RESUMO
Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitary-adrenal (HPA)-axis. Most likely, this dysregulation gradually develops, and is triggered by stressors occurring early in life (early-life stress [ELS]). ELS may be particularly impactful when overlapping with the period of epileptogenesis. To examine this in a controlled and prospective manner, the present study investigated the effect of repetitive variable stressors or control treatment between postnatal day (PND) 12 and 24 in male mice exposed on PND10 to hyperthermia (HT)-induced prolonged seizures (control: normothermia). A number of peripheral and central indices of HPA-axis activity were evaluated at pre-adolescent and young adult age (ie, at PND25 and 90, respectively). At PND25 but not at PND90, body weight gain and absolute as well as relative (to body weight) thymus weight were reduced by ELS (vs control), whereas relative adrenal weight was enhanced, confirming the effectiveness of the stress treatment. Basal and stress-induced corticosterone levels were unaffected, though, by ELS at both ages. HT by itself did not affect any of these peripheral markers of HPA-axis activity, nor did it interact with ELS. However, centrally we did observe age-specific interaction effects of HT and ELS with regard to hippocampal glucocorticoid receptor mRNA expression, neurogenesis with the immature neurone marker doublecortin and the number of hilar (ectopic) granule cells using Prox1 staining. This lends some support to the notion that exposure to repetitive stress after HT-induced seizures may dysregulate central components of the stress system in an age-dependent manner. Such dysregulation could be one of the mechanisms conferring higher vulnerability of individuals with epilepsy to develop seizures in the face of stress.
Assuntos
Envelhecimento/fisiologia , Hipertermia Induzida , Convulsões/etiologia , Convulsões/psicologia , Estresse Psicológico/fisiopatologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Animais , Comportamento Animal/fisiologia , Corticosterona/sangue , Feminino , Hipocampo/química , Hipocampo/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Tamanho do Órgão , RNA Mensageiro/análise , Receptores de Glucocorticoides/genética , Convulsões/fisiopatologia , Estresse Psicológico/psicologia , Timo/crescimento & desenvolvimento , Aumento de PesoRESUMO
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11ß-HSD1 reverses the deficits in cognition with aging, a state of elevated glucocorticoid levels. However, any impact of 11ß-HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11ß-HSD1 inhibitor UE2316 modifies the effect of stress on hippocampal long-term potentiation and fear conditioning, a learning paradigm that is strongly modulated by glucocorticoids. We found that novelty stress suppresses hippocampal synaptic potentiation. This effect was completely prevented by administration of UE2316 one hour before stress exposure. A single injection of UE2316 also impaired contextual, but not tone-cue-fear conditioning. These observations suggest that local metabolism of glucocorticoids is relevant for the outcome of stress effects on hippocampal synaptic plasticity and contextual fear conditioning. Selective 11ß-HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology.