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Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior.
Mol Psychiatry 2018; 23(1):143-153MP

Abstract

The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular γ-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD-assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function.

Authors+Show Affiliations

Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA. Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Department of Psychology, University of Vermont, Burlington, VT, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA.Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. Department of Cell Biology and Physiology, and Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA.Department of Psychology, University of Vermont, Burlington, VT, USA.Department of Psychology, University of Vermont, Burlington, VT, USA.Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27956747

Citation

Mazzone, C M., et al. "Acute Engagement of Gq-mediated Signaling in the Bed Nucleus of the Stria Terminalis Induces Anxiety-like Behavior." Molecular Psychiatry, vol. 23, no. 1, 2018, pp. 143-153.
Mazzone CM, Pati D, Michaelides M, et al. Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry. 2018;23(1):143-153.
Mazzone, C. M., Pati, D., Michaelides, M., DiBerto, J., Fox, J. H., Tipton, G., ... Kash, T. L. (2018). Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Molecular Psychiatry, 23(1), pp. 143-153. doi:10.1038/mp.2016.218.
Mazzone CM, et al. Acute Engagement of Gq-mediated Signaling in the Bed Nucleus of the Stria Terminalis Induces Anxiety-like Behavior. Mol Psychiatry. 2018;23(1):143-153. PubMed PMID: 27956747.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. AU - Mazzone,C M, AU - Pati,D, AU - Michaelides,M, AU - DiBerto,J, AU - Fox,J H, AU - Tipton,G, AU - Anderson,C, AU - Duffy,K, AU - McKlveen,J M, AU - Hardaway,J A, AU - Magness,S T, AU - Falls,W A, AU - Hammack,S E, AU - McElligott,Z A, AU - Hurd,Y L, AU - Kash,T L, Y1 - 2016/12/13/ PY - 2015/12/28/received PY - 2016/09/21/revised PY - 2016/10/11/accepted PY - 2016/12/14/pubmed PY - 2018/12/18/medline PY - 2016/12/14/entrez SP - 143 EP - 153 JF - Molecular psychiatry JO - Mol. Psychiatry VL - 23 IS - 1 N2 - The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular γ-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD-assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/27956747/Acute_engagement_of_Gq_mediated_signaling_in_the_bed_nucleus_of_the_stria_terminalis_induces_anxiety_like_behavior_ L2 - http://dx.doi.org/10.1038/mp.2016.218 DB - PRIME DP - Unbound Medicine ER -