title: Single rodent mesohabenular axons release glutamate and GABA.
abstract: The lateral habenula (LHb) is involved in reward, aversion, addiction and depression through descending interactions with several brain structures, including the ventral tegmental area (VTA). The VTA provides reciprocal inputs to LHb, but their actions are unclear. Here we show that the majority of rat and mouse VTA neurons innervating LHb coexpress markers for both glutamate signaling (vesicular glutamate transporter 2; VGluT2) and GABA signaling (glutamic acid decarboxylase; GAD, and vesicular GABA transporter; VGaT). A single axon from these mesohabenular neurons coexpresses VGluT2 protein and VGaT protein and, surprisingly, establishes symmetric and asymmetric synapses on LHb neurons. In LHb slices, light activation of mesohabenular fibers expressing channelrhodopsin2 driven by VGluT2 (Slc17a6) or VGaT (Slc32a1) promoters elicits release of both glutamate and GABA onto single LHb neurons. In vivo light activation of mesohabenular terminals inhibits or excites LHb neurons. Our findings reveal an unanticipated type of VTA neuron that cotransmits glutamate and GABA and provides the majority of mesohabenular inputs.
authors.affiliation: Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Root
authors.affiliation: Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Mejias-Aponte
authors.affiliation: Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
authors.affiliation: Neuronal Networks Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA.
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D019262:Habenula / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D017207:Rats, Sprague-Dawley; D012201:Reward; D013569:Synapses / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid