Puberty is a critical developmental period that is characterized by significant brain development. Exposure to stress during this time can alter brain functioning setting the stage for long-lasting behavioural outcomes. The objective of this study was to investigate age and sex differences in the peripheral and central immune responses, along with sickness behaviour, following immune stress. The results showed that LPS treatment increased serum cytokine levels and sickness symptoms in all mice. Pubertal males displayed increased IL-1β concentrations at 2 h and increased IL-6 concentrations at 8 h post-treatment whereas increased concentrations of TNFα, IL-10, IL-12, IL-1β, IFNγ, and IL-6 persisted at 8 and 24 h in adult females. Consistent with peripheral cytokines, pubertal males displayed greater IL-1β, TNFα, and IL-6 mRNA expression in the prefrontal cortex at 2 h, whereas adult males expressed more of the aforementioned cytokines at 8 h compared to saline controls. Adult males also displayed greater IL-1β mRNA expression compared to their female counterparts, and adult females displayed greater TNFα mRNA expression compared to their male counterparts. These results not only provide a better understanding of the age and sex differences in acute immune response, but also show important region- and time-specific differences in the response to an immune challenge, and that the peripheral immune response differs from the central response. This highlights the need to examine immune markers in both the periphery and the central nervous system for an accurate depiction of acute immune response following an immune challenge.

Sickness behavior monitoring, a technique for examining the development of sickness symptomatology following infection, is necessary in experiments studying neurochemical and physiological changes associated with pathogen-induced immune activation. However, the results of sickness behavior monitoring are difficult to reconcile due to inconsistencies in protocol methods and rater bias. The protocol described herein offers a non-invasive and unbiased approach to assess the progression of pathogen-induced sickness behaviors. This simple, straightforward method uses a five-point scale to assess animals for the presence of four sickness behaviors (i.e., '"0" = no sickness behaviors; "4" = four sickness behaviors) at various time points following exposure to a pathogen. This approach removes the ambiguity and bias inherent to other methods of sickness behavior monitoring that rely on subjective ratings of severity for individual symptoms. This protocol has been successfully applied to male and female rodents injected intraperitoneally with lipopolysaccharide and polyinosinic:polycytidylic acid, and has been effective in pubertal and adult populations. Protocols for changes in body temperature and weight are also provided as physiological markers of sickness. © 2017 by John Wiley & Sons, Inc.

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The mechanistic relationship between the sexually dimorphic neuroimmune system and the sex-specific outcomes of a pubertal immune challenge is unclear. Therefore, we examined sex differences in the progression of cytotoxic microglial responses and blood-brain barrier (BBB) disruption to a peripubertal lipopolysaccharide (LPS) treatment in brain regions relevant to stress responses and cognitive function. Six-week-old (i.e., stress-sensitive pubertal period) male and female CD-1 mice were treated with LPS (1.5 ​mg/kg body weight, ip ) or 0.9% saline (LPS-matched volume, ip ). Sex and treatment differences in microglial (Iba1 + ) and apoptotic neuronal (caspase-3 + /NeuN + ) and non-neuronal (caspase-3 + /NeuN − ) expression were examined in the hippocampus, medial prefrontal cortex (mPFC), and paraventricular nucleus 24 ​h (sickness), one week (symptomatic recovery) and four weeks (early adulthood) post-treatment ( n ​= ​8/group). Microglial morphology was quantified with fractal analyses. Group differences in BBB permeability to 14 C-sucrose were examined 24 ​h (whole-brain, hippocampus, prefrontal cortex, hypothalamus, and cerebellum) and one week (whole-brain) post-treatment. The acute effects of pubertal LPS were specific to females (i.e., global BBB disruption, altered microglial expression and morphology in the mPFC and hippocampus, increased hippocampal apoptosis). The residual effects of pubertal LPS-induced sickness observed in microglia persisted into adulthood in a sex- and region-specific manner. In addition to highlighting these sex-specific responses of the pubertal neuroimmune system, we report baseline region-specific sex differences in microglia spanning puberty through adulthood. We propose that these sex differences in neuroimmune-neurovascular interactions during the stress-sensitive pubertal period create sex biases in stress-related disorders of brain and behaviour.

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