Ventral pallidal perineuronal nets regulate opioid relapse.
bioRxiv : the preprint server for biology January 22, 2026 Margareth Nogueira, Giuseppe Giannotti, Carley N Miller et al.
Heroin self-administration increases the density of perineuronal nets (PNNs) in the ventral pallidum (VP) of mice. Depleting these PNNs with an enzyme prevents cue-induced reinstatement of heroin seeking, reduces the intrinsic excitability of parvalbumin-expressing VP neurons, strengthens inhibitory synaptic inputs onto them, and lowers Fos expression in those neurons after reinstatement. Chemogenetic activation of VP parvalbumin neurons rescues the suppressive effect of PNN depletion on heroin seeking, while chemogenetic inhibition mimics it. VP parvalbumin neurons and their PNNs are critical drivers of opioid seeking, and targeting PNNs in the VP may offer a novel therapeutic approach for relapse in opioid use disorder.