Kevin M Manz1, Lillian J Brady2, Erin S Calipari3, Brad A Grueter4. 1. Medical Scientist Training Program, Vanderbilt University, Nashville, Tennessee; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: kevin.m.manz@vanderbilt.edu. 2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee. 3. Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee. 4. Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: brad.grueter@vumc.org.
Abstract
BACKGROUND: Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. METHODS: We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell. RESULTS: HA enhanced CIN output through an H2 receptor (H2R)-dependent effector pathway requiring Ca2+-activated small-conductance K+ channels, with a small but discernible contribution from H1Rs and synaptic H3Rs. While PV-IN excitability was unaffected by HA, presynaptic H3Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A) signaling. H3R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus-evoked feedforward inhibition and increased mesoaccumbens dopamine release. CONCLUSIONS: HA targets H1R, H2R, and H3Rs in the NAc shell to engage synapse- and cell type-specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain.
BACKGROUND: Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. METHODS: We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell. RESULTS: HA enhanced CIN output through an H2 receptor (H2R)-dependent effector pathway requiring Ca2+-activated small-conductance K+ channels, with a small but discernible contribution from H1Rs and synaptic H3Rs. While PV-IN excitability was unaffected by HA, presynaptic H3Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A) signaling. H3R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus-evoked feedforward inhibition and increased mesoaccumbens dopamine release. CONCLUSIONS: HA targets H1R, H2R, and H3Rs in the NAc shell to engage synapse- and cell type-specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain.
Authors: G Drutel; N Peitsaro; K Karlstedt; K Wieland; M J Smit; H Timmerman; P Panula; R Leurs Journal: Mol Pharmacol Date: 2001-01 Impact factor: 4.436
Authors: Kevin M Manz; Dipanwita Ghose; Brandon D Turner; Anne Taylor; Jennifer Becker; Carrie A Grueter; Brad A Grueter Journal: Cell Rep Date: 2020-07-28 Impact factor: 9.423
Authors: Melissa A Stouffer; Catherine A Woods; Jyoti C Patel; Christian R Lee; Paul Witkovsky; Li Bao; Robert P Machold; Kymry T Jones; Soledad Cabeza de Vaca; Maarten E A Reith; Kenneth D Carr; Margaret E Rice Journal: Nat Commun Date: 2015-10-27 Impact factor: 14.919