title: Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.
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.
authors: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors: Estela
authors: E
authors: Castilla-Ortega
authors: Departament de Pedagogia i Psicología, Facultat d'Educació, Psicologia i Treball Social, Universitat de Lleida, Spain.
authors: Eduardo
authors: E
authors: Blanco
authors: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors: Antonia
authors: A
authors: Serrano
authors: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, Spain.
authors: David
authors: D
authors: Ladrón de Guevara-Miranda
authors: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors: María
authors: M
authors: Pedraz
authors: Unidad de Gestión Clínica Intercentros de Neurociencias y ECAI de Microscopía, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Spain.
authors: Guillermo
authors: G
authors: Estivill-Torrús
authors: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors: Francisco Javier
authors: FJ
authors: Pavón
authors: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.
authors: Fernando
authors: F
authors: Rodríguez de Fonseca
authors: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Psicología, Universidad de Málaga, Spain.
authors: Luis J
authors: LJ
authors: Santín
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002755:Choice Behavior / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005108:Extinction, Psychological; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015999:Multivariate Analysis; D009434:Neural Pathways / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D003606:Dacarbazine; D003042:Cocaine; D000077204:Temozolomide
keywords: Brain networks connectivity; drug addiction vulnerability; early immediate gene c-Fos; extinction and reinstatement; principal components factorial analysis PCA; temozolomide TMZ