Accumbal Histamine Signaling Engages Discrete Interneuron Microcircuits

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 (PV)-expressing fast-spiking interneurons (PV-INs) and tonically-active cholinergic interneurons (CINs) in the NAc shell (NAcSh). Results HA enhances 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 signaling. H3R-dependent plasticity was differentially expressed at mediodorsal thalamus (MDT) and prefrontal cortex (PFC) synapses onto PV-INs, with MDT synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN and CIN-controlled microcircuits, including near-complete collapse of MDT-evoked feedforward inhibition and increased mesoaccumbens dopamine release. Conclusions HA targets H1R, H2R, and H3Rs in the NAcSh 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.