Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking

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Specific Aims A major challenge for individuals suffering from substance use disorders (SUDs) is the lack of effective treatments that reduce relapse vulnerability. Drug predictive cues in the environment are powerful triggers for relapse and understanding how these persistent associations are formed and maintained is a critical focus of preclinical SUD research. In this proposal, we have built on our discovery that immediately after the end of cocaine self administration (SA), an infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic (PL) prefrontal cortex prevents the cocaine SA-induced dephosphorylation of key glutamatergic-related plasticity- related proteins (PRPs), including GluN2A, GluN2B, ERK MAP kinase, and CREB32,96. This early intervention with BDNF also prevents prolonged cocaine-induced deficits in PL-NA core glutamatergic transmission that promote subsequent cocaine seeking9. In contrast, by the end of the first week of abstinence, protein kinase A (PKA)-dependent augmentation of GluA1 and CREB phosphorylation emerges. At that time, intra-PL BDNF has no effect on relapse8 but intra-PL infusion of a PKA inhibitor, Rp-cAMPs, reverses the hyperphosphorylation and decreases relapse70,92. More recently, we have shown that the biphasic changes in GluA1 and pCREB within the first week of abstinence are associated with similar biphasic changes in the head diameters (dH) of dendritic spines of PL–NA core neurons89. These data have spurred the overall hypothesis that interventions to decrease drug seeking must be tailored to the dynamic changes in neuroadaptations that emerge during different phases of the addiction cycle. In chemogenetic studies to investigate the contribution of specific pathways originating in PL cortex to drug seeking, we discovered that PL-NA core and PL-posterior paraventricular thalamic nucleus (pPVT) pathways oppose each others’ effects during early withdrawal. Selective cre-dependent DREADD inhibition of PL-NA core neurons infected with a retrogradely transported cre-AAV immediately after cocaine SA has no effect by itself, but reverses the suppressive effect of intra-PL BDNF on subsequent drug seeking31. In contrast, selective inhibition of the PL-pPVT pathway immediately after cocaine SA decreases subsequent cocaine- seeking, an effect that is prevented by intra-PL BDNF31. Interestingly, we also found that selective inhibition of the PL-pPVT pathway reduces anxiety-related behavior in rats withdrawing from cocaine and inactivation of pPVT decreases conditioned aversion to cocaine, suggesting that cocaine’s engagement of anxiety- and aversion-related circuitry that contributes to drug seeking includes pPVT. Taken together, our new findings suggest the novel hypothesis that cocaine SA produces differential regulation of PL-NA core and PL-pPVT pathways and that these two distinct circuits conspire to support future drug seeking. In this proposal, we will use pathway-specific, combinatorial chemogenetic approaches, slice electrophysiology, and state-of-the-art dendritic spine and PRP imaging in PL-NA core and PL-pPVT circuitry to explore the time-dependent plasticity occurring in this network that influences cocaine seeking and aversion. We will use these approaches in the following aims that will be performed in male and female rats. Aim 1. BDNF regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons during early withdrawal. Using viral vector approaches, we will investigate the effects of intra-PL BDNF infusion on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL-PVT neurons during early withdrawal. Aim 2. PKA regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons after 7 and 30 days of abstinence. (A) We will investigate the effects of inhibiting cAMP/PKA signaling on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL- PVT neurons after 7 or 30 days of abstinence with or without relapse testing. Aim 3. The role of PL-NA core and PL-pPVT neurons in cocaine-induced anxiety and aversion in relationship to cocaine seeking after abstinence. We will use a retro-Gi DREADD approach to test the effects of inhibiting PL-NA core or PL-pPVT neurons (A) on withdrawal-induced anxiety immediately after the end of cocaine SA and (B) on conditioned avoidance of cocaine in an operant runway task before or after cocaine SA followed by cue-induced relapse testing. Scientific Impact: These studies will expand our understanding of how to reverse critical neuroadaptations underlying prefrontal dysfunctions during different phases of the addiction cycle that trigger relapse to drug- seeking. By understanding temporally dynamic, differential neuroadaptations in the PL networks regulating reward and aversion, we may be able to discover novel therapeutic targets to decrease drug-seeking.