Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups

Abstract

Objective: Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15. Methods: Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively. Results: LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1β, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1β protein, but these were attenuated in MS-LPS pups. Conclusion: Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…In male rats, MS and MD resulted in decreased GFAP reactivity and reduced cytoskeletal complexity in the hippocampus (Roque, Ochoa‐Zarzosa, & Torner, ; Saavedra, Fenton Navarro, & Torner, ) and cortex (Musholt et al, ) within 24 hr after MS or MD. Similarly, in Octodon degus , MD resulted in decreased density of GFAP + astrocytes in the cortex, associated with reduced length and ramification of astrocytic processes (Braun, Antemano, Helmeke, Büchner, & Poeggel, ).…”

“…At this stage, more research is necessary to elucidate the specific order of events. Interestingly, also MD/MS induced alterations on astrocytes were sometimes accompanied by activation of microglia (Réus et al, ; Roque et al, ; Saavedra et al, ). It is striking that despite the similar activation of microglia, different effects were described for GFAP, with lasting upregulation after immune challenges but no persistent changes in GFAP after MD/MS, suggesting alternative mediators and processes involved.…”

“…It is possible that alterations in astrocytes caused by ELA, either through MD/MS or an inflammatory result, are not always detectable under baseline conditions and only become apparent when exposure to another stressful event occurs, a so‐called “second hit.” Evidence for this is provided by studies showing that MS or prenatal restraint stress‐exposed offspring exhibit greater vulnerability of astrocytes to an immune challenge later in life (Diz‐Chaves et al, ; Saavedra et al, ). This data suggests that astrocytes are sensitized or “primed” by ELA, possibly underlying greater susceptibility to later disease states.…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…Early life stress models in which mothers and pups are given access to limited amounts of bedding, result in impaired glutamate uptake by hypothalamic astrocytes (Gunn et al, 2013). Maternal separation, another early-life stress, impacts the number of astrocytes in the hippocampus (Saavedra, Fenton Navarro, & Torner, 2017). Considering the role for astrocytes in synapse formation and maturation (Allen et al, 2012;Blanco-Suarez, Liu, Kopelevich, & Allen, 2018;Stogsdill et al, 2017), impairment of astrocyte function at early stages of postnatal development should have dramatic consequences on neuronal function.…”

Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

“…Interestingly, there is emerging evidence that astrocytes are also implicated in effects of ES (reviewed in [33]). ES leads to immediate and permanent changes in astrocyte number and morphology [34][35][36][37][38] that may contribute to cognitive deficits. Furthermore, we have shown that ES leads to persistent alterations in microglia up to the age of 10 months.…”