Programming Effects of Pubertal Lipopolysaccharide Treatment in Male and Female CD-1 Mice

Abstract

Puberty is a critical period of development marked by sexual, immune, and neural maturation. Exposure to stress during this period can lead to enduring changes in brain functioning and in behavior; however, the underlying mechanisms and the programming effects of stress during puberty remain unknown. Therefore, the objective of this study was to investigate the programming effects of pubertal immune challenge in response to a homotypic stressor later in life in CD-1 mice. Age and sex differences in the peripheral and central cytokine levels, along with sickness behavior and telemetry data, were analyzed following the secondary treatment. The results showed that pretreatment with LPS attenuated the immune response to a second homotypic challenge. Males pretreated with LPS during puberty and in early adulthood displayed an attenuated hypothermic response following the second LPS treatment compared with saline-pretreated controls, which is consistent with the attenuated peripheral IL-6 and IFN-g concentrations. Females pretreated with LPS during puberty displayed lower IL-1b, TNF-a, and IL-6 mRNA expression in the prefrontal cortex following the secondary immune challenge compared with saline controls. The results of this study show that exposure to LPS during puberty programs the peripheral and central immune responses, resulting in an attenuated immune response following a subsequent homotypic stressor. Thus, exposure to an immune challenge during puberty affects immune function later in life, which could permanently affect brain function and have implications on mental health.

Sex-specific responses of the pubertal neuroimmune axis in CD-1 mice

“…For example, CD-1 mice treated with the bacterial endotoxin lipopolysaccharide (LPS) (1.5 ​mg/kg body weight, intraperitoneal [ ip ]) during the stress-sensitive pubertal period (i.e., six weeks of age) show female-skewed increases in depression-like behaviours and male-biased increases in anxiety-like behaviours and reactivity to novel stressors ( Murray et al., 2019 ). Similar sex-dependent effects of pubertal LPS treatment are observed in stress and immune responses ( Cai et al., 2016 ; Girard-Joyal et al., 2015 ; Sharma et al., 2019 ), behavioural responsiveness to gonadal hormones ( Ismail et al., 2013 ; Laroche et al., 2009a , Laroche et al., 2009b ; Olesen et al., 2011 ), spatial learning and hippocampal cell development ( Kolmogorova et al., 2019 ), and dopamine-sensitive behaviours ( Girard-Joyal and Ismail, 2017 ). The neural mechanisms driving the sex-specific acute and enduring effects of LPS treatment during the stress-sensitive pubertal period remain elusive.…”

“…Microglia play critical roles in immune responses, homeostatic process (e.g., debris clearance), the shaping of immature neural networks, and programming of adult behaviours ( Lenz and Nelson, 2018 ; Li and Barres, 2018 ; Mottahedin et al., 2017 ; Nelson et al., 2019 ; Wolf et al., 2016 ). Therefore, the residual effects of LPS-induced sickness on microglial expression and morphology in the hippocampus, mPFC, and the PVN suggest mechanistic involvement of these cells in the sex-specific outcomes of pubertal LPS on related behaviours (i.e., stress and immune responses [ Cai et al., 2016 ; Girard-Joyal et al., 2015 ; Sharma et al., 2019 ]; depression-like behaviours [ Murray et al., 2019 ]; spatial retention errors on hippocampus-dependent tasks [ Kolmogorova et al., 2019 ]; reactivity to novel stressors and expression of anxiety-like behaviours ( Murray et al., 2019 ]).…”

“…Six-week-old mice received either LPS (from Escherichia coli serotype O26:B6; L#3755; Sigma Chemical Co., St. Louis, MO, USA; 1.5 ​mg/kg body weight, ip ) or 0.9% sterile saline (LPS-matched volume, ip ) towards the end of the light phase ( n ​= ​96/treatment). During puberty, this LPS dose induces sickness for approximately 48 ​h in both sexes and impairs stress- and cognition-related neurocircuitry and behaviour in a sex-dependent manner ( Cai et al., 2016 ; Girard-Joyal et al., 2015 ; Kolmogorova et al., 2019 ; Sharma et al., 2019 ).…”

Sex differences of inflammatory and immune response in pups of Wistar rats with SIRS

“…Nevertheless, a day after the LPS injection an increase in the concentration of both estradiol and testosterone was observed in males, but not in females. It is possible that sex differences in hormonal changes at SIRS are due to LPS-induced damage of the hypothalamus–pituitary–adrenal (HPA) and the hypothalamus-pituitary-gonads (HPG) axis in males, which led to changes in the metabolism and synthesis of sex steroids by the testes 20 . According to the literature, an increase in estradiol concentration is an unfavorable factor in inflammatory reactions and contributes to the synthesis of LPS—binding protein (LBP) 21 .…”

Linking Puberty and the Gut Microbiome to the Pathogenesis of Neurodegenerative Disorders

“…For example, pubertal LPS treatment permanently decreases GR expression in the paraventricular nucleus of the hypothalamus of adult male mice [112]. Furthermore, LPS treatment during puberty followed by a secondary immune challenge in adulthood results in an attenuated immune response as shown through decreases in peripheral IL6 and IFNγ concentrations and decreases in IL1β, TNFα, and IL6 mRNA expression in the PFC [113]. Pubertal LPS treatment also causes enduring learning and spatial memory deficits in both male and female mice and increases Parkinsonlike behaviors in male, but not in female mice, indicating an increased susceptibility to neurodegeneration [109,111,114].…”