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.

Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice induces behavioural and biological changes relevant to depression

“…Previous studies 7, 8 have examined processes mainly associated with the dorsal hippocampus and accordingly used a 4-week TMZ treatment protocol to deplete an entire cohort of new neurons as maturation of dorsal hippocampal neurons is roughly 4 weeks. However, the maturation rate of the mood-associated ventral dentate gyrus is slightly slower and is approximately 6 weeks.…”

“…7 Specifically, several studies have used TMZ to examine different functions in animal models thought to be neurogenesis dependent including aspects of spatial learning and addiction. 7, 8, 9, 10, 11 These studies have not, however, addressed any potential links between neurogenesis depletion as a result of TMZ with depression. Owing to its low toxicity in animals and published anti-neurogenic effects, TMZ is a good drug to model the effects of chemotherapy.…”

The pharmacological reduction of hippocampal neurogenesis attenuates the protective effects of cannabidiol on cocaine voluntary intake

“…Prior to any behavioural manipulation, animals were treated with two consecutive cycles of TMZ, as reported by Niibori et al, Akers et al, and Castilla‐Ortega et al Each cycle involved the intraperitoneal (i.p.) administration of 25 mg/kg TMZ once a day for three consecutive days (Figure A).…”

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

“…In regards to CPP, IG‐IR does not change retrieval of cocaine CPP in rat (Brown et al, ). In the mouse, pharmacological reduction of ABGCs prior to CPP impairs extinction of cocaine CPP, while reduction after CPP enhances retention (Castilla‐Ortega et al, ). As distinct classes of drugs of abuse differ in their underlying longer term effects (Becker, Kieffer, & Le Merrer, ), it is surprising that no studies have examined whether IG‐IR and subsequent loss of ABGCs in the rodent alters CPP to opiates, such as morphine.…”