Cited by 635Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorDeep Brain Stimulation and Movement Disorders

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Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

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Li, Bo, Piriz, Joaquin, Mirrione, Martine, Chung, ChiHye, Proulx, Christophe D., Schulz, Daniela, Henn, Fritz, Malinow, Roberto·2011·Nature

DOI 10.1038/nature09742PMC PMC3285101

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Abstract

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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Background
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Self-citation
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BackgroundMethodInfluential
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Background
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Self-citation
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Background
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Background
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Background
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BackgroundInfluential
Circuit to Construct Mapping: A Mathematical Tool for Assisting the Diagnosis and Treatment in Major Depressive Disorder
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“…underlying LHb hyperactivity in depression, we used an unbiased, highthroughput, quantitative proteomic screen to compare habenular protein expression between congenitally learned helpless (cLH) (Henn and Vollmayr 2005) and wild-type Sprague–Dawley (SD) rats (Li et al. 2013; Cui et al. 2018).”
BackgroundMethod
Tonic activity in lateral habenula neurons acts as a neutral valence brake on reward-seeking behavior
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“Pathology in the habenula nuclei has been demonstrated, which mediate communication between the forebrain including the mPFC and the midbrain (Li et al. 2011).”
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“Persistent elevated activity in the lateral habenula is implicated in depression (Li et al., 2011; Yang et al., 2018; Andalman et al., 2019).”
Background
NMDA receptor-dependent long-term depression in the lateral habenula: implications in physiology and depression
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A change in hippocampal protocadherin gamma expression in a learned helpless rat
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“GluA2 expression in neurons varies considerably with low GluA2 levels in a wide variety of neurons that display tonic activity, such as olfactory neurons, glutamatergic neurons in the lateral habenula, neostriatal cholinergic interneurons, auditory neurons in the deep cerebellar nucleus (DCN), and GABAergic interneuro…”
Background
Activation and Blockade of Serotonin-4 Receptors in the Lateral Habenula Produce Antidepressant Effects in the Hemiparkinsonian Rat
Guo, Y., Zhang, L., Zhang, J., Lv, S.-X., Du, C., Wang, T., Wang, H., Xie, W., & Liu, J. (2020) · Neuropsychobiology · doi:10.1159/000508680 · Cited by 16
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Manganese-Enhanced MRI Reflects Both Activity-Independent and Activity-Dependent Uptake within the Rat Habenulomesencephalic Pathway
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“A higher release probability at synapses on VTA-projecting LHb neurons enhanced learned helplessness behaviors in the acute or congenital learned helplessness rat model of depression (55).”
BackgroundInfluential
Whole-brain connections of glutamatergic neurons in the mouse lateral habenula in both sexes
Huang, H., Liu, X., Wang, L., & Wang, F. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00611-5 · Cited by 17
“Additionally, cellular and synaptic mechanisms that promote the activity of LHb glutamatergic neurons have been linked to depressive-like behaviors in animal models [24, 25], despite well-documented sex differences in major depressive disorder in clinical reports [26].”
Background
The effects of prenatal and postnatal environmental interaction: Prenatal environmental adaptation hypothesis
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“, 2008) as well neuronal activity in the epithalamic nucleus, habenula (Li et al., 2011; Yu et al., 2002).”
Acute 5 Hz deep brain stimulation of the lateral habenula is associated with depressive-like behavior in male wild-type Wistar rats
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Lateral habenula dysfunctions in Tm4sf2−/y mice model for neurodevelopmental disorder
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The Habenula in the Link Between ADHD and Mood Disorder
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Circadian Influences on the Habenula and Their Potential Contribution to Neuropsychiatric Disorders
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“More specifically, elevated neural activity in the rodent LHb has been associated with various depression models including learned helplessness (Li et al., 2011; Cui et al., 2018), chronic stress (Cerniauskas et al.”
Background
Stria medullaris innervation follows the transcriptomic division of the habenula
Juárez-Leal, I., Carretero-Rodríguez, E., Almagro‐García, F., Martı́nez, S., Echevarrı́a, D., & Puelles, E. (2022) · Scientific Reports · doi:10.1038/s41598-022-14328-1 · Cited by 13
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The impact of hemodynamic variability and signal mixing on the identifiability of effective connectivity structures in BOLD fMRI
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“On the other hand, we have state- space models which infer effective connectivity on the basis of the temporal patterns in the dynamics [e.g., Dynamic Causal Modeling, DCM (Friston, Harrison, & Penny, 2003), Granger Causality, GC, (Granger, 1969; Roebroeck, Formisano, & Goebel, 2011; Seth, Barrett, & Barnett, 2015; So…”
Influential

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
ORCID: Li, Bo
Chung, ChiHye
Proulx, Christophe D.
Schulz, Daniela
Malinow, Roberto
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-02
Volume: 470
Issue: 7335
Pages: 535-539
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09742
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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Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

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