title: GABAergic neurons in the ventral tegmental area receive dual GABA/enkephalin-mediated inhibitory inputs from the bed nucleus of the stria terminalis.
abstract: Activation of mu-opioid receptor (MOR) disinhibits dopaminergic neurons in the ventral tegmental area (VTA) through inhibition of γ-aminobutyric acid (GABA)ergic neurons. This mechanism is thought to play a pivotal role in mediating reward behaviors. Here, we characterised VTA-projecting enkephalinergic neurons in the anterior division of the bed nucleus of the stria terminalis (BST) and investigated their targets by examining MOR expression in the VTA. In the BST, neurons expressing preproenkephalin mRNA were exclusively GABAergic, and constituted 37.2% of the total GABAergic neurons. Using retrograde tracer injected into the VTA, 21.6% of VTA-projecting BST neurons were shown to express preproenkephalin mRNA. Enkephalinergic projections from the BST exclusively formed symmetrical synapses onto the dendrites of VTA neurons. In the VTA, 74.1% of MOR mRNA-expressing neurons were GABAergic, with the rest being glutamatergic neurons expressing type-2 vesicular glutamate transporter mRNA. However, MOR mRNA was below the detection threshold in dopaminergic neurons. By immunohistochemistry, MOR was highly expressed on the extrasynaptic membranes of dendrites in GABAergic VTA neurons, including dendrites innervated by BST-VTA projection terminals. MOR was also expressed weakly on GABAergic and glutamatergic terminals in the VTA. Given that GABAA α1 is expressed at GABAergic BST-VTA synapses on dendrites of GABAergic neurons [T. Kudo et al. (2012) J. Neurosci., 32, 18035-18046], our results collectively indicate that the BST sends dual inhibitory outputs targeting GABAergic VTA neurons; GABAergic inhibition via 'wired' transmission, and enkephalinergic inhibition via 'volume' transmission. This dual inhibitory system provides the neural substrate underlying the potent disinhibitory control over dopaminergic VTA neurons exerted by the BST.
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kudo
authors.forename: Kohtarou
authors.initials: K
authors.lastname: Konno
authors.forename: Motokazu
authors.initials: M
authors.lastname: Uchigashima
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition; D019581:Neuropil / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D012686:Septal Nuclei / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D004745:Enkephalins; C546241:Gabra1 protein, mouse; D011498:Protein Precursors; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D017450:Receptors, Opioid, mu; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D005680:gamma-Aminobutyric Acid; C033660:preproenkephalin
keywords: GABAergic neuron; bed nucleus of the stria terminalis; dopaminergic neuron; immunohistochemistry; mouse; ventral tegmental area