Tronson, N. C. | Search bioRxiv

bioRxiv2018

Sex-specific memory deficits after subchronic immune challenge

Memory impairments and cognitive decline persist long after recovery from major illness or injury, and correlate with increased risk of later dementia. Here we developed a subchronic peripheral immune challenge model to examine delayed and persistent memory impairments in females and in males. We show that intermittent injections of either lipopolysaccharide or Poly I:C cause memory decline in both sexes that are evident eight weeks after the immune challenge. Importantly, we observed sex-specific patterns of deficits. Females showed impairments in object recognition one week after challenge that persisted for at least eight weeks. In contrast, males had intact memory one week after the immune challenge but exhibited broad impairments in memory tasks including object recognition, and both context and tone fear conditioning several months later. The differential patterns of memory deficits in males and in females were observed without sustained microglial activation or changes in blood-brain barrier permeability. Together, these data suggest that transient neuroimmune activity results in differential vulnerabilities of females and males to memory decline after immune challenge. This model will be an important tool for determining the mechanisms in both sexes that contribute to memory impairments that develop over the weeks and months after recovery from illness. Future studies using this model will provide new insights into the role of chronic inflammation in the pathogenesis of long-lasting memory decline and dementias.

animal behavior and cognition↗

bioRxiv2018

Sex differences in hippocampal cytokines after systemic immune challenge

Increased production of cytokines in the in the brain during illness or injury modulates physiological processes, behavior, and cognitive function. It is likely that the pattern of cytokines, rather than the activation of any individual cytokine, determines the functional outcome of neuroimmune signaling. Cytokine networks may thus be particularly useful for understanding sex differences in immune and neuroimmune activation and outcomes. In this project, we aimed to determine the activation and resolution of hippocampal cytokine networks in both male and female mice. We measured 32 cytokines in the hippocampus and periphery of male and female mice at rest, 2, 6, 24, 48, and 168 hours after an acute systemic injection of lipopolysaccharide (LPS; 250g/kg). We hypothesized that males and females would exhibit both differences in individual cytokine levels and differences in network dynamics of hippocampal cytokines. Cytokines with sex-specific activation by LPS included male-specific elevations of IFN{gamma}, CSF1, CSF2, and IL-10; and female-specific activation of the IL-2 family and IL-4. We also observed differences in time course, where females showed more rapid elevations, and faster resolution of cytokine activity compared with males. Network analysis using ARACNE and Cytoscape demonstrated markedly different hippocampal cytokine networks across sex even at baseline, and sex differences in cytokine network activation states in response to LPS. Analysis of global shifts in cytokine concentrations further identified a period of cytokine and chemokine downregulation at 48 hours that was more pronounced in females compared with males. Together, these findings demonstrate that sex differences in neuroimmune responses include both differences in intensity of the cytokine response, and importantly differences in cytokine networks activated. Such sex differences in cytokine networks in the brain are likely critical for short and long-term functional outcomes associated with neuroimmune activation.

neuroscience↗