Early post-sepsis innate behavioral changes in aged mice occur independently of detectable neuroinflammation

Sepsis disproportionately causes long-term cognitive and functional impairments in elderly survivors, including deficits in activities of daily living and functional independence. The neurobiological mechanisms driving this vulnerability in the aged brain remain poorly understood. We tested whether the aged brain possesses a unique vulnerability to sepsis-induced impairment in the early post-acute recovery period.

Polymicrobial sepsis was induced in young (3-months) and aged (18-months) mice via cecal slurry injection, with dosing adjusted for comparable acute illness severity. Behavioral assessments (learning, memory, locomotion, innate behaviors) were performed through Day 7 post-infection. On Day 8, brains were analyzed for inflammatory cytokines, glial activation, neuronal protein expression, and blood-brain barrier (BBB) permeability.

Aged septic mice exhibited alterations in nest building and sociability, whereas young mice with comparable illness severity remained behaviorally resilient. The behavioral changes in aged mice occurred in the absence of broad systemic or neuroinflammation. Conversely, young septic mice maintained normal behavior despite significantly elevated systemic and neuroinflammation. Aged mice displayed signs of glial activation, neuronal protein modulation, and BBB permeability compared to young mice, but sepsis did not significantly exacerbate these markers in either group.

Our findings demonstrate an age-dependent divergence in neurologic recovery after sepsis: while young mice exhibit behavioral resilience despite systemic and neuroinflammation, aged mice display alterations in innate behavior that are present even after the apparent resolution of acute illness. This suggests that the changes in innate behavior in the aged mice are not driven solely by sepsis-induced inflammation, but rather by a cumulative burden of age-related vulnerabilities, including microglial priming, astrocytic activation, and increased BBB permeability, that render aged brains unable to compensate for a severe acute physiological challenge.