Ventral pallidal perineuronal nets regulate opioid relapse.
bioRxiv : the preprint server for biology – January 22, 2026
Source: PubMed
Summary
Heroin exposure boosts specialized brain structures called perineuronal nets (PNNs) in the ventral pallidum, a brain region critical for reward. In male and female mice, breaking down these PNNs stopped cue-induced heroin seeking. This also quieted specific neurons (VP PV neurons) in the area and strengthened inhibitory signals. Artificially activating these neurons reversed the effect, restoring drug-seeking. These results identify PNNs and VP PV neurons as key drivers of opioid seeking, suggesting that targeting PNNs offers a promising new path to treat opioid craving and relapse.
Abstract
Opioid use disorder remains a major health challenge worldwide. Neuronal activity in the ventral pallidum (VP) regulates opioid reward and relapse to opioid seeking but the underlying cellular mechanisms remain largely unknown. A sizable population of VP neurons previously linked to drug relapse expresses the calcium binding protein parvalbumin (VP PV ). Across the brain parvalbumin neurons are often ensheathed by perineuronal nets (PNNs), specialized extracellular structures that regulate intrinsic activity and constrain synaptic plasticity onto these neurons. The VP contains high levels of PNNs but the role of these structures in the neurophysiology of VP PV neurons and in relapse to opioid seeking has not been studied. To investigate whether VP PNNs are altered by opioid exposure, male and female mice were trained to self-administer intravenous heroin. We found that heroin increased the density of PNNs in the VP, and that an intracranial microinfusion of the PNN-degrading enzyme, chondroitinase ABC, prevented cue-induced reinstatement of heroin seeking. VP PNN depletion also reduced the intrinsic excitability of VP PV neurons, potentiated inhibitory synaptic inputs onto these cells, and diminished Fos expression in VP PV neurons following reinstatement. The suppressive effect of VP PNN depletion on heroin seeking was rescued by chemogenetic activation of VP PV neurons and mimicked by chemogenetic VP PV neuron inhibition. Taken together, our results identify VP PV neurons and their associated PNNs as critical drivers of opioid seeking. Given the key role of PNNs in regulating neural plasticity and memory processes, targeting PNNs in the VP could provide a useful novel therapeutic avenue for treating persistent craving and relapse in opioid use disorder.