Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm

• Published in: Addiction biology Vol. 21; no. 3; pp. 575 - 588
• Main Authors: Castilla-Ortega, Estela, Blanco, Eduardo, Serrano, Antonia, Ladrón de Guevara-Miranda, David, Pedraz, María, Estivill-Torrús, Guillermo, Pavón, Francisco Javier, Rodríguez de Fonseca, Fernando, Santín, Luis J.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.05.2016; John Wiley & Sons, Inc
• Subjects: Addictions; Animals; Antineoplastic Agents, Alkylating - pharmacology; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Brain networks connectivity; c-Fos protein; Choice Behavior - drug effects; Circuits; Cocaine; Cocaine - pharmacology; Conditioning (Psychology); Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dentate gyrus; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; Dopamine Uptake Inhibitors - pharmacology; Drug abuse; drug addiction vulnerability; early immediate gene c-Fos; extinction and reinstatement; Extinction behavior; Extinction, Psychological; Functional morphology; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hypothalamus; Male; Mice; Multivariate Analysis; Neural networks; Neural Pathways - drug effects; Neurogenesis; Neurogenesis - drug effects; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Place preference conditioning; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; principal components factorial analysis PCA; Proto-Oncogene Proteins c-fos - drug effects; Proto-Oncogene Proteins c-fos - metabolism; Reinstatement; Rodents; Temozolomide; temozolomide TMZ; early immediate gene c-Fos; principal components factorial analysis PCA; Brain networks connectivity; drug addiction vulnerability; temozolomide TMZ; extinction and reinstatement
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12248

We investigated the role of adult hippocampal neurogenesis in cocaine‐induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine‐induced CPP to study c‐Fos expression in the hippocampus and in extrahippocampal addiction‐related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis‐reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine‐induced CPP under neurogenesis‐reduced conditions were delayed in extinguishing their drug‐seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long‐term CPP retention was found, suggesting that some roles of the adult‐born neurons may differ depending on whether they are generated before or after drug–contextual associations are established. Importantly, cocaine‐induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction‐related functional brain circuits, and reduction of the adult‐born hippocampal neurons increases cocaine seeking in the CPP model. We investigated the role of adult hippocampal neurogenesis in the cocaine‐induced conditioned place preference (CPP) paradigm and the functional brain circuitry involved. The neurogenesis‐reduced mice showed normal CPP acquisition but engaged an alternate brain network where the functional connectivity of the dentate gyrus was decreased. Moreover, neurogenesis reduction delayed extinction of CPP behaviour and enhanced its cocaine‐primed reinstatement. The results show that adult hippocampal neurogenesis sculpts the addiction‐related functional brain circuits, and reduction of the adult‐born hippocampal neurons increases cocaine‐seeking.