Abstract
BackgroundThe postnatal period is a critical time window during which inflammatory events have significant and enduring effects on the brain, and as a consequence, induce alterations of emotional behavior and/or cognition later in life. However, the long-term effect of neonatal inflammation on behavior during adolescence, a sensitive period for the development of neurodevelopmental psychiatric disorders, has been little studied. In this study, we examined whether an early-life inflammatory challenge could alter emotional behaviors and spatial memory at adolescence and adulthood and whether stress axis activity, inflammatory response and neurogenesis were affected.MethodsLipopolysaccharide (LPS, 100 μg/kg) was administered to mice on postnatal day (PND) 14 and cytokine expression was measured in the plasma and in brain structures 3 hours later. Anxiety-like and depressive-like behavior (measured in the novelty-suppressed feeding test and the forced swim test, respectively) and spatial memory (Y-maze test) were measured at adolescence (PND30) and adulthood (PND90). Hypothalamic-pituitary-adrenal (HPA) axis activity (plasma corticosterone and glucocorticoid receptors in the hippocampus and prefrontal cortex) was measured at adulthood. In addition, the impact of a novel adult LPS challenge (100 μ/kg) was measured on spatial memory (Y-maze test), neurogenesis (doublecortin-positive cell numbers in the hippocampus) and plasma cytokine expression.ResultsFirst, we show in PND14 pups that a peripheral administration of LPS induced the expression of pro- and anti-inflammatory cytokines in the plasma and brain structures that were studied 3 hours after administration. Anxiety-like behavior was altered in adolescent, but not in adult, mice, whereas depressive-like behavior was spared at adolescence and increased at adulthood. This was accompanied by a decreased phosphorylation of the glucocorticoid receptor in the prefrontal cortex, with no effect on corticosterone levels. Second, neonatal LPS treatment had no effect on spatial memory in adolescence and adulthood. However, a second challenge of LPS in adulthood impaired spatial memory performance and neurogenesis and increased circulating levels of CCL2.ConclusionsOur study shows for the first time, in mice, that a peripheral LPS treatment at PND14 differentially alters emotional behaviors, but not spatial memory, at adolescence and adulthood. The behavioral effect of LPS at PND14 could be attributed to HPA axis deregulation and neurogenesis impairment.
Highlights
According to the concept of perinatal programming of adult behavior [1], the postnatal period is a critical timewindow during which an adverse event can have significant and enduring effects on the development of the central nervous system, and as a consequence, on behavior later in life
At PND14, the neonatal stress axis is no longer in a hyporesponsive state [14], and pups exhibit an enhanced response of adrenocorticotropic hormone (ACTH) and corticosterone to LPS [15] that could contribute to altered brain development
In the current study on mice, we evaluated whether an exposure to LPS in neonatal life 1) alters emotional behavior and spatial memory at adolescence and adulthood; 2) is associated with HPA axis dysfunctions at adulthood as manifested by alterations in corticosterone and glucocorticoid receptors (GR) expression in the brain; and 3) alters memory, neurogenesis and inflammatory markers in response to a second hit of LPS at adulthood
Summary
According to the concept of perinatal programming of adult behavior [1], the postnatal period is a critical timewindow during which an adverse event can have significant and enduring effects on the development of the central nervous system, and as a consequence, on behavior later in life In this context, an inflammatory event during brain development has been shown to strongly increase the risk for the development of psychiatric disorders such as autism or schizophrenia [2,3]. Immune challenge has been reported to stimulate the production of proinflammatory cytokines, such as interleukin(IL)-1β, IL-6 and tumor necrosis alpha (TNFα), both at the periphery and in the brain [7], together with enhanced corticosterone levels [8] These factors have been proposed to adversely impacts fetal brain development [9,10] such as hippocampal neurogenesis [11]. We examined whether an early-life inflammatory challenge could alter emotional behaviors and spatial memory at adolescence and adulthood and whether stress axis activity, inflammatory response and neurogenesis were affected
Sign-in/Register to view highlights & summary 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.
