Nucleus accumbens fast-spiking interneurons regulate opioid reward and addiction

Project Abstract Opioid addiction is a public health crisis, characterized by compulsive drug seeking and a pervasive vulnerability to relapse, with few therapeutic options available. The nucleus accumbens (NAc) is a central hub within reward circuitry and plays a critical role in the motivational value of drugs and drug-associated cues. Within the heterogeneous neuronal subtypes of the NAc exist the sparsely distributed fast-spiking interneurons (FSIs). The NAc FSIs receive strong excitatory inputs from cortical, thalamic and limbic regions and exert powerful inhibition over the local projection neurons, making them a prime candidate for translational therapeutic strategies to reduce the burden of the opioid abuse epidemic. The overall objectives of this application are to elucidate how NAc FSI circuitry responds to, and mediates, opioid self-administration. Under the primary mentorship of Dr. Patrick Rothwell at the University of Minnesota, Dr. Lefevre has utilized graduate training in molecular and behavioral pharmacology techniques, and post-doctoral training in ex- vivo electrophysiology to study adaptations in NAc circuitry in non-contingent opioid addiction models. This Pathway to Independence Award will provide the opportunity to broaden the candidate’s expertise to include in vivo fiber photometry calcium imaging, and chemogenetics, under the continued mentorship of Dr. Rothwell. To expand career development in addiction research, Dr. Lefevre will receive additional support from co-mentor Dr. Mark Thomas in the implementation of contingent opioid self-administration models in female and male mice. During the mentored (K99) phase of the award, fiber photometry calcium imaging will be used to monitor in vivo activity patterns of NAc FSIs in an Intermittent Access (IntA) fentanyl self-administration protocol to identify how this neural population responds to contingent fentanyl and fentanyl-associated cues. Subsequently, a chemogenetic approach, which will involve targeted expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) by NAc FSIs, will be used to test the hypothesis that these neurons play a functional role in addiction-related behavior. Following fentanyl self-administration, DREADDs will be used to excite or inhibit NAc FSIs prior to progressive ratio and cue-induced reinstatement tests. This innovative combination of tools will be used to test the relationship between NAc FSIs and the manifestation of fentanyl self-administration. The R00 phase of the award will distinguish Dr. Lefevre’s independent research from her mentors and broaden to identifying the role of excitatory synaptic inputs to NAc FSIs. Ex-vivo electrophysiology will be utilized to define input-specific excitatory synaptic plasticity adaptations in NAc FSIs induced by fentanyl self- administration. Additionally, the R00 aims will incorporate electrophysiology, optogenetic and calcium imaging expertise to develop stimulation protocols that restore opioid induced shifts in FSI circuitry and addiction-like behavior. Overall, the aims proposed in this award will identify key FSI circuits in opioid self-administration and provide the foundation for Dr. Lefevre’s independent research program studying the neural circuitry of addiction.