There is strong evidence that the immune system changes dramatically during pregnancy in order to prevent the developing fetus from being "attacked" by the maternal immune system. Due to these alterations in peripheral immune function, many women that suffer from autoimmune disorders actually find significant relief from their symptoms throughout pregnancy; however, these changes can also leave the mother more susceptible to infections that would otherwise be mitigated by the inflammatory response (Robinson and Klein, 2012). Only one other study has looked at changes in microglial number and morphology during pregnancy and the postpartum period (Haim et al., 2016), but no one has yet examined the neuroimmune response following an immune challenge during this time. Therefore, in this study, we investigated the impact of an immune challenge during various time-points throughout pregnancy and the postpartum period on the expression of immune molecules in the brain of the mother and fetus. Our results indicate that similar to the peripheral immune suppression measured during pregnancy, we also see significant suppression of the immune response in the maternal brain, particularly during late gestation. In contrast to the peripheral immune system, immune modulation in the maternal brain extends moderately into the postpartum period. Additionally, we found that the fetal immune response in the brain and placenta is also suppressed just before parturition, suggesting that cytokine production in the fetus and placenta are mirroring the peripheral cytokine response of the mother.

Neuroimmune signaling is increasingly identified as a critical component of neuronal processes underlying memory, emotion and cognition. The interactions of microglia and astrocytes with neurons and synapses, and the individual cytokines and immune signaling molecules that mediate these interactions are a current focus of much research. Here, we discuss neuroimmune activation as a mechanism triggering different states that modulate cognitive and affective processes to allow for appropriate behavior during and after illness or injury. We propose that these states lie on a continuum from a naïve homeostatic baseline state in the absence of stimulation, to acute neuroimmune activity and chronic activation. Importantly, consequences of illness or injury including cognitive deficits and mood impairments can persist long after resolution of immune signaling. This suggests that neuroimmune activation also results in an enduring shift in the homeostatic baseline state with long lasting consequences for neural function and behavior. Such different states can be identified in a multidimensional way, using patterns of cytokine and glial activation, behavioral and cognitive changes, and epigenetic signatures. Identifying distinct neuroimmune states and their consequences for neural function will provide a framework for predicting vulnerability to disorders of memory, cognition and emotion both during and long after recovery from illness.

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Postpartum depression is a specific type of depression that affects approximately 10-15% of mothers (Wisner et al., 2013). While many have attributed the etiology of postpartum depression to the dramatic change in hormone levels that occurs immediately postpartum, the exact causes are not well-understood. It is well-known; however, that pregnancy induces a number of dramatic changes in the peripheral immune system that foster the development of the growing fetus. It is also well-known that changes in immune function, specifically within the brain, have been linked to several neuropsychiatric disorders including depression. Thus, we sought to determine whether pregnancy induces significant neuroimmune changes postpartum and whether stress or immune activation during pregnancy induce a unique neuroimmune profile that may be associated with depressive-like behaviors postpartum. We used late-gestation sub-chronic stress and late-gestation acute immune activation to examine the postpartum expression of depressive-like behaviors, microglial activation markers, and inflammatory cytokines within the medial prefrontal cortex (mPFC) and the hippocampus (HP). The expression of many immune molecules was significantly altered in the brain postpartum, and postpartum females also showed significant anhedonia, both independently of stress. Following late-gestation immune activation, we found a unique set of changes in neuroimmune gene expression immediately postpartum. Thus, our data indicate that even in the absence of additional stressors, postpartum females exhibit significant changes in the expression of cytokines within the brain that are associated with depressive-like behavior. Additionally, different forms of antenatal stress produce varying profiles of postpartum neuroimmune gene expression and associated depressive-like behaviors.

BackgroundIn addition to its classical effects on opioid receptors, morphine can activate glia and stimulate the production of pro-inflammatory immune molecules which in turn counteract the analgesic properties of morphine. We hypothesized that decreased morphine analgesia in females may be the result of exaggerated microglial activation in brain regions critical for analgesia.MethodsMale and female rats were treated with morphine and/or minocycline and morphine analgesia was examined using the hot plate. We also examined the expression of microglial and astrocyte markers in the pain pathway.ResultsMales treated with minocycline, a microglial inhibitor, exhibited a significant increase in acute morphine analgesia as previously shown; however, morphine analgesia was not affected by minocycline pretreatment in female rats. Minocycline decreased the expression of glial activation markers in the male spinal cord and periaqueductal gray as expected; however, these same molecules were upregulated in the female.ConclusionsThese data describe a significant difference between males and females in the behavioral effects following co-administration of morphine and minocycline.

Background The 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. Methods Here, 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. Results We 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. Conclusion Our 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.

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The 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 neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. Here, 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/6 mice. We 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-1a, IL-1β, IL-4, IL-6, TNFa, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNa 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. This suggests that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on synaptic plasticity and cognition. 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 including Alzheimer’s Disease and depression.