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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.
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“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]
In the citing paper
“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]
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“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]
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Citations
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Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression
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BackgroundMethodInfluentialSelf-citationSynaptic and cellular profile of neurons in the lateral habenula
Meye, F. J., Lecca, S., Valentinova, K., & Mameli, M. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00860 · Cited by 92
“However, the function of mGluRs in the LHb and their relationship with the CP-AMPARs in this structure remains unknown.”
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“ORIGINAL RESEARCH ARTICLE published: 03 February 2014 doi: 10.3389/fnhum.2014.00029 Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior”
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“Promising preclinical work in rodents using DBS of the LHb has yielded significant reversal of depressive-like behaviors (Li et al., 2011).”
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“…effective treatment specifically for anhedonia, suppression of habenula neuron firing has been shown to resolve depressive-like behaviour in rats (Li et al., 2011) and was reported to treat symptoms in a treatment-refractory patient through deep-brain stimulation (DBS) (Sartorius et al., 2010),…”
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“Consequently, the LHb is thought to be involved in the etiology of major depression, bipolar disorder, and schizophrenia (Shepard et al., 2006; Sartorius et al., 2010; Li et al., 2011).”
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“A separate group of rats implanted with cannulae in the LHb, were trained to drink sucrose under intermittent access to 2% sucrose by the two-bottle choice procedure, 7 days after the surgery, as described (Li et al, 2011b).”
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“Limei Zhang 1*‡, Vito S. Hernández 1*‡, Erika Vázquez-Juárez 1, Freya K. Chay 1 † and Rafael A. Barrio 2 1Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico, 2Departamento de Física Química, Instituto de Física, Universidad Nacional Autónoma de México, C…”
BackgroundStress transforms lateral habenula reward responses into punishment signals
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“6, 7, 9, 11, 15, 35 LHb neurons, especially in the medial part of the LHb, are activated by aversive emotional cues including stress, disappointment, fear, aggression or anticipation of a negative reward in monkeys, as well as rodents.”
InfluentialPathological ATPergic Signaling in Major Depression and Bipolar Disorder
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“In an animal model of depression, the learned helplessness test, the lateral habenula activity is significantly increased, and the activity of brainstem dopaminergic neurons was concomitantly inhibited (19).”
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“It is now well documented that LHbM is the primary target of diverse inputs, headed by extensive hypothalamic afferents from a lateral preoptic area (LPO)—lateral hypothalamus continuum (Barker et al., 2017; Kowski, Geisler, Krauss, & Veh, 2008; Lazaridis et al., 2019; Li et al., 2011; Poller, Madai, Bernard, Laube, &…”
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“In mice, we first assessed densities of PNNs across the 24-h cycle in brain regions involved in emotional memory processing and implicated in psychiatric disorders (Vyas et al., 2002; Sartorius et al., 2010; Li et al., 2011; Mahan and Ressler, 2012; Mauney et al., 2013; Meyer et al., 2014; Pantazopoulos et al., 2017;…”
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“Conversely, inhibition of LHb neuronal activity suppresses depressive-like behaviors in animal models of depression (Li et al., 2011a, 2013; Meye et al., 2015).”
InfluentialUnderstanding the habenula: A major node in circuits regulating emotion and motivation
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“Stereotaxic pharmacological (Winter et al, 2011) and stereotaxic electric (Li et al, 2011) inhibition of the LHb have been found to lead to the improvement of depressive ‐ like behaviour in translation studies using a model of depression with the Learned Helpless-ness paradigm.”
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“…Razi, Buhmann, & Friston, 2016; K. J. Friston, Kahan, Biswal, & Razi, 2011; Havlicek et al., 2015; Kiebel, Kloppel, Weiskopf, & Friston, 2007; Li et al., 2011; Marreiros, Kiebel, & Friston, 2008; Prando, Zorzi, Bertoldo, & Chiuso, 2017; Razi & Friston, 2016; Seghier & Friston, 2013; Stephan…”
Encore: Behavioural animal models of stress, depression and mood disorders
Petković, A., & Chaudhury, D. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.931964 · Cited by 74
Hamani, C., Amorim, B. O., Wheeler, A. L., Diwan, M., Driesslein, K., Covolan, L., Butson, C. R., & Nóbrega, J. N. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.007 · Cited by 71
“the Acb or ventromedial prefrontal cortex; vmPFC) (Gersner et al., 2010; Hamani et al., 2010a, 2010b, 2012; Li et al., 2011).”
BackgroundThe Role of the Medial Habenula Cholinergic System in Addiction and Emotion-Associated Behaviors
Lee, H. W., Yang, S. H., Kim, J. Y., & Kim, H. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00100 · Cited by 73
Sexual relationship power and depression among HIV-infected women in Rural Uganda
Hatcher, A. M., Tsai, A. C., Kumbakumba, E., Dworkin, S. L., Hunt, P. W., Martin, J. N., Clark, G., Bangsberg, D. R., & Weiser, S. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049821 · Cited by 67
“Learned helplessness, in turn, has long been associated with depression in clinical populations [63–65], and recent studies in animal models have begun to establish its pathophysiology [66–70].”
BackgroundThe Role of the Habenula in Nicotine Addiction
Baldwin, P. R., Alanis, R., & Salas, R. (2012) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.s1-002 · Cited by 67
“There was a correlation between the level of potentiation and the level of behavioral helplessness, suggesting that at least in this model of depression, increased lateral habenula activity may be implicated in the etiology of depression [54].”
BackgroundLv, Q., Yang, L., Li, G., Wang, Z., Shen, Z., Yu, W., Jiang, Q., Hou, B., Pu, J., Hu, H., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.02.028 · Cited by 70
“Due to limited spatial resolution here, we could not assess the potential effects involving the habenula (included in the thalamus node), a region heavily implicated in the depression circuit (57) and demonstrated in our recent work (58).”
Wagner, F., French, L., & Veh, R. W. (2014) · Brain Structure and Function · doi:10.1007/s00429-014-0891-9 · Cited by 64
“These excitatory neurons, however, project to inhibitory GABAergic cells, either directly within the VTA or inside the rostromedial tegmental nucleus (RMTg; Jhou et al. 2009; Kaufling et al. 2010).”
InfluentialBerger, A. L., Henricks, A. M., Lugo, J. M., Wright, H. R., Warrick, C. R., Sticht, M. A., Morena, M., Río, I. B., Laredo, S. A., Craft, R. M., et al. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.04.018 · Cited by 66
Ambrosi, E., Arciniegas, D. B., Curtis, K. N., Patriquin, M. A., Spalletta, G., Sani, G., Frueh, B. C., Fowler, J. C., Madan, A., & Salas, R. (2018) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.17120351 · Cited by 67
A unified model of ketamine’s dissociative and psychedelic properties
Marguilho, M., Figueiredo, I., & Castro-Rodrigues, P. (2022) · Journal of Psychopharmacology · doi:10.1177/02698811221140011 · Cited by 71
“In fact, the LHb has been implicated in coding of negative emotions (Matsumoto and Hikosaka, 2007; Shabel et al., 2012) and is aberrantly hyperactive in individuals with depression (Li et al., 2011, 2013; Morris et al., 1999; Shumake and GonzalezLima, 2003).”
BackgroundKim, S., Wallace, M. L., El-Rifai, M., Knudsen, A. R., & Sabatini, B. L. (2022) · Neuron · doi:10.1016/j.neuron.2022.01.007 · Cited by 58
“Curiously, the postsynaptic scaffolding protein gephyrin, but not PSD95, is highly enriched near EP Sst+ terminals despite the clear glutamatergic nature of these boutons (Li et al., 2011; Maroteaux and Mameli, 2012).”
BackgroundBeyond depression: Toward a process‐based approach to research, diagnosis, and treatment.
Forgeard, M. J. C., Haigh, E. A. P., Beck, A. T., Davidson, R. J., Henn, F. A., Maier, S. F., Mayberg, H. S., & Seligman, M. E. P. (2011) · Clinical Psychology Science and Practice · doi:10.1111/j.1468-2850.2011.01259.x · Cited by 70
Self-citationHong, S., & Hikosaka, O. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00778 · Cited by 70
“HUMAN NEUROSCIENCE ORIGINAL RESEARCH ARTICLE published: 13 November 2013 doi: 10.3389/fnhum.2013.00778 Diverse sources of reward value signals in the basal ganglia nuclei transmitted to the lateral habenula in the monkey”
InfluentialVerwey, M., Dhir, S. K., & Amir, S. (2016) · F1000Research · doi:10.12688/f1000research.9180.1 · Cited by 65
“Remarkably, a more recent paper has shown that the lateral habenula also responds to learned helplessness 119 , the same model of depression used by Landgraf et al .”
MethodDown-regulation of cholinergic signaling in the habenula induces anhedonia-like behavior
Han, S., Yang, S. H., Kim, J. Y., Mo, S., Yang, E., Song, K. M., Ham, B., Mechawar, N., Turecki, G., Lee, H. W., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01088-6 · Cited by 67
An update on NMDA antagonists in depression
Pochwat, B., Nowak, G., & Szewczyk, B. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1643237 · Cited by 67
“More importantly, the neural activity of LHb was increased in stressed animals compared to the control animals in different animal stress paradigms [61].”
BackgroundAn emerging role for the lateral habenula in aggressive behavior
Flanigan, M. E., Aleyasin, H., Takahashi, A., Golden, S. A., & Russo, S. J. (2017) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2017.05.003 · Cited by 61
A Central Amygdala-Substantia Innominata Neural Circuitry Encodes Aversive Reinforcement Signals
Cui, Y., Lv, G., Jin, S., Peng, J., Yuan, J., He, X., Gong, H., Xu, F., Xu, T., & Li, H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.062 · Cited by 65
Han, L., Zhang, L., Li, L., Sun, Y., Wang, Y., Chen, L., Guo, Y., Zhang, Y., Zhang, Q.-J., & Liu, J. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.01.024 · Cited by 63
“Further, several studies have also found that LHb neurons show increases in synaptic activity and spike output in animal models of depression (Li et al., 2011, 2013).”
BackgroundInfluentialPeriaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression
Ho, Y., Lin, T.-B., Hsieh, M., Lai, C., Chou, D., Chau, Y., Chen, G., & Peng, H. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.199 · Cited by 67
“This suggests LH was successfully established by chronic inescapable and unpredictable stress (Li et al, 2011; Maier, 1984).”
BackgroundPesarico, A. P., Bueno-Fernandez, C., Guirado, R., Gómez-Climent, M. Á., Curto, Y., Carceller, H., & Nacher, J. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00197 · Cited by 62
Kokane, S. S., Armant, R. J., Bolaños‐Guzmán, C. A., & Perrotti, L. I. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112548 · Cited by 63
“Increased activation of neurons projecting from the lateral habenula to the VTA has been observed in mice expressing depressive phenotypes following exposure to the learned helplessness and the chronic social defeat paradigms [19,85].”
BackgroundNuno‐Perez, A., Trusel, M., Lalive, A. L., Congiu, M., Gastaldo, D., Tchenio, A., Lecca, S., Soiza‐Reilly, M., Bagni, C., & Mameli, M. (2021) · Neuron · doi:10.1016/j.neuron.2021.01.008 · Cited by 58
“Both acute and chronic stressors perturb LHb function, yet this occurs through distinct mechanisms and by engaging diverse neuronal circuits (Cerniauskas et al., 2019; Knowland et al., 2017; Lecca et al., 2016; Li et al., 2011; Shabel et al., 2014).”
BackgroundDopaminergic system and neurons: Role in multiple neurological diseases
Chen, H., Li, J., Huang, Z., Fan, X., Wang, X., Chen, X., Guo, H., Liu, H., Li, S., Yu, S., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110133 · Cited by 69
Kaufling, J. (2019) · Cell and Tissue Research · doi:10.1007/s00441-019-03007-9 · Cited by 62
Lv, S., Yao, K., Zhang, Y., & Zhu, S. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109378 · Cited by 60
Tao, C., Zhang, G., Huang, J., Li, Z., Tao, H. W., & Zhang, L. I. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01397-2 · Cited by 62
Update on GPCR-based targets for the development of novel antidepressants
Mantas, I., Saarinen, M., Xu, Q., & Svenningsson, P. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01040-1 · Cited by 61
Bambico, F. R., & Belzung, C. (2012) · Current topics in behavioral neurosciences · doi:10.1007/7854_2012_234 · Cited by 61
Mathis, V., Cosquer, B., Avallone, M., Cassel, J., & Lecourtier, L. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.140 · Cited by 55
Wagner, F., Stroh, T., & Veh, R. W. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23554 · Cited by 55
“In parallel, evidence is mounting that the habenula is involved in the etiology of different psychiatric disorders, including major depression (Sartorius et al., 2010; Li et al., 2011; Winter et al., 2011) and schizophrenia (Sandyk, 1992; Ellison, 1994; Lecourtier et al., 2004).”
BackgroundZhou, X., Liu, L., Zhang, Y., Pu, J., Yang, L., Zhou, C., Yuan, S., Zhang, H., & Xie, P. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.11.038 · Cited by 57
“This is consistent with other findings (Li et al., 2011).”
Zhu, Y., Qi, S., Zhang, B., He, D., Teng, Y., Hu, J., & Wei, X. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00371 · Cited by 55
“It is not surprising to observe the insula and amygdala because they are the neuroanatomical core of MDD pathology and closely related to anxiety (27).”
BackgroundInfluentialPPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors
Scheggi, S., Melis, M., De Felice, M., Aroni, S., Muntoni, A. L., Pelliccia, T., Gambarana, C., De Montis, M. G., & Pistis, M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.024 · Cited by 56
Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits
Lazaridis, I., Crittenden, J. R., Ahn, G., Hirokane, K., Wickersham, I. R., Yoshida, T., Mahar, A., Skara, V., Loftus, J., Parvataneni, K., et al. (2024) · Current Biology · doi:10.1016/j.cub.2024.09.070 · Cited by 58
“90,92 Here, we focus on the conclusion supported by our anatomical and functional findings that there are parallel strio-some-derived and matrix-derived direct and indirect pathways differentially targeting motor output neurons (matrix) and dopamine neurons (striosomes).”
BackgroundHsu, Y. A., Morton, G., Guy, E. G., Wang, S. D., & Turner, E. E. (2016) · eNeuro · doi:10.1523/eneuro.0109-16.2016 · Cited by 53
“In contrast, ablation of the entire habenula attenuates the learned helplessness response (Amat et al., 2001), an effect which may be attributable to the LHb, because the induction of learned helplessness increases synaptic inputs to LHb neurons (B. Li et al., 2011).”
BackgroundPuryear, C. B., Brooks, J. M., Tan, L. A., Smith, K. L., Li, Y., Cunningham, J. I., Todtenkopf, M. S., Dean, R. L., & Sánchez, C. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.12.007 · Cited by 60
Furman, D. J., & Gotlib, I. H. (2016) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsw019 · Cited by 54
“Finally, deep-brain stimulation (DBS) of the habenula leads to acute reversal of learned helplessness and depression-like behaviors (Li et al., 2011; Meng et al., 2011).”
Background
Metadata
- 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 (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- 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
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