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Title: Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.
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
Keywords: Brain networks connectivity;drug addiction vulnerability;early immediate gene c-Fos;extinction and reinstatement;principal components factorial analysis PCA;temozolomide TMZ
metadata.dc.subject.mesh: Animals
Antineoplastic Agents, Alkylating
Behavior, Animal
Choice Behavior
Conditioning, Psychological
Dentate Gyrus
Dopamine Uptake Inhibitors
Extinction, Psychological
Multivariate Analysis
Neural Pathways
Nucleus Accumbens
Paraventricular Hypothalamic Nucleus
Prefrontal Cortex
Proto-Oncogene Proteins c-fos
Issue Date: 14-Apr-2015
Abstract: 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.
metadata.dc.identifier.doi: 10.1111/adb.12248
Appears in Collections:Producción 2020

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