title: Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit.
abstract: Kappa opioid receptors (KORs) are involved in a variety of aversive behavioral states, including anxiety. To date, a circuit-based mechanism for KOR-driven anxiety has not been described. Here, we show that activation of KORs inhibits glutamate release from basolateral amygdala (BLA) inputs to the bed nucleus of the stria terminalis (BNST) and occludes the anxiolytic phenotype seen with optogenetic activation of BLA-BNST projections. In addition, deletion of KORs from amygdala neurons results in an anxiolytic phenotype. Furthermore, we identify a frequency-dependent, optically evoked local dynorphin-induced heterosynaptic plasticity of glutamate inputs in the BNST. We also find that there is cell type specificity to the KOR modulation of the BLA-BNST input with greater KOR-mediated inhibition of BLA dynorphin-expressing neurons. Collectively, these results provide support for a model in which local dynorphin release can inhibit an anxiolytic pathway, providing a discrete therapeutic target for the treatment of anxiety disorders.
authors.affiliation: Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Crowley
authors.affiliation: Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bloodgood
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Hardaway
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kendra
authors.affiliation: Neuroscience Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jordan G
authors.initials: JG
authors.lastname: McCall
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ream
authors.initials: R
authors.lastname: Al-Hasani
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nora M
authors.initials: NM
authors.lastname: McCall
authors.affiliation: Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Waylin
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Schools
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krashes
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.affiliation: Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, CA, 94806, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
authors.affiliation: Neuroscience Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bruchas
authors.affiliation: Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: tkash@med.unc.edu.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D000075402:Channelrhodopsins; D004399:Dynorphins / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008856:Microscopy, Fluorescence; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012686:Septal Nuclei / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; D007093:Imidazoles; D011725:Pyridines; D017473:Receptors, Opioid, kappa; D018698:Glutamic Acid; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580