Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit

Nicole A Crowley; Daniel W Bloodgood; J Andrew Hardaway; Alexis M Kendra; Jordan G McCall; Ream Al-Hasani; Nora M McCall; Waylin Yu; Zachary L Schools; Michael J Krashes; Bradford B Lowell; Jennifer L Whistler; Michael R Bruchas; Thomas L Kash

doi:10.1016/j.celrep.2016.02.069

Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit

Cell Rep. 2016 Mar 29;14(12):2774-83. doi: 10.1016/j.celrep.2016.02.069. Epub 2016 Mar 17.

Affiliations

¹ 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.
² Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ 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.
⁴ 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.
⁵ Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ 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.
⁷ 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.
⁸ Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, CA, 94806, USA.
⁹ 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.

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.

Publication types

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

MeSH terms

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
Amygdala / drug effects*
Amygdala / metabolism
Animals
Anxiety*
Behavior, Animal / drug effects
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Channelrhodopsins
Dynorphins / pharmacology*
Evoked Potentials / drug effects
Glutamic Acid / pharmacology
Imidazoles / pharmacology
Male
Maze Learning / drug effects
Memory / drug effects
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Microscopy, Fluorescence
Patch-Clamp Techniques
Pyridines / pharmacology
Receptors, Opioid, kappa / agonists
Receptors, Opioid, kappa / genetics
Receptors, Opioid, kappa / metabolism
Septal Nuclei / physiology
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Channelrhodopsins
Imidazoles
Pyridines
Receptors, Opioid, kappa
Glutamic Acid
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
Dynorphins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
p38 Mitogen-Activated Protein Kinases
SB 203580

Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding