title: α(2A)-adrenergic receptors filter parabrachial inputs to the bed nucleus of the stria terminalis.
abstract: α2-adrenergic receptors (AR) within the bed nucleus of the stria terminalis (BNST) reduce stress-reward interactions in rodent models. In addition to their roles as autoreceptors, BNST α(2A)-ARs suppress glutamatergic transmission. One prominent glutamatergic input to the BNST originates from the parabrachial nucleus (PBN) and consists of asymmetric axosomatic synapses containing calcitonin gene-related peptide (CGRP) and vGluT2. Here we provide immunoelectron microscopic data showing that many asymmetric axosomatic synapses in the BNST contain α(2A)-ARs. Further, we examined optically evoked glutamate release ex vivo in BNST from mice with virally delivered channelrhodopsin2 (ChR2) expression in PBN. In BNST from these animals, ChR2 partially colocalized with CGRP, and activation generated EPSCs in dorsal anterolateral BNST neurons that elicited two cell-type-specific outcomes: (1) feedforward inhibition or (2) an EPSP that elicited firing. We found that the α(2A)-AR agonist guanfacine selectively inhibited this PBN input to the BNST, preferentially reducing the excitatory response in ex vivo mouse brain slices. To begin to assess the overall impact of α(2A)-AR control of this PBN input on BNST excitatory transmission, we used a Thy1-COP4 mouse line with little postsynaptic ChR2 expression nor colocalization of ChR2 with CGRP in the BNST. In slices from these mice, we found that guanfacine enhanced, rather than suppressed, optogenetically initiated excitatory drive in BNST. Thus, our study reveals distinct actions of PBN afferents within the BNST and suggests that α(2A)-AR agonists may filter excitatory transmission in the BNST by inhibiting a component of the PBN input while enhancing the actions of other inputs.
authors.affiliation: Department of Molecular Physiology & Biophysics, Neuroscience Program in Substance Abuse, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Flavin
authors.affiliation: Department of Molecular Physiology & Biophysics, John F. Kennedy Center for Research on Human Development, and Neuroscience Program in Substance Abuse, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615.
authors.forename: Robert T
authors.identifier: http://orcid.org/0000-0002-1235-3802
authors.initials: RT
authors.lastname: Matthews
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: E Chris
authors.initials: EC
authors.lastname: Muly
authors.affiliation: Department of Molecular Physiology & Biophysics, John F. Kennedy Center for Research on Human Development, and Neuroscience Program in Substance Abuse, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, danny.winder@vanderbilt.edu.
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000166:cytology / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012686:Septal Nuclei / Q000166:cytology* / Q000502:physiology*; D017552:Solitary Nucleus / Q000166:cytology* / Q000502:physiology*
chemical_list: D018341:Receptors, Adrenergic, alpha-2
keywords: adrenergic receptors; bed nucleus of the stria terminalis; excitatory transmission; extended amygdala; norephinephrine; optogenetics