RESUMEN
The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data.
Asunto(s)
Hipocampo/efectos de los fármacos , Hiperfagia/inmunología , Tamaño de la Camada/inmunología , Microglía/efectos de los fármacos , Minociclina/administración & dosificación , Minociclina/farmacología , Animales , Animales Recién Nacidos , Recuento de Células , Femenino , Hipocampo/inmunología , Lipopolisacáridos , Masculino , Microglía/inmunología , RatasRESUMEN
Interleukin-12 (IL-12) is a major pro-inflammatory cytokine, which promotes cell-mediated immunity and T(H)1 differentiation. In vitro studies indicated suppression of IL-12 production by several stress-related factors, but no effects of behavioral stress were shown on plasma IL-12 levels. Therefore, in the current study we (i) examined the in vivo effects of various behavioral and pharmacological stress paradigms on baseline plasma IL-12 levels; (ii) compared these in vivo findings to those obtained following in vitro stimulation of leukocytes from the same rats; and (iii) assessed potential sexual dimorphism in these outcomes. The findings indicated that plasma IL-12 levels were significantly reduced by social confrontation, wet-cage exposure, surgery, and the administration of corticosterone, epinephrine, or prostaglandin-E(2). Notably, most in vivo impacts on plasma levels were not evident when assessed in vitro. The IL-12-reducing effects of wet-cage exposure, and of corticosterone and epinephrine administration, were significantly greater in males than in females, although females exhibited greater total corticosterone levels following stress. The duration of acute stressors predicted the degree of IL-12 reduction, but more prolonged stressors did not. Furthermore, seven days of alternating behavioral stressors reduced plasma IL-12 levels more than 14 days. These findings suggest animals' behavioral habituation to stress conditions, or a specific immune mechanism restricting the duration of IL-12 reduction. Overall, our findings indicate a generic and robust stress-induced reduction in plasma IL-12 levels, and suggest epinephrine, corticosterone, and prostaglandin-E(2), as potential mediators that should be scrutinized in vivo in the context of natural physiological stress responses.
Asunto(s)
Interleucina-12/sangre , Estrés Psicológico/sangre , Animales , Corticosterona/sangre , Corticosterona/farmacología , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Ambiente , Ensayo de Inmunoadsorción Enzimática , Epinefrina/farmacología , Femenino , Vivienda para Animales , Laparotomía , Masculino , Oligodesoxirribonucleótidos/farmacología , Ratas , Ratas Endogámicas F344 , Ratas Long-Evans , Restricción Física , Caracteres Sexuales , Medio Social , Estrés Fisiológico/fisiología , Natación/psicologíaRESUMEN
Neonatal lipopolysaccharide (LPS) exposure increases anxiety-like behaviour in adulthood. Our current aim was to examine whether neonatal LPS exposure is associated with changes in microglial activation, and whether these alterations correspond with alterations in behaviour. In adulthood, LPS-treated animals exhibited significantly increased anxiety-like behaviour and hippocampal microglial activation. The efficacy of the LPS challenge was confirmed by increased neonatal plasma corticosterone and tyrosine hydroxylase (TH) phosphorylation in the adrenal medulla. These findings suggest a neuroimmune pathway which may underpin the long-term behavioural and neuroendocrine changes following neonatal infection.
Asunto(s)
Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Lipopolisacáridos/farmacología , Microglía/efectos de los fármacos , Médula Suprarrenal/efectos de los fármacos , Médula Suprarrenal/metabolismo , Animales , Animales Recién Nacidos , Ansiedad/inmunología , Conducta Animal/fisiología , Corticosterona/sangre , Hipocampo/inmunología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/metabolismo , Microglía/inmunología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.