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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]
In the citing paper
“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
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
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
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889 · cited 5×
“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
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
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
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
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
Adult hippocampal neurogenesis in depression
Sahay, A., & Hen, R. (2007) · Nature Neuroscience · doi:10.1038/nn1969 · Cited by 1,206 · cited 2×
“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
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
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
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×
“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×
“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
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
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
Ji, H., & Shepard, P. D. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0958-07.2007 · Cited by 388
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
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 311
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
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
Lecourtier, L., & Kelly, P. H. (2007) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.01.004 · Cited by 283
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
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
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
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
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 226
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
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
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
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 139
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
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
Self-citation
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
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
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
“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
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
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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