title: A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward.
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.
authors.affiliation: Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Stamatakis
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Jennings
authors.forename: Randall L
authors.initials: RL
authors.lastname: Ung
authors.forename: Grace A
authors.initials: GA
authors.lastname: Blair
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Frederick
authors.initials: F
authors.lastname: Boyce
authors.forename: Joanna
authors.initials: J
authors.lastname: Mattis
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: Garret D
authors.initials: GD
authors.lastname: Stuber
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D059290:Dopaminergic Neurons / Q000502:physiology; D055724:Electrophysiological Phenomena; D005260:Female; D019262:Habenula / Q000502:physiology*; D008297:Male; D008636:Mesencephalon / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D016634:Radiosurgery; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000502:physiology; D012201:Reward; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase