Contrasting Disease Progression, Microglia Reactivity, Tolerance, and Resistance to Toxoplasma gondii Infection in Two Mouse Strains.

Our study investigated the innate immune response to Toxoplasma gondii infection by assessing microglial phenotypic changes and sickness behavior as inflammatory response markers post-ocular tachyzoite instillation. Disease progression in Swiss albino mice was compared with the previously documented outcomes in BALB/c mice using an identical ocular route and parasite burden (2 × 105 tachyzoites), with saline as the control. Contrary to expectations, the Swiss albino mice displayed rapid, lethal disease progression, marked by pronounced sickness behaviors and mortality within 11-12 days post-infection, while the survivors exhibited no apparent signs of infection. Comparative analysis revealed the T. gondii-infected BALB/c mice exhibited reduced avoidance of feline odors, while the infected Swiss albino mice showed enhanced avoidance responses. There was an important increase in microglial cells in the dentate gyrus molecular layer of the infected Swiss albino mice compared to the BALB/c mice and their respective controls. Hierarchical cluster and discriminant analyses identified three microglial morphological clusters, differentially affected by T. gondii infection across strains. The BALB/c mice exhibited increased microglial branching and complexity, while the Swiss albino mice showed reduced shrunken microglial arbors, diminishing their morphological complexity. These findings highlight strain-specific differences in disease progression and inflammatory regulation, indicating lineage-specific mechanisms in inflammatory responses, tolerance, and resistance. Understanding these elements is critical in devising control measures for toxoplasmosis.

Behavioral and Neuropathological Changes After Toxoplasma gondii Ocular Conjunctival Infection in BALB/c Mice.

Ocular infection with Toxoplasma gondii causes toxoplasmosis in mice. However, following ocular infection with tachyzoites, the cause of the accompanying progressive changes in hippocampal-dependent tasks, and their relationship with the morphology and number of microglia, is less well understood. Here, in 6-month-old, female BALB/c mice, 5 µl of a suspension containing 48.5 × 106 tachyzoites/ml was introduced into the conjunctival sac; control received an equal volume of saline. Before and after instillation, all mice were subject to an olfactory discrimination (OD) test, using predator (cat) feces, and to an open-field (OF) task. After the behavioral tests, the animals were culled at either 22 or 44 days post-instillation (dpi), and the brains and retinas were dissected and processed for immunohistochemistry. The total number of Iba-1-immunolabeled microglia in the molecular layer of the dentate gyrus was estimated, and three-dimensional reconstructions of the cells were evaluated. Immobility was increased in the infected group at 12, 22, and 43 dpi, but the greatest immobility was observed at 22 dpi and was associated with reduced line crossing in the OF and distance traveled. In the OD test, infected animals spent more time in the compartment with feline fecal material at 14 and at 43 dpi. No OD changes were observed in the control group. The number of microglia was increased at 22 dpi but returned to control levels by 44 dpi. These changes were associated with the differentiation of T. gondii tachyzoites into bradyzoite-enclosed cysts within the brain and retina. Thus, infection of mice with T. gondii alters exploratory behavior, gives rise to a loss in predator's odor avoidance from 2 weeks after infection, increased microglia number, and altered their morphology in the molecular layer of the dentate gyrus.

What Do Microglia Really Do in Healthy Adult Brain?

Microglia originate from yolk sac-primitive macrophages and auto-proliferate into adulthood without replacement by bone marrow-derived circulating cells. In inflammation, stroke, aging, or infection, microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, which have been studied extensively. However, less is known about their role in the healthy adult brain. Astrocytes and oligodendrocytes are widely accepted to strongly contribute to the maintenance of brain homeostasis and to modulate neuronal function. On the other hand, contribution of microglia to cognition and behavior is only beginning to be understood. The ability to probe their function has become possible using microglial depletion assays and conditional mutants. Studies have shown that the absence of microglia results in cognitive and learning deficits in rodents during development, but this effect is less pronounced in adults. However, evidence suggests that microglia play a role in cognition and learning in adulthood and, at a cellular level, may modulate adult neurogenesis. This review presents the case for repositioning microglia as key contributors to the maintenance of homeostasis and cognitive processes in the healthy adult brain, in addition to their classical role as sentinels coordinating the neuroinflammatory response to tissue damage and disease.

Reversible demyelination, blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain.

Interleukin-1beta (IL-1) expression is associated with a spectrum of neuroinflammatory processes related to chronic neurodegenerative diseases. The single-bolus microinjection of IL-1 into the central nervous system (CNS) parenchyma gives rise to delayed and localized neutrophil recruitment, transient blood-brain barrier (BBB) breakdown, but no overt damage to CNS integrity. However, acute microinjections of IL-1 do not mimic the chronic IL-1 expression, which is a feature of many CNS diseases. To investigate the response of the CNS to chronic IL-1 expression, we injected a recombinant adenovirus expressing IL-1 into the striatum. At the peak of IL-1 expression (days 8 and 14 post-injection), there was a marked recruitment of neutrophils, vasodilatation, and breakdown of the BBB. Microglia and astrocyte activation was evident during the first 14 days post-injection. At days 8 and 14, extensive demyelination was observed but the number of neurons was not affected by any treatment. Finally, at 30 days, signs of inflammation were no longer present, there was evidence of tissue reorganization, the BBB was intact, and the process of remyelination was noticeable. In summary, our data show that chronic expression of IL-1, in contrast to its acute delivery, can reversibly damage CNS integrity and implicates this cytokine or downstream components as major mediators of demyelination in chronic inflammatory and demyelinating diseases.