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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BackgroundInfluential
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“…LHb is emerging as a crucial area for emotional information transmission (Byun and Noh, 2024; Hikosaka et al., 2008; Lee et al., 2019; Matsumoto and Hikosaka, 2009a) and a key target for the treat-ment of mood disorders such as major depressive disorder (Li et al., 2011; Yang et al., 2018).”
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“Collaborative work in our laboratories [49,94] and others [43,45,47] investigating the behavioral constructs influenced by LHbL→RMTg→VTA circuitry suggest a role for this circuit in depression-related behaviors including the development of helplessness following an uncontrollable stressor [49] and the RMTg in response…”
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Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective
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InfluentialSelf-citation
NMDA-induced lesions of the nucleus accumbens core increase the innately rewarding saccharin solution intake and methamphetamine-induced conditioned place preference but not conditioned taste aversion in rats
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“The aLH rat is a well-studied animal model that has undergone validation by various research groups with behaviors akin to depression, such as despair and anhedonia, extensively studied (Li et al., 2011; Li et al., 2013; Park et al., 2017b).”
InfluentialSelf-citation
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Background
The mineralocorticoid receptor and extra-synaptic NMDA receptor in the lateral habenula involve in the vulnerability to early life stress in the maternal separation model
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BackgroundInfluential
Effects of Space Radiation and Combined Impact of Radiation and Other Spaceflight Factors on CNS Functions in Model Experiments on Animals
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Habenula contributions to negative self-cognitions
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Background

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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