Abstract
Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL)6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS)-induced and psychological novel environment stress (NES) in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to NES (cage switch) or LPS (100 μg/kg) in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that NES-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after NES and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF-IL6-positive cells in the pituitary after NES or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME), NF-IL6-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-IL6-CD68-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFα into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFα production by the pituitary cells. In the old rats, this specific cytokine interaction could not be detected. Overall, the present results revealed strong differences in the activation patterns and pathways between old and young rats after both stressors. The prolonged hyperthermic and inflammatory response seen in aged animals seems to be linked to dysregulated pituitary cytokine interactions and brain cell activation (NF-IL6) in the hypothalamus-pituitary-adrenal axis.
Highlights
Stress is an omnipresent stimulus in animals and humans i.e., an alarm reaction as first outlined by Hans Selye in 1936 (Rochette and Vergely, 2017)
Hyperthermia was clearly enhanced in the old rats from 35 to 90 min (P < 0.05) compared to the young group and was still present at the end of the experiment in the old animals, while the temperature in the young rats had returned to baseline levels at this time point
We analyzed a range of relevant inflammatory mediators and markers of hypothalamus pituitary adrenal (HPA)-axis activation in order to further investigate the influence of psychological stress on central signaling pathways involved in the manifestation of the febrile response as well as potential age-related differences (Figure 2)
Summary
Stress is an omnipresent stimulus in animals and humans i.e., an alarm reaction as first outlined by Hans Selye in 1936 (Rochette and Vergely, 2017). A variety of stressors can elicit this hallmark of stress reaching from so-called stage fright or in German literally translated “lamp fever,” when giving a speech in front of a big audience or before examinations in humans (Marazziti et al, 1992), to novel environment, restraint, capture, or social defeat in animals (Oka et al, 2001; Bouwknecht et al, 2007; Meyer et al, 2008; Nakamura, 2015) Such an increase in body core temperature can persist for weeks to even years when the psychological stress is exposed repeatedly and/or is of high intensity; a scenario like this is termed “psychogenic fever” (Timmerman et al, 1992; Oka et al, 2001; Nakamura, 2015). For example, social defeat stress induces chronic hyperthermia lasting at least 8 days after cessation of the stressor (Hayashida et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
