Abstract:
Background: Very preterm infants exhibit high rates of injury and impaired growth of white and grey matter, which are highly associated with subsequent neurodevelopmental impairment. There is strong evidence for a link between brain injury and exposure to lowlevel infection or inflammation around the time of birth. However, the mechanisms and exact timing of brain injury following infection are not fully understood. In this study, we examined the time course of inflammatory, pathological, and microstructural changes in the brain after mild, repeated inflammation in the very immature rat. Methods: Rat pups received repeated, daily injections of intraperitoneal saline (control) or lipopolysaccharide (LPS, 0.3 mg/kg/day) from postnatal day (PND) 1 to 3. Animals were sacrificed at +4 h, +10 h, or +24 h after a single dose of LPS at PND1, or at PND4 or PND21 after 3 doses of LPS, to assess the short-term and long-term changes in growth, cytokine responses, white and grey matter injury and growth, and neurodevelopmental/motor milestones. Results: LPS was associated with a rapid, acute elevation of peripheral and central cytokines/chemokines, which partially resolved by PND4. In the white matter, LPS was associated with long-term reductions in volume, numbers of oligodendrocytes, and axonal myelination (increased g-ratios), as well as ultrastructural changes assessed by diffusion MRI. Further, LPS was associated with a long-term reduction in cortical volume and ultrastructural changes, but no change in numbers of neurons or dendritic complexity. Functionally, there was a transient reduction in the righting reflex from PND5–7, and motor function was mildly impaired at PND21 after LPS exposure. Conclusion: These data suggest that mild but repeated peripheral inflammation at a very immature stage of development leads to an acute inflammatory response in the brain, with acute white matter cell death, followed by chronic deficits in white matter and cortical development. The continuing central inflammation during exposure to LPS suggests that there may be a window for anti-inflammatory interventions even after the start of infection/inflammation.