Cited by 696Neurotransmitter Receptor Influence on BehaviorMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses.

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Jhou, Thomas C., Fields, Howard L., Baxter, Mark G., Saper, Clifford B., Holland, Peter C.·2009·Neuron

Abstract

Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons.

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Crossref · 10.1016/j.neuron.2009.02.001

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  • GABAergic inputs to the VTA come from a list of regions including substantia nigra pars reticulata, nucleus accumbens, ventral pallidum/globus pallidus, laterodorsal tegmentum, pedunculopontine nuclei, diagonal band of Broca, bed nucleus of the stria terminalis, and rostromedial tegmental nucleus.

    “GABAergic inputs arrive at the VTA from the substantia nigra pars reticulata, nucleus accumbens, ventral pallidum/globus pallidus, laterodorsal tegmentum, pedunculopontine nuclei, diagonal band of Broca, bed nucleus of the stria terminalis, and the caudal tip of the VTA, termed the rostromedial tegmental nucleus (RMTg) (Geisler and Zahm 2005; Jhou et al. 2009; Kaufling et al. 2009).”

    From Nicotine Withdrawal (2015) · cites this paper as Jhou et al. 2009

    The Introduction and Results identify the RMTg as a GABAergic projection to the VTA, and the Discussion (‘Anatomic specificity of RMTg function’) identifies GABAergic VTA afferents from the nucleus accumbens, ventral pallidum, and substantia nigra pars reticulata. The copy does not establish the full attributed list as GABAergic VTA inputs; in particular, it does not do so for the laterodorsal tegmentum, diagonal band of Broca, or bed nucleus of the stria terminalis. Page numbers were not available in the indexed passages. (LLM, conf=0.85)

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  • Based on current knowledge, likely pathways for VLPAG outputs are that they may relay in the rostral ventral medulla to modulate premotor neurons that project to the spinal cord, or they may relay in the rostral ventral midbrain onto dopaminergic neurons of the substantia nigra; in either case, those neurons would modulate motor loops in the striatum, producing immobility.

    “Based on current knowledge, the likely pathways for VLPAG outputs are as follows: the outputs may relay in the rostral ventral medulla to modulate premotor neurons that project to the spinal cord, or they may relay in the rostral ventral midbrain onto dopaminergic neurons of the substantia nigra; in either case, those neurons would modulate, in turn, motor loops in the striatum (basal ganglia),”

    From Fear and the Defense Cascade (2015) · cites this paper as [66]

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  • The LHb projects densely to the RMTg and has a well-established inhibitory effect on midbrain DA neuron firing.

    “In particular, the LHb projects densely to the rostromedial tegmental nucleus (RMTg) (Jhou et al. 2009), and has a well-established inhibitory effect on the firing of midbrain DA neurons (Lecourtier and Kelly 2007;Matsumoto and Hikosaka 2009;Hikosaka 2010;Bromberg-Martin and Hikosaka 2011).”

    From Mechanisms of Nicotine Addiction (2021) · cites this paper as Jhou et al. 2009

  • Changes in DAergic activity can signal punishment, aversion, or lack of expected reward, not only hedonic effects.

    “Although it was originally postulated that the DA released from the VTA only mediates the hedonic or pleasurable effects of natural reinforcers, it is now clear that changes in DAergic activity can also signal punishment, aversion, or lack of expected reward [53–58].”

    From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [54]

  • Neurons in the rostromedial tegmental nucleus, which receive a major input from the lateral habenula, project to VTA DA neurons and are activated after food deprivation.

    “Moreover, neurons in the rostromedial tegmental nucleus, which receive a major input from the lateral habenula, project to VTA DA neurons and are activated after food deprivation (158).”

    From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [158]

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References 92 · Cited by 696

Research works printed but not linked: 2

  1. Holstege G Bandler R Saper CB 1996 The emotional motor system Prog Brain Res 107 3 6 8782510
  2. Wise RA 1994 A brief history of the anhedonia hypothesis Appetite: Neural and Behavioural Bases Legg CR Booth DA Oxford University Press 243 263

Authors
Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B., & Holland, P. C.
Affiliations
  • National Institute on Drug Abuse (US)
  • University of California, San Francisco (US)
  • University of Oxford (GB)
  • Beth Israel Deaconess Medical Center (US)
  • Johns Hopkins University (US)
Corresponding author
Jhou, Thomas C.
Venue
Neuron
Publisher
Elsevier BV
Published
2009-03
Volume
61
Issue
5
Pages
786-800
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2093398004
Cited by
696
References
92
Citations by year
2026: 23 · 2025: 23 · 2024: 71 · 2023: 30 · 2022: 37 · 2021: 38 · 2020: 45 · 2019: 33 · 2018: 50 · 2017: 33 · 2016: 46 · 2015: 53 · 2014: 47 · 2013: 50 · 2012: 43
FWCI
15.94
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (Z99 DA999999)
  • National Heart, Lung, and Blood Institute (HL 60292, P50HL060292)
  • National Institute of Mental Health (R01MH060179, R01MH053667, MH53667, R37MH053667, MH 60179)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
rostromedial tegmental nucleus, lateral habenula, midbrain dopaminergic neurons, aversive stimuli, fear behavior, GABAergic afferents, reward processing, extended amygdala, periaqueductal gray, septum, footshock, food deprivation, reward omission, Fos induction, inhibitory interneurons
MeSH terms
Action Potentials, Afferent Pathways, Animals, Appetitive Behavior, Avoidance Learning, Conditioning, Classical, Cues, Dopamine, Electroshock, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Male, Mesencephalon, Motor Activity, Neurons, Oncogene Proteins v-fos, Rats, Sprague-Dawley, Maze Learning, Pedunculopontine Tegmental Nucleus, Rats

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