A Unique Population of Ventral Tegmental Area Neurons Inhibits the Lateral Habenula to Promote Reward

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2013 Nov 26

PMID 24267654

Citations 184

Authors

Alice M Stamatakis

Joshua H Jennings

Randall L Ung

Grace A Blair

Richard J Weinberg

Rachael L Neve

Frederick Boyce

Joanna Mattis

Charu Ramakrishnan

Karl Deisseroth

Garret D Stuber

Affiliations

Soon will be listed here.

Abstract

Lateral habenula (LHb) neurons convey aversive and negative reward conditions through potent indirect inhibition of ventral tegmental area (VTA) dopaminergic neurons. Although VTA dopaminergic neurons reciprocally project to the LHb, the electrophysiological properties and the behavioral consequences associated with selective manipulations of this circuit are unknown. Here, we identify an inhibitory input to the LHb arising from a unique population of VTA neurons expressing dopaminergic markers. Optogenetic activation of this circuit resulted in no detectable dopamine release in LHb brain slices. Instead, stimulation produced GABA-mediated inhibitory synaptic transmission, which suppressed the firing of postsynaptic LHb neurons in brain slices and increased the spontaneous firing rate of VTA dopaminergic neurons in vivo. Furthermore, in vivo activation of this pathway produced reward-related phenotypes that were dependent on intra-LHb GABAA receptor signaling. These results suggest that noncanonical inhibitory signaling by these hybrid dopaminergic-GABAergic neurons act to suppress LHb output under rewarding conditions.

Citing Articles

Lateral habenula induces cognitive and affective dysfunctions in mice with neuropathic pain via an indirect pathway to the ventral tegmental area.

Liu Y, Wu K, Dong Y, Jia R, Chen X, Ge A Neuropsychopharmacology. 2025; .

PMID: 40089563 DOI: 10.1038/s41386-025-02084-5.

Cross-species dissection of the modular role of the ventral tegmental area in depressive disorders.

Morris L, Beltran J, Beltran J, Murrough J, Morel C Neuroscience. 2025; 569:248-266.

PMID: 39914519 PMC: 11885014. DOI: 10.1016/j.neuroscience.2025.02.008.

Input-output specific orchestration of aversive valence in lateral habenula during stress dynamics.

Huang T, Guo X, Huang X, Yi C, Cui Y, Dong Y J Zhejiang Univ Sci B. 2025; 25(12):1055-1065.

PMID: 39743292 PMC: 11693385. DOI: 10.1631/jzus.B2300933.

Monosynaptic ventral tegmental area glutamate projections to the locus coeruleus enhance aversive processing.

Parker K, Kuo C, Buckley A, Patterson A, Duong V, Hunter S bioRxiv. 2024; .

PMID: 39713345 PMC: 11661122. DOI: 10.1101/2024.10.04.615025.

The Lateral Habenula Is Necessary for Maternal Behavior in the Naturally Parturient Primiparous Mouse Dam.

Benedict J, Cudmore R, Oden D, Spruell A, Linden D eNeuro. 2024; 12(1).

PMID: 39689968 PMC: 11734883. DOI: 10.1523/ENEURO.0092-24.2024.

References

Jennings J, Sparta D, Stamatakis A, Ung R, Pleil K, Kash T . Distinct extended amygdala circuits for divergent motivational states. Nature. 2013; 496(7444):224-8. PMC: 3778934. DOI: 10.1038/nature12041. View

Jhou T, Good C, Rowley C, Xu S, Wang H, Burnham N . Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J Neurosci. 2013; 33(17):7501-12. PMC: 3865501. DOI: 10.1523/JNEUROSCI.3634-12.2013. View

Ungless M, Magill P, Bolam J . Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science. 2004; 303(5666):2040-2. DOI: 10.1126/science.1093360. View

Schultz W, Dayan P, Montague P . A neural substrate of prediction and reward. Science. 1997; 275(5306):1593-9. DOI: 10.1126/science.275.5306.1593. View

Balcita-Pedicino J, Omelchenko N, Bell R, Sesack S . The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus. J Comp Neurol. 2011; 519(6):1143-64. PMC: 4054696. DOI: 10.1002/cne.22561. View

McCulloch J, Savaki H, Sokoloff L . Influence of dopaminergic systems on the lateral habenular nucleus of the rat. Brain Res. 1980; 194(1):117-24. DOI: 10.1016/0006-8993(80)91322-0. View

Kim U, Lee T . Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. Eur J Neurosci. 2012; 35(8):1253-69. DOI: 10.1111/j.1460-9568.2012.08030.x. View

Meier C, Herrling P . N-methyl-D-aspartate induces regular firing patterns in the cat lateral habenula in vivo. Neuroscience. 1993; 52(4):951-9. DOI: 10.1016/0306-4522(93)90542-n. View

Poller W, Madai V, Bernard R, Laube G, Veh R . A glutamatergic projection from the lateral hypothalamus targets VTA-projecting neurons in the lateral habenula of the rat. Brain Res. 2013; 1507:45-60. DOI: 10.1016/j.brainres.2013.01.029. View

10.

Ford C, Mark G, Williams J . Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location. J Neurosci. 2006; 26(10):2788-97. PMC: 3623681. DOI: 10.1523/JNEUROSCI.4331-05.2006. View

11.

Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verriele L, Carpentier N . Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes. J Pharmacol Exp Ther. 2002; 303(2):815-22. DOI: 10.1124/jpet.102.039883. View

12.

Cohen J, Haesler S, Vong L, Lowell B, Uchida N . Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature. 2012; 482(7383):85-8. PMC: 3271183. DOI: 10.1038/nature10754. View

13.

Tsai H, Zhang F, Adamantidis A, Stuber G, Bonci A, De Lecea L . Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science. 2009; 324(5930):1080-4. PMC: 5262197. DOI: 10.1126/science.1168878. View

14.

Cruikshank S, Urabe H, Nurmikko A, Connors B . Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons. Neuron. 2010; 65(2):230-45. PMC: 2826223. DOI: 10.1016/j.neuron.2009.12.025. View

15.

Hnasko T, Hjelmstad G, Fields H, Edwards R . Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J Neurosci. 2012; 32(43):15076-85. PMC: 3685320. DOI: 10.1523/JNEUROSCI.3128-12.2012. View

16.

Lammel S, Ion D, Roeper J, Malenka R . Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron. 2011; 70(5):855-62. PMC: 3112473. DOI: 10.1016/j.neuron.2011.03.025. View

17.

Phillips P, Stuber G, Heien M, Wightman R, Carelli R . Subsecond dopamine release promotes cocaine seeking. Nature. 2003; 422(6932):614-8. DOI: 10.1038/nature01476. View

18.

Kuhlman S, Huang Z . High-resolution labeling and functional manipulation of specific neuron types in mouse brain by Cre-activated viral gene expression. PLoS One. 2008; 3(4):e2005. PMC: 2289876. DOI: 10.1371/journal.pone.0002005. View

19.

Sparta D, Stamatakis A, Phillips J, Hovelso N, van Zessen R, Stuber G . Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nat Protoc. 2011; 7(1):12-23. PMC: 8647635. DOI: 10.1038/nprot.2011.413. View

20.

Margolis E, Coker A, Driscoll J, Lemaitre A, Fields H . Reliability in the identification of midbrain dopamine neurons. PLoS One. 2010; 5(12):e15222. PMC: 3000317. DOI: 10.1371/journal.pone.0015222. View