Targeting PFC interneurons for personalized treatments in OUD

Abstract New treatments are desperately needed for opioid use disorder (OUD). Approved medications and available treatments do not adequately address long-term changes in mood, motivation, and cravings. The prefrontal cortex (PFC) is involved in persistent OUD symptoms, and preclinical studies indicate the PFC can be targeted

to attenuate opioid-seeking and affective disturbances. Electroencephalography (EEG) is an affordable, accessible, and portable neurophysiological approach to assess PFC function in the clinic and in rodent models. Despite these strengths, we currently have a limited understanding of how PFC EEG frequency bands

map onto discrete cell types, electroconductive molecules, and neuromodulatory elements. Delineating these bidirectional relationships should be instrumental in developing biomarkers for individualized treatments for OUD and in assessing target engagement for new medications. Towards these goals, this proposal aims to

characterize EEG signatures following maladaptive opioid use and PFC interneuron modulation. Individuals with OUD, on a population level, display enhanced power in the theta (θ) band in frontal areas, but how this disease signature relates to the function of discrete cell types is not known. At the cellular level,

inhibitory neurons (INs) comprise only 20% of PFC neurons, but extraordinary connectivity and specializations enable INs to govern PFC circuit function and oscillatory activities. The two predominant IN subtypes in deep layers of PFC exhibit mutually exclusive expression of parvalbumin (PV) or somatostatin (SST), and

optogenetic studies have revealed that these cell types differentially guide PFC oscillatory activities. Our goal is to define how neural activity within PV-INs and SST-INs contributes to PFC EEG signatures, through combination fiber photometry calcium imaging and quantitative EEG. In parallel, we will assess how EEG

signatures and IN function are altered by chronic opioid use by using a long-access vapor fentanyl self- administration model. Finally, we will scrutinize underlying physiological mechanisms using whole cell electrophysiology and assess their contribution to fentanyl-seeking and abstinence-associated affective

disturbances in behavioral studies. Our goals are: Aim 1: Test that individual differences in θ power and PFC IN physiology correlate with fentanyl self- administration and affective disturbances in abstinence. Aim 2: Test that PFC PV-INs and SST-INs bidirectionally modulate θ power following opioid use.

Aim 3: Test that PFC PV-INs and SST-INs regulate opioid use behaviors and affective disturbances. Together, the results of these comprehensive studies will improve our understanding of how several cell type- specific signaling pathways regulate PFC circuit function and behavioral changes related to OUD. We expect

these findings will lay the foundation for the development of next-generation treatments for OUD.