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Thesis/Dissertation
Date
2023-08
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Biomedical Sciences
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https://doi.org/10.34944/z6rw-aj93
Abstract
Drug craving triggered by cues that were once associated with drug intoxication is a main contributor to continued drug-seeking behaviors. Addictive drugs engage molecular pathways of associative learning in which reactivation of a memory is followed by its reconsolidation. Reactivated memories are vulnerable to interference. Here we examined the circuitry of cocaine contextual memory reconsolidation and explored neuroplasticity following memory reactivation. Mice underwent chemogenetic inhibition of either nucleus accumbens (NA) neurons or the glutamatergic projection neurons from the ventral hippocampus (vHPC) to NA using inhibitory designer receptors exclusively activated by designer drugs (iDREADD). Mice underwent cocaine conditioned place preference followed by reactivation of the cocaine contextual memory. Clozapine N-Oxide (CNO) was administered after memory reactivation to inhibit either NA neurons or the accumbens–projecting glutamatergic neurons from the vHPC during the reconsolidation period. When retested 3 days later, a significant reduction in the previously established preference for the cocaine context was found in both conditions, but not in control groups. FosTRAP2-Ai14 mice were used to identify neurons activated by cocaine memory recall and to evaluate plasticity in NA medium spiny neurons (MSN) upon recall of cocaine memories. Results indicate a significant increase in dendritic spine density in NA MSNs activated by cocaine memory recall. Of these active cells, 43% expressed D1 receptors compared to 34% expressing D2 receptors. These results implicate a circuit involving glutamatergic projections from the vHPC onto NA neurons which is necessary for the reconsolidation of cocaine memories. Attenuation of cocaine memory reconsolidation reduced drug-seeking behavior.
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