Lentiviral Infections Persist in Brain despite Effective Antiretroviral Therapy and Neuroimmune Activation

Antiretroviral therapy (ART) suppresses HIV-1 in plasma and CSF to undetectable levels. However, the impact of contemporary ART on HIV-1 brain reservoirs remains uncertain.

Sex differences and similarities in the neuroimmune response to central administration of poly I:C

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.

Anxiolytic effects of NLRP3 inflammasome inhibition in a model of chronic sleep deprivation

Sleep deprivation is a form of stress that provokes both inflammatory responses and neuropsychiatric disorders. Because persistent inflammation is implicated as a physiological process in anxiety disorders, we investigated the contributions of NLRP3 inflammasome signaling to anxiety and anxiolytic properties of flavanol diets in a model of chronic sleep deprivation. The results show a flavanol-rich dietary preparation (FDP) exhibits anxiolytic properties by attenuating markers of neuroimmune activation, which included IL-1β upregulation, NLRP3 signaling, and microglia activation in the cortex and hippocampus of sleep-deprived mice. Production of IL-1β and NLRP3 were critical for both anxiety phenotypes and microglia activation. Individual FDP metabolites potently inhibited IL-1β production from microglia following stimulation with NLRP3-specific agonists, supporting anxiolytic properties of FDP observed in models of sleep deprivation involve inhibition of the NLRP3 inflammasome. The study further showed sleep deprivation alters the expression of the circadian gene Bmal1, which critically regulated NLRP3 expression and IL-1β production.

Sex differences and similarities in the neuroimmune response to central administration of poly I:C

ABSTRACTThe 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.

Imaging of neuroinflammation in migraine with aura

ObjectiveTo determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.MethodsThirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.ResultsCompared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.ConclusionsThese findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

Major illnesses, including heart attack and sepsis, can cause cognitive impairments, depression, and progressive memory decline that persist long after recovery from the original illness. In rodent models of sepsis or subchronic immune challenge, memory deficits also persist for weeks or months, even in the absence of ongoing neuroimmune activation. This raises the question of what mechanisms in the brain mediate such persistent changes in neural function. Here, we used RNA-sequencing as a large-scale, unbiased approach to identify changes in hippocampal gene expression long after a subchronic immune challenge previously established to cause persistent memory impairments in both males and females. We observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, Surprisingly, we also found striking sex differences in both the magnitude of changes and the specific genes and pathways altered, where males showed persistent changes in both immune- and plasticity-related genes three months after immune challenge, whereas females showed few such changes. In contrast, females showed striking differential gene expression in response to a subsequent immune challenge. Thus, immune activation has enduring and sex-specific consequences for hippocampal gene expression and the transcriptional response to subsequent stimuli. Together with findings of long-lasting memory impairments after immune challenge, these data suggest that illnesses can cause enduring vulnerability to, cognitive decline, affective disorders, and memory impairments via dysregulation of transcriptional processes in the brain.