title: Three types of neurochemical projection from the bed nucleus of the stria terminalis to the ventral tegmental area in adult mice.
abstract: Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) play crucial roles in motivational control of behaviors, and their activity is regulated directly or indirectly via GABAergic neurons by extrinsic afferents from various sources, including the bed nucleus of the stria terminalis (BST). Here, the neurochemical composition of VTA-projecting BST neurons and their outputs to the VTA were studied in adult mouse brains. By combining retrograde tracing with fluorescence in situ hybridization for 67 kDa glutamate decarboxylase (GAD67) and vesicular glutamate transporters (VGluTs), VTA-targeting BST neurons were classified into GAD67-positive (GAD67(+))/VGluT3-negative (VGluT3(-)), GAD67(+)/VGluT3(+), and VGluT2(+) neurons, of which GAD67(+)/VGluT3(-) neurons constituted the majority (∼90%) of VTA-projecting BST neurons. GABAergic efferents from the BST formed symmetrical synapses on VTA neurons, which were mostly GABAergic neurons, and expressed GABA(A) receptor α1 subunit on their synaptic and extrasynaptic membranes. In the VTA, VGluT3 was detected in terminals expressing vesicular inhibitory amino acid transporter (VIAAT), plasmalemmal serotonin transporter, or neither. Of these, VIAAT(+)/VGluT3(+) terminals, which should include those from GAD67(+)/VGluT3(+) BST neurons, formed symmetrical synapses. When single axons from VGluT3(+) BST neurons were examined, almost all terminals were labeled for VIAAT, whereas VGluT3 was often absent from terminals with high VIAAT loads. VGluT2(+) terminals in the VTA exclusively formed asymmetrical synapses, which expressed AMPA receptors on postsynaptic membrane. Therefore, the major mode of the BST-VTA projection is GABAergic, and its activation is predicted to disinhibit VTA DAergic neurons. VGluT2(+) and VGluT3(+) BST neurons further supply additional projections, which may principally convey excitatory or inhibitory inputs, respectively, to the VTA.
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kudo
authors.forename: Motokazu
authors.initials: M
authors.lastname: Uchigashima
authors.forename: Taisuke
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Kohtarou
authors.initials: K
authors.lastname: Konno
authors.forename: Miwako
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D059330:GABAergic Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009434:Neural Pathways / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D012686:Septal Nuclei / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D050599:Vesicular Glutamate Transport Protein 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1