Accumbal Histamine Signaling Engages Discrete Interneuron Microcircuits

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.

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.

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.

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.