Mesoaccumbal glutamate neurons drive reward via glutamate release but aversion via dopamine co-release.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 8809320 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4199 (Electronic) Linking ISSN: 08966273 NLM ISO Abbreviation: Neuron Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, Mass. : Cell Press, c1988-
    • Subject Terms:
      Glutamic Acid*/physiology ; Dopamine*; Mice ; Animals ; Reward ; Ventral Tegmental Area/physiology ; Dopaminergic Neurons/metabolism ; Vesicular Glutamate Transport Protein 2/genetics ; Vesicular Glutamate Transport Protein 2/metabolism ; Tyrosine 3-Monooxygenase/metabolism
    • Abstract:
      Ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) drive reward-related motivation. Although dopamine neurons are predominant, a substantial glutamatergic projection is also present, and a subset of these co-release both dopamine and glutamate. Optogenetic stimulation of VTA glutamate neurons not only supports self-stimulation but can also induce avoidance behavior, even in the same assay. Here, we parsed the selective contribution of glutamate or dopamine co-release from VTA glutamate neurons to reinforcement and avoidance. We expressed channelrhodopsin-2 (ChR2) in mouse VTA glutamate neurons in combination with CRISPR-Cas9 to disrupt either the gene encoding vesicular glutamate transporter 2 (VGLUT2) or tyrosine hydroxylase (Th). Selective disruption of VGLUT2 abolished optogenetic self-stimulation but left real-time place avoidance intact, whereas CRISPR-Cas9 deletion of Th preserved self-stimulation but abolished place avoidance. Our results demonstrate that glutamate release from VTA glutamate neurons is positively reinforcing but that dopamine release from VTA glutamate neurons can induce avoidance behavior.
      Competing Interests: Declaration of interests The authors declare no competing interests.
      (Copyright © 2023 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      P30 DA048736 United States DA NIDA NIH HHS; R01 DA036612 United States DA NIDA NIH HHS; F32 MH122192 United States MH NIMH NIH HHS; I01 BX003759 United States BX BLRD VA; K99 MH130688 United States MH NIMH NIH HHS; I01 BX005782 United States BX BLRD VA
    • Contributed Indexing:
      Keywords: CRISPR-Cas9; VGLUT2; dopamine; glutamate; reinforcement; reward; ventral tegmental area
    • Accession Number:
      3KX376GY7L (Glutamic Acid)
      VTD58H1Z2X (Dopamine)
      0 (Vesicular Glutamate Transport Protein 2)
      EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
    • Publication Date:
      Date Created: 20231212 Date Completed: 20240214 Latest Revision: 20240310
    • Publication Date:
      20240310
    • Accession Number:
      PMC10922836
    • Accession Number:
      10.1016/j.neuron.2023.11.002
    • Accession Number:
      38086374