M7 Systemic neuroinflammation

Topic

Microglia—the resident immune cells of the central nervous system—become persistently activated in response to damage signals, and it is this sustained microglial activation that defines systemic neuroinflammation.

Activated microglia release pro-inflammatory cytokines that produce three distinct effects. First, these pro-inflammatory cytokines increase blood-brain barrier permeability, similar to the effects observed with the mass effect of a brain tumor. Second, they induce "sickness behavior"—specifically, a reduction in motivation and exploratory behavior. Third, they impair synaptic plasticity, extending the plasticity mechanism previously described regarding effective synaptic weight in another model, and paralleling the mechanism by which major depression impairs that same synaptic plasticity.

When this microglial activation and the resulting systemic neuroinflammation become chronic and sustained, they can induce progressive neurodegeneration, extending the concept of neuronal populations previously described in neurodevelopmental models.

Under normal conditions, however, microglia do not remain activated indefinitely: the system tends to resolve the systemic neuroinflammation, and the microglia return to a basal cytokine state—the same state they were in prior to receiving the damage signal that triggered their activation. Ultimately, it is these microglia—activated by damage signals and releasing pro-inflammatory cytokines that affect the blood-brain barrier, behavior, and synaptic plasticity—that determine whether systemic neuroinflammation resolves and returns to a basal cytokine state or, conversely, becomes chronic and leads to progressive neurodegeneration.

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