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Lateral Habenula Stimulation Inhibits Rat Midbrain Dopamine Neurons through a GABAA Receptor-Mediated Mechanism
Open accessAbstract
Transient changes in the activity of midbrain dopamine neurons encode an error signal that contributes to associative learning. Although considerable attention has been devoted to the mechanisms contributing to phasic increases in dopamine activity, less is known about the origin of the transient cessation in firing accompanying the unexpected loss of a predicted reward. Recent studies suggesting that the lateral habenula (LHb) may contribute to this type of signaling in humans prompted us to evaluate the effects of LHb stimulation on the activity of dopamine and non-dopamine neurons of the anesthetized rat. Single-pulse stimulation of the LHb (0.5 mA, 100 micros) transiently suppressed the activity of 97% of the dopamine neurons recorded in the substantia nigra and ventral tegmental area. The duration of the cessation averaged approximately 85 ms and did not differ between the two regions. Identical stimuli transiently excited 52% of the non-dopamine neurons in the ventral midbrain. Electrolytic lesions of the fasciculus retroflexus blocked the effects of LHb stimulation on dopamine neurons. Local application of bicuculline but not the SK-channel blocker apamin attenuated the effects of LHb stimulation on dopamine cells, indicating that the response is mediated by GABA(A) receptors. These data suggest that LHb-induced suppression of dopamine cell activity is mediated indirectly by orthodromic activation of putative GABAergic neurons in the ventral midbrain. The habenulomesencephalic pathway, which is capable of transiently suppressing the activity of dopamine neurons at a population level, may represent an important component of the circuitry involved in encoding reward expectancy.
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“RMTg neurons, in turn, project to the VTA and are largely responsible for the predominantly inhibitory action of LHb projections onto VTA dopaminergic neurons [256].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [256]
In the citing paper
“Furthermore, electrical stimulation of the LHb inhibits the vast majority of DA neurons [69, 71, 72]. Such inhibition is not direct, but rather occurs through the stimulation of neurons in the rostromedial tegmental nucleus (RMTg) [73].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [72]
In the citing paper
“It was shown that the LHb has an inhibitory influence on dopaminergic neurons (Matsumoto and Hikosaka, 2007) via GABAergic interneurons in the rostromedial tegmental nucleus (Ji and Shepard, 2007; Jhou et al., 2009), which is reflected by the fact that lesioning of the habenula leads to an increase of cortical and striatal dopamine levels (Nishikawa et al., 1986).”
From Circuit Mechanisms of Reward, Anhedonia, and Depression (2019) · cites this paper as Ji and Shepard, 2007
In the citing paper
“In support of the latter result, habenula stimulation elicits inhibitory electrophysiological dopamine responses139–141 through an intermediate reticular nucleus138, rather than the excitatory responses required for a postulated aversive dopamine influence on place preferences137.”
From Dopamine reward prediction-error signalling: A two-component response (2016) · cites this paper as [140]
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Metadata
- Authors
- Ji, H., & Shepard, P. D.
- Affiliations
- University of Maryland, Baltimore (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-06-27
- Volume
- 27
- Issue
- 26
- Pages
- 6923-6930
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672239
- OpenAlex
- W2014239075
- Cited by
- 388
- References
- 65
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 15 · 2023: 15 · 2022: 16 · 2021: 19 · 2020: 15 · 2019: 15 · 2018: 29 · 2017: 25 · 2016: 34 · 2015: 22 · 2014: 23 · 2013: 28 · 2012: 24
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Institute of Mental Health (MH-072647, R24MH072647)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- lateral habenula, dopaminergic neurons, GABAA receptor, substantia nigra, ventral tegmental area, fasciculus retroflexus, reward expectancy, error signal, bicuculline, apamin, GABAergic neurons, midbrain dopamine, single-pulse stimulation
- MeSH terms
- Animals, Dopamine, Electric Stimulation, gamma-Aminobutyric Acid, Male, Mesencephalon, Neural Inhibition, Neural Pathways, Synaptic Transmission, Neurons, Receptors, GABA-A, Reward, Substantia Nigra, Rats, Sprague-Dawley, Ventral Tegmental Area, GABA Antagonists, Habenula, Potassium Channel Blockers, Rats
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.
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