Abstract
BackgroundThe neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation.MethodsHere, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice.ResultsWe observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus.ConclusionOur data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.
Highlights
The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors
We aimed to identify a broader set of inflammatory cytokines induced in the hippocampus by direct neuroimmune stimulation via central administration of polycytidylic acid (poly I):C in both males and females
We focused on cytokines and chemokines that have previously been implicated in cognitive and affective dysfunction, including the commonly studied IL-1β, IL-6, IL-10, and TNF⍺ [48, 49]; as well as IL-4 [50, 51], IL-2 [46, 52], C-X-C motif chemokine ligand (CXCL10) [31, 53], and C-C motif chemokine ligand 2 (CCL2) [53]; as well as virusspecific responses (IFNα and IFNβ [54];); and measures of generic microglial and astrocyte activation (CD11b and Glial fibrillary acidic protein (GFAP) [55, 56];)
Summary
The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. The neuroimmune system is responsible for surveying the microenvironment and responding to illness, injury, and infection. It is required for behavioral responses to infection [1, 2] and normal, non-immune neural processes [3,4,5] including synaptic plasticity and memory formation [6, 7]. Understanding sex differences in the hippocampus is important for understanding exactly how Posillico et al Journal of Neuroinflammation (2021) 18:193 neuroimmune activation impacts cognition and contributes to psychiatric and neurological disorders in both sexes
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