Localizing circuits of cocaine contextual memories
Authors: Caban Rivera Carolina , Do Chau , Fitzsimmons Emma M. , Price Rachael E. , Shi Xiangdang , Smith George M. , Unterwald Ellen M. 
Published: May 2022

Addiction is characterized by compulsive drug seeking and taking behaviors. Cravings triggered by the presence of environmental cues that were once associated to drug use are a main contributor of relapse and once these drug‐cue memories are formed they are difficult to erase. Addictive drugs like cocaine engage molecular pathways of associate learning, in which recall of an established memory is followed by its reconsolidation, strengthening that memory. The reactivation period is a critical time wherein memories are labile and vulnerable to behavioral and pharmacological interference. Given the widespread negative impact of drug use in our society, it is of great importance to understand the mechanisms underlying drug seeking behaviors to generate effective preventions and treatments. The goal of this study is to elucidate the neural substrate in the nucleus accumbens crucial for the maintenance of cocaine contextual memories, and explore neural plasticity involved. Designer receptors exclusively activated by designer drugs (DREADDs) were used to inhibit neurons at the nucleus accumbens. To accomplish this, adult male mice underwent bilateral intracranial injections of an inhibitory DREADD followed by a cocaine conditioned place preference paradigm. Nucleus accumbens neurons were inhibited via systemic injection of clozapine N‐oxide immediately following reactivation of cocaine contextual memory, and mice were re‐tested for place preference 72 hours and 7 days later. A separate cohort of mice underwent the same cocaine conditioned place preference paradigm, 24 hours post preference testing animals were returned to the cocaine context in a drug‐free state to reactivate cocaine memories. Sixty minutes after, brains were collected and prepared for quantitative RT‐PCR to measure activity‐regulated cytoskeleton‐associate protein (Arc) mRNA. To evaluate the functional plasticity in medium spiny neurons at the nucleus accumbens, upon reconsolidation of cocaine contextual memories, we utilized the fosTRAP2‐Ai14 mouse model. A cohort of male and female fosTRAP2‐Ai14 mice underwent cocaine conditioned place preference exactly as in the previous experiment and brains collected 9 days after recall of cocaine contextual memory and 4‐hydroxytamoxifen induction. Dendritic spine density of fosTRAP cells activated by recall of cocaine context were analyzed. Results show that chemogenetic inhibition of the nucleus accumbens immediately following reactivation of cocaine contextual memory significantly reduced a once established preference for the cocaine context. Furthermore, Arc mRNA expression is upregulated at the nucleus accumbens following exposure to the prior cocaine‐paired context. Finally, we show a significant increase in dendritic spine density in medium spiny neurons at the nucleus accumbens following recall of cocaine context. These findings suggest the nucleus accumbens is important for the reconsolidation of cocaine contextual memories and exhibits dendritic neuroplastic changes upon reconsolidation of cocaine memories.