Accumbal Histamine Signaling Engages Discrete Interneuron Microcircuits

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.