Nonsteroidal Anti-Inflammatory Treatment Prevents Delayed Effects of Early Life Stress in Rats

Abstract

Background Early developmental insults can cause dysfunction within parvalbumin (PVB)-containing interneurons in the prefrontal cortex. The neuropsychiatric disorders associated with such dysfunction might involve neuroinflammatory processes. Cyclooxygenase-2 (COX-2) is a key mediator of inflammation and is therefore a potential target for preventive treatment. Here, we investigated whether the developmental trajectories of PVB expression and COX-2 induction in the prelimbic region of the prefrontal cortex are altered after maternal separation stress in male rats. Methods Male rat pups were separated from their mother and littermates for 4 hours/day between postnatal Days 2 and 20. Western blotting and immunohistochemistry were used to analyze PVB and COX-2 expression in the prefrontal cortex and hippocampus. A separate cohort of animals was treated with a COX-2 inhibitor during preadolescence and analyzed for PVB, COX-2, and working memory performance. Results We demonstrate that maternal separation causes a reduction of PVB and an increase in COX-2 expression in the prefrontal cortex in adolescence, with concurrent working memory deficits. Parvalbumin was not affected earlier in development. Prophylactic COX-2 inhibition preadolescence prevents PVB loss and improves working memory deficits induced by maternal separation. Conclusions These data are the first to show a preventive pharmacological intervention for the delayed effects of early life stress on prefrontal cortex interneurons and working memory. Our results suggest a possible mechanism for the relationship between early life stress and interneuron dysfunction in adolescence.

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

“…The cytotoxic stress generated might block the phosphorylation cascades and affect the kinases that inhibit NFkB and in the end decrease the levels of proinflammatory cytokines to a second challenge. Further studies using the double hit (MS-LPS) model followed by the administration of antidepressive [63] or antiinflammatory substances [64] could help to address the contribution of specific mediators and the timing of the responses to microglial cells and cytokine levels.…”

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

“…For example, rodent pups separated from their mothers later showed more depressive-like symptoms and lower prefrontal cortex parvalbumin levels (a GABAergic marker) compared to unchallenged pups (Leussis et al, 2012), and these differences were reduced by the administration of an anti-inflammatory cyclo-oxygenase 2 (COX-2) inhibitor (Brenhouse and Andersen, 2011b) or anti-inflammatory IL-10 (Wieck et al, 2013). More indirectly, physical exercise and anti-depressant medications have antiinflammatory effects (Gleeson et al, 2011;Hannestad et al, 2011) and they have both appeared to buffer the effects of early-life stress on brain and behavioral outcomes (Harrison and Baune, 2014).…”

“…First, higher baseline levels of inflammation have been associated with greater stress-induced responses in animal models (Hodes et al, 2014) and humans (Eraly et al, 2014;Michopoulos et al, 2015). Second, administration of anti-inflammatory agents, such as COX-2 inhibitors or IL-10, can buffer the expression of biological and clinical sequelae of early-life stress in rodents, including the reduction in prefrontal cortex parvalbumin levels and the onset of depressive-like symptoms (Brenhouse and Andersen, 2011b;Wieck et al, 2013). Third, non-pharmacological strategies with anti-inflammatory properties, physical exercise, and anti-depressant medications, can buffer the effects of earlylife stress on brain and behavioral outcomes in animal models (Harrison and Baune, 2014).…”

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

“…[36][37][38] Ultimately, interneuron dysfunction could contribute to altered sensory perception, 39 deficits in working memory, 18,40 attention, 41 and learning. 42 Recent studies have revealed anomalies in hippocampal and/or prefrontal PVI in many preclinical animal models aiming to reproduce genetic vulnerabilities [43][44][45][46] or environmental risk factors 47 such as prenatal maternal stress, 48 maternal and perinatal immune challenge, 49,50 hypoxia, 51,52 early-life iron deficiency, 53 maternal separation, 54 and social isolation. 55,56 Similarly, nongenetic developmental models also result in altered prefrontal PVI.…”