Ventral pallidal perineuronal nets regulate opioid relapse.

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.

Study at a glance

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.