Mifsud, K.R., Gutierrez-Mecinas, M., Collins , A., Trollope, A.F., Carter, S.D., and Reul, J.M.H.M. (2012) Forced swim stress enhances the survival of new dentate gyrus neurons in rat through a glucocorticoid receptor-dependent mechanism. European Neuropsychopharmacology, 22 (Supplement 1). S29-S30.

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Abstract

Adaptive and coping behaviours such as immobility in the forced swim (FS) retest are dependent on successful memory formation during initial training/tests. It has been suggested that stressful learning paradigms such as Morris water maze learning lead to enhanced survival of newly born neurons in the dentate gyrus (DG) and that these newly generated neurons may be involved in long-term memory formation. We have previously identified a signaling pathway, involving activation of ERK1/2 (extracellular signal-regulated kinase1/2), MSK1 (mitogen- and stress-activated kinase1), and Elk-1 (ets-domain- containing protein1) signaling molecules and activated within DG granule neurons following FS, which results in distinct epigenetic changes and induction of immediate early genes (IEGs; e.g. c-Fos/Egr-1) and the consolidation of the adaptive behavioural immobility response [1,2]. Glucocorticoid hormones, released as part of the stress response and acting via glucocorticoid receptors (GRs), enhance signaling through the ERK1/2/MSK1-Elk-1 pathway and thereby increase the impact on epigenetic and gene expression mechanisms. We aimed to determine if this signaling pathway leading to IEG induction is activated specifically in young adult-born dentate neurons following FS. Rats were injected twice daily for 5 days with BrdU to label new neurons. One, six or twelve weeks after BrdU treatment the rats were forced to swim (15 min, 25°C-water), before being killed 1h later and tissue analyzed by immunofluorescence. FS-induced c-Fos was observed at all time points but there was no co-localization of the IEG with BrdU. Next, given that experiences during the first 1−2 weeks of a young adult-born DG neuron's life is important for its survival [3], we studied whether FS would promote neuronal survival. Rats were injected with BrdU for 5 days and split into groups: control and FS groups. The FS group underwent a 15-min FS challenge one week after the BrdU injections, whereas the control group remained in their home cages. Four weeks after the initial FS test both groups (i.e. control group and FS group) underwent another FS procedure and killed 1h later. The FS group, which had undergone a FS challenge four weeks previously, showed significantly more immobility behavior compared with controls (n = 8, p<0.01, Students t-test), indicating that they had remembered the initial FS test. No co-localization of c-Fos with BrdU was found in either group. The number of BrdU-positive neurons was higher in the dentate gyrus of the FS group (19.6±2.1 neurons, n = 8) than in control animals (12.0±1.1 neurons, n=4) (p<0.03, Student's t-test). To investigate a role of GRs in the survival-promoting effect of FS we pre-treated rats with the GR antagonist RU486 before the initial FS challenge. RU486 impaired the behavioural immobility response in the 4-week retest (n = 7/group; p<0.01, post-hoc Bonferroni test) and abolished the FS-evoked increase in neuronal survival compared with the vehicle-pre-treated group (n = 5/control group, 7/FS group; p<0.001, post-hoc Bonferroni test). Thus, a single FS challenge promotes the survival of new adult-born DG granule neurons, which requires GR activation at the time of the stressful challenge and which may contribute to the formation of long-term memories of the FS event.

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