Inhibitory regulation of itch and associated negative emotions by ventral hippocampal neurons in rats

Itch is a sensory experience accompanied by negative emotions and evokes a strong desire to scratch. Under pathological conditions, severe and chronic itch-scratching and the associated negative emotions can form a vicious cycle, leading to treatment resistance and reduced QOL. Although the hippocampus regulates emotion and pain, its role in itch remains unclear. Using fiber photometry, we found that ventral hippocampus (vHPC) activity decreased during scratching and increased after the cessation of scratching. Pharmacogenetic activation of either global vHPC neurons or specific vHPC neurons projecting to the infralimbic cortex suppressed both scratching and itch-related conditioned place aversion. In contrast, selective activation of vHPC glutamatergic neurons projecting to the prelimbic cortex produced the opposite effect-significantly increasing scratching behavior without altering conditioned place aversion. Circuit mapping showed that both pyramidal neurons and gamma-aminobutyric acidergic neurons in the prelimbic cortex and infralimbic cortex receive approximately equal inputs from the vHPC; the projection from the vHPC to the infralimbic cortex is denser than that to the prelimbic cortex. These results provide initial evidence that global vHPC neuronal activity inhibits both itch-scratching behavior and its accompanying aversive states through the vHPC→infralimbic cortex pathway rather than the vHPC→prelimbic cortex pathway.