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
Affiliations
Nicole A. Crowley
Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Daniel W. Bloodgood
Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
J. Andrew Hardaway
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Alexis M. Kendra
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jordan G. McCall
Neuroscience Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Ream Al-Hasani
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Nora M. McCall
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Waylin Yu
Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Zachary L. Schools
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Michael J. Krashes
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Bradford B. Lowell
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Jennifer L. Whistler
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, CA, 94806, USA
Michael R. Bruchas
Neuroscience Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA
Thomas L. Kash
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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.
