 · Cited by 213 · see citing works
VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons
Qi, J., Zhang, S., Wang, H., Barker, D. J., Miranda-Barrientos, J. A., & Morales, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4281 · Cited by 203 · see citing works
Cellular Circadian Clocks in Mood Disorders
McCarthy, M. J., & Welsh, D. K. (2012) · Journal of Biological Rhythms · doi:10.1177/0748730412456367 · Cited by 203 · see citing works
Jhou, T. C., Good, C. H., Rowley, C. S., Xu, S., Wang, H., Burnham, N. W., Hoffman, A. F., Lupica, C. R., & Ikemoto, S. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.3634-12.2013 · Cited by 198 · see citing works
“Notably, acute cessation of cocaine intake causes accumbens DA levels to fall below baseline (Weiss et al., 1992), whereas reduced accumbens DA signaling in turn produces conditioned place aversion (Shippenberg et al., 1991; Liu et al., 2008).”
BackgroundThe lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview
Lecca, S., Meye, F. J., & Mameli, M. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12480 · Cited by 196 · see citing works
“Specifically, AMPAR activation in the LHb mediates excitatory postsynaptic currents (EPSCs) that are inwardly rectifying, a biophysical property typical of high-conductive calcium-permeable (CP) AMPARs (Burnashev et al., 1992; Li et al., 2011; Maroteaux & Mameli, 2012).”
BackgroundInfluentialPenzo, M. A., Robert, V., & Li, B. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4166-13.2014 · Cited by 187 · see citing works
“Standard surgical procedures were followed for stereotaxic injection (Li et al., 2011; Li et al., 2013).”
MethodSelf-citationLecca, S., Pelosi, A., Tchenio, A., Moutkine, I., Lujan, R., Hervé, D., & Mameli, M. (2016) · Nature Medicine · doi:10.1038/nm.4037 · Cited by 176 · see citing works
A hypothalamus-habenula circuit controls aversion
Lazaridis, I., Tzortzi, O., Weglage, M., Märtin, A., Xuan, Y., Parent, M. A., Johansson, Y., Fuzik, J., Fürth, D., Fenno, L. E., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0369-5 · Cited by 180 · see citing works
Depression: from psychopathology to pathophysiology.
Belzung, C., Willner, P., & Philippot, P. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.013 · Cited by 171 · see citing works
“The LHb encodes aversive states [31] such as omission of an expected reward [32] leading, on the one hand, to increased processing of negative information by the amygdala and, on the other, to decreased processing of positive information by the nucleus accumbens [30 ].”
BackgroundInfluentialShifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse
Meye, F. J., Soiza-Reilly, M., Smit, T., Diana, M. A., Schwarz, M. K., & Mameli, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4334 · Cited by 173 · see citing works
Zhu, X., Tang, H.-D., Dong, W., Kang, F., Liu, A., Mao, Y., Xie, W., Zhang, X., Cao, P., Zhou, W., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00811-x · Cited by 176 · see citing works
Stephenson‐Jones, M., Floros, O., Robertson, B., & Grillner, S. E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119348109 · Cited by 167 · see citing works
“In mammals, these direct habenula connections to monoaminergic neurons have been confirmed by ultrastructural analysis; as with the lamprey, they have been shown to arise from separate populations in the LHb (33, 57).”
BackgroundEfferent Pathways of the Mouse Lateral Habenula
Quina, L. A., Tempest, L., Ng, L., Harris, J. A., Ferguson, S. M., Jhou, T. C., & Turner, E. E. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23662 · Cited by 165 · see citing works
“Increased excitatory synaptic inputs to VTA-projecting LHb neurons are associated with learned helplessness in response to inescapable shock, and behavioral aspects of this state are reversed by in vivo stimulation of the LHb, which may deplete these synaptic inputs (Li et al., 2011).”
BackgroundTranslating the habenula-from rodents to humans
Boulos, L.-J., Darcq, E., & Kieffer, B. L. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.06.003 · Cited by 164 · see citing works
“Repeated stimulation of LHb afferences in animals displaying learned helplessness suppressed synaptic drive onto VTA-projecting LHb neurons and increased escape behavior in an active avoidance task (36).”
BackgroundTranscriptional and spatial resolution of cell types in the mammalian habenula
Hashikawa, Y., Hashikawa, K., Rossi, M. A., Basiri, M. L., Liu, Y., Johnston, N. L., Ahmad, O. R., & Stuber, G. D. (2020) · Neuron · doi:10.1016/j.neuron.2020.03.011 · Cited by 167 · see citing works
Carlson, P. J., Diazgranados, N., Nugent, A. C., Ibrahim, L., Luckenbaugh, D. A., Brutsche, N., Herscovitch, P., Manji, H. K., Zarate, C. A., & Drevets, W. C. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.008 · Cited by 168 · see citing works
Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments
Kadriu, B., Musazzi, L., Henter, I. D., Graves, M., Popoli, M., & Zarate, C. A. (2019) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyy094 · Cited by 165 · see citing works
Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents
Klein, M. E., Chandra, J., Sheriff, S., & Malinow, R. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1916570117 · Cited by 156 · see citing works
“Rats were subjected to a 1-d modified forced swim test (mFST) as cLH animals do not require a “pretest” swim day to display immobility behavior (32).”
MethodSelf-citationThe role of the habenula in drug addiction
Velasquez, K. M., Molfese, D. L., & Salas, R. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00174 · Cited by 155 · see citing works
“In mice, learned helplessness (an animal model for studying depression-like symptoms) results in potentiation of LHb outputs, suggesting an increase in negative neural signaling (Li et al., 2011).”
BackgroundDeep Brain Stimulation for Psychiatric Disease: Contributions and Validity of Animal Models
Hamani, C., & Temel, Y. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003722 · Cited by 157 · see citing works
The habenula encodes negative motivational value associated with primary punishment in humans
Lawson, R. P., Seymour, B., Loh, E., Lutti, A., Dolan, R. J., Dayan, P., Weiskopf, N., & Roiser, J. P. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1323586111 · Cited by 153 · see citing works
“Abnormalities in habenula structure and function have been reported in depressed patients (29, 30), as well as in animal models (31).”
Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset
Zheng, Z., Guo, C., Li, M., Yang, L., Liu, P., Zhang, X., Liu, Y., Guo, X., Cao, S., Dong, Y., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.011 · Cited by 142 · see citing works
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148 · see citing works
“Thus, given the role of the lateral habenula (LHb) in depressive disorders, it is not surprising that an interest in its role in drug addiction has recently emerged (Li et al., 2011; Maroteaux and Mameli, 2012; Zuo et al., 2013; Lecca et al., 2014).”
BackgroundZhao, H., Zhang, B., Yang, S., & Rusak, B. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.09.016 · Cited by 147 · see citing works
Are We Getting Closer to Valid Translational Models for Major Depression?
Berton, O., Hahn, C.-G., & Thase, M. E. (2012) · Science · doi:10.1126/science.1222940 · Cited by 148 · see citing works
Negative learning bias is associated with risk aversion in a genetic animal model of depression
Shabel, S. J., Murphy, R. T., & Malinow, R. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00001 · Cited by 148 · see citing works
“The LHb, a key regulator of monoaminergic brain regions (Amat et al., 2001; Ji and Shepard, 2007; Hikosaka et al., 2008), is metabolically and synaptically hyperactive in helpless rats (Caldecott-Hazard, 1988; Shumake et al., 2003; Li et al., 2011, 2013).”
BackgroundInfluentialSelf-citationLiu, H., Zhang, C., Ji, Y., & Yang, L. (2018) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2018.00326 · Cited by 149 · see citing works
Neuronal Correlates of Depression
Chaudhury, D., Liu, H., & Han, M.-H. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2044-6 · Cited by 139 · see citing works
“Studies have shown increased activity of LHb neurons projecting to the VTA in mice exhibiting the depressed-phenotype following exposure to a learned helplessness model of depression [43] and to a chronic social defeat stress paradigm [185].”
BackgroundStress and VTA synapses: implications for addiction and depression
Polter, A. M., & Kauer, J. A. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12490 · Cited by 141 · see citing works
“atory synapses on habenula neurons and reversed the helpless phenotype of the rats (Li et al., 2011).”
BackgroundInfluentialTreatment-resistant depression: are animal models of depression fit for purpose?
Willner, P., & Belzung, C. (2015) · Psychopharmacology · doi:10.1007/s00213-015-4034-7 · Cited by 140 · see citing works
“…finding is that individuals homozygous for the short allele of the 5-HTTLPR gene are less responsive to antidepressant treatment than individuals homozygous for the long allele, with heterozygotes showing an intermediate response (Serretti et al. 2007; Zobel and Maier 2010; Licinio and Wong 2011).”
BackgroundInfluentialNamboodiri, V. M. K., Rodríguez-Romaguera, J., & Stuber, G. D. (2016) · Current Biology · doi:10.1016/j.cub.2016.08.051 · Cited by 143 · see citing works
Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance
Cui, W., Mizukami, H., Yanagisawa, M., Aida, T., Nomura, M., Isomura, Y., Takayanagi, R., Ozawa, K., Tanaka, K., & Aizawa, H. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1465-14.2014 · Cited by 139 · see citing works
“This hypothesis is based on the observation that the DBS protocol used in patients effectively reduces excitatory synaptic transmission in the rat LHb (Li et al., 2011).”
BackgroundMethodInfluentialKim, U., & Lee, T. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08030.x · Cited by 133 · see citing works
“…to reward, attention, nociception, feeding, depression, drug addiction etc. (Sutherland, 1982; Mahieux & Benabid, 1987; Terenzi et al., 1990; Amat et al., 2001; Shumake et al., 2003; Klemm, 2004; Lecourtier & Kelly, 2007; Morissette & Boye, 2008; Friedman et al., 2010, 2011; Li et al., 2011).”
Learning shapes the aversion and reward responses of lateral habenula neurons
Wang, D., Li, Y., Feng, Q., Guo, Q., Zhou, J., & Luo, M. (2017) · eLife · doi:10.7554/elife.23045 · Cited by 141 · see citing works
“The LHb has emerged as a centrally-important brain region in the pathophysiology of depression that often involves social defeat in humans and animal models (Li et al., 2011, Li et al., 2013; Lecca et al., 2014; Proulx et al., 2014).”
Endocannabinoid signalling modulates susceptibility to traumatic stress exposure
Bluett, R. J., Báldi, R., Haymer, A., Gaulden, A. D., Hartley, N. D., Parrish, W. P., Baechle, J. J., Marcus, D. J., Bey, R. M., Shonesy, B. C., et al. (2017) · Nature Communications · doi:10.1038/ncomms14782 · Cited by 136 · see citing works
Deep brain stimulation for treatment-resistant depression: Efficacy, safety and mechanisms of action
Anderson, R. J., Frye, M. A., Abulseoud, O. A., Lee, K. H., McGillivray, J., Berk, M., & Tye, S. J. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.06.001 · Cited by 137 · see citing works
Left Habenula Mediates Light-Preference Behavior in Zebrafish via an Asymmetrical Visual Pathway
Zhang, B.-B., Yao, Y.-Y., Zhang, H.-F., Kawakami, K., & Du, J.-L. (2017) · Neuron · doi:10.1016/j.neuron.2017.01.011 · Cited by 115 · see citing works
The medial habenula: still neglected
Viswanath, H., Carter, A. Q., Baldwin, P. R., Molfese, D. L., & Salas, R. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00931 · Cited by 133 · see citing works
Lin, S., Huang, L., Luo, Z.-C., Li, X., Jin, S., Du, Z., Wu, D., Xiong, W., Huang, L., Luo, Z.-Y., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.02.014 · Cited by 130 · see citing works
Unmasking the mysteries of the habenula in pain and analgesia
Shelton, L., Becerra, L. R., & Borsook, D. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.01.004 · Cited by 128 · see citing works
“…involved in numerous behavioral functions that are implicated in pain processing (viz., cognition, addition, aversion, learned helplessness, and reward, Hikosaka, 2007; Matsumoto and Hikosaka, 2007; Frahm et al., 2011; Friedman et al., 2011; Paul et al., 2011; Li et al., 2011; Paul et al., 2011).”
A neural pathway controlling motivation to exert effort
Proulx, C. D., Aronson, S., Milivojevic, D., Molina, C., Loi, A., Monk, B., Shabel, S. J., & Malinow, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801837115 · Cited by 119 · see citing works
Self-citationElectric foot shock stress: a useful tool in neuropsychiatric studies
Bali, A., & Jaggi, A. S. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0015 · Cited by 127 · see citing works
“The authors described that the excitatory synapse onto the VTA-projecting neurons of the lateral habenula is potentiated, and the synaptic potentiation correlates with the helplessness behavior (Li et al., 2011).”
Lateral Preoptic Control of the Lateral Habenula through Convergent Glutamate and GABA Transmission
Barker, D. J., Miranda-Barrientos, J. A., Zhang, S., Root, D. H., Wang, H.-L., Liu, B., Calipari, E. S., & Morales, M. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.066 · Cited by 125 · see citing works
“The LHb has been implicated in addiction and depression, among other mental disorders (Jhou et al., 2013; Li et al., 2011; Meye et al., 2016; Shabel et al., 2014; Yang et al., 2008), which may result from alterations of LHb neuronal signaling at the molecular, cellular, or neurocircuitry levels.”
BackgroundSego, C., Gonçalves, L., Lima, L. B., Furigo, I. C., Donato, J., & Metzger, M. (2013) · The Journal of Comparative Neurology · doi:10.1002/cne.23533 · Cited by 126 · see citing works
“…(wileyonlinelibrary.com)VC 2013 Wiley Periodicals, Inc. 1454 The Journal of Comparative Neurology | Research in Systems Neuroscience 522:1454–1484 (2014) Hazard et al., 1988; Morris et al., 1999; Amat et al., 2001; Shumake et al., 2003; Sartorius et al., 2010; Li et al., 2011; Meng et al., 2011).”
BackgroundMapping pain activation and connectivity of the human habenula
Shelton, L., Pendse, G., Maleki, N., Moulton, E. A., Lebel, A., Becerra, L. R., & Borsook, D. (2012) · Journal of Neurophysiology · doi:10.1152/jn.00012.2012 · Cited by 128 · see citing works
Laterodorsal tegmentum interneuron subtypes oppositely regulate olfactory cue-induced innate fear
Yang, H., Yang, J., Wang, X., Hao, S., Luo, B., He, X., Zhu, L., Lou, H., Yu, Y., Xu, F., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4208 · Cited by 123 · see citing works
Phylogeny and Ontogeny of the Habenular Structure
eAizawa, H., Amo, R., & Okamoto, H. (2011) · Frontiers in Neuroscience · doi:10.3389/fnins.2011.00138 · Cited by 119 · see citing works
“The habenula shows phylogenetic conservation from fish to human, and studies using genetically accessible model animals have provided molecular insights into the developmental mechanisms of the habenula.”
InfluentialSynaptic Modifications in the Medial Prefrontal Cortex in Susceptibility and Resilience to Stress
Wang, M., Perova, Z., Arenkiel, B. R., & Li, B. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5294-13.2014 · Cited by 116 · see citing works
“…responses to stress, we used mice that have been subjected to an inescapable and unpredictable stressor (Seligman, 1978; Sherman et al., 1982; Maier, 1984; Caldarone et al., 2000; Vollmayr and Henn, 2001; Ukai et al., 2002; Chourbaji et al., 2005a, b; Li et al., 2011) (see Materials and Methods).”
BackgroundMethodInfluentialSelf-citationThe medial habenula as a regulator of anxiety in adult zebrafish
Mathuru, A. S., & Jesuthasan, S. J. (2013) · Frontiers in Neural Circuits · doi:10.3389/fncir.2013.00099 · Cited by 119 · see citing works
“In this scenario, transmission via the lateral habenula would be increased, and the outcome would be similar to that seen in rats where such an increase is associated with a predisposition for helpless behavior (Li et al., 2011), which includes increased freezing.”
BackgroundSachs, B. D., Ni, J. R., & Caron, M. G. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1416866112 · Cited by 121 · see citing works
“Similarly, deep brain stimulation-mediated inhibition of the LHb in rats has been shown to lead to antidepressant-like effects (22).”
BackgroundThe molecular pathophysiology of depression and the new therapeutics
Tian, H., Hu, Z., Xu, J., & Wang, C. (2022) · MedComm · doi:10.1002/mco2.156 · Cited by 122 · see citing works
Perova, Z., Delevich, K. M., & Li, B. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2670-14.2015 · Cited by 116 · see citing works
Self-citationDeep Brain Stimulation for Intractable Psychiatric Disorders
Goodman, W. K., & Alterman, R. L. (2010) · Annual Review of Medicine · doi:10.1146/annurev-med-052209-100401 · Cited by 115 · see citing works
Animal Models of (or for) Aggression Reward, Addiction, and Relapse: Behavior and Circuits
Golden, S. A., Jin, M., & Shaham, Y. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0151-19.2019 · Cited by 121 · see citing works
“, 2016), and glutamatergic neurons from lateral hypothalamus, anterior cingulate, medial PFC, and entopeduncular nucleus (Li et al., 2011; Poller et al., 2013; Stamatakis et al., 2016).”
BackgroundLim, L. W., Prickaerts, J., Huguet, G., Kadar, E., Hartung, H., Sharp, T., & Temel, Y. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.24 · Cited by 116 · see citing works
Anatomical and single-cell transcriptional profiling of the murine habenular complex
Wallace, M. L., Huang, K. W., Hochbaum, D., Hyun, M., Radeljic, G., & Sabatini, B. L. (2020) · eLife · doi:10.7554/elife.51271 · Cited by 113 · see citing works
Hsu, Y. A., Wang, S. D., Wang, S., Morton, G., Zariwala, H. A., de la Iglesia, H. O., & Turner, E. E. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1861-14.2014 · Cited by 115 · see citing works
“An examination of ZsGreen expression in the habenula of phenotypically normal mice showed that Cre activity in the MHb was confined almost entirely to the dorsal part, and activation of reporter expression in scattered neurons in the LHb was also noted (Fig.”
MethodYang, Y., Wang, Z.-H., Jin, S., Gao, D., Liu, N., Chen, S., Zhang, S., Liu, Q., Liu, E., Wang, X., et al. (2016) · Nature Communications · doi:10.1038/ncomms11935 · Cited by 111 · see citing works
“The current emotion-related laboratory studies are mainly focused on the negative aspects using ‘learned helplessness’ (LHL) or depression as model 6,7 , and there is a lack of animal model to mimic the positive motivation during stressful experience that may be denominated as ‘learned hopefulness’…”
Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression
Meng, H., Wang, Y., Huang, M. H., Lin, W., Wang, S., & Zhang, B. (2011) · Brain Research · doi:10.1016/j.brainres.2011.08.041 · Cited by 113 · see citing works
Guan, Y., Huang, G., Xu, M.-D., Gao, F., Lin, S., Huang, J., Wang, J., Li, Y., Wu, C.-H., Yao, S., et al. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.032 · Cited by 112 · see citing works
How does ketamine elicit a rapid antidepressant response?
Kavalali, E. T., & Monteggia, L. M. (2014) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2014.11.005 · Cited by 109 · see citing works
- Authors
- Li, B., Piriz, J., Mirrione, M., Chung, C., Proulx, C. D., Schulz, D., Henn, F., & Malinow, R.
- Affiliations
- University of California San Diego (US)
- Brookhaven National Laboratory (US)
- Corresponding author
- Li, Bo
- Malinow, Roberto
- Venue
- Nature
- Published
- 2011-02
- Volume
- 470
- Issue
- 7335
- Pages
- 535-539
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3285101
- OpenAlex
- W1969186778
- Cited by
- 634
- References
- 34
- Citations by year
- 2026: 27 · 2025: 31 · 2024: 61 · 2023: 33 · 2022: 50 · 2021: 49 · 2020: 47 · 2019: 56 · 2018: 41 · 2017: 47 · 2016: 50 · 2015: 31 · 2014: 38 · 2013: 33 · 2012: 29
- FWCI
- 25.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (R01AG032132)
- National Institute of Mental Health (R01MH091119, R01MH049159, R01MH091903)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- lateral habenula, learned helplessness, depression, synaptic potentiation, presynaptic release probability, ventral tegmental area, deep brain stimulation, negative rewards, aversive outcomes, dopamine, excitatory synapses
- MeSH terms
- Animals, Avoidance Learning, Depression, Disease Models, Animal, Dopamine, Electric Stimulation, Helplessness, Learned, Male, Models, Neurological, Synaptic Transmission, Neurons, Reward, Synapses, Thalamus, Rats, Sprague-Dawley, Ventral Tegmental Area, Presynaptic Terminals, Excitatory Postsynaptic Potentials, Deep Brain Stimulation, Rats, Neuroanatomical Tract-Tracing Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
