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Published on: September 21, 2021
Early Postnatal Neuroinflammation Produces Key Features of Diffuse Brain White Matter Injury in Rats
John Waddell1, Shuying Lin2, Kathleen Carter1
1Division of Neonatology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Insights
Early-life neuroinflammation in rats, triggered by lipopolysaccharide (LPS), causes white matter injury and gray matter deficits, leading to long-term neurological impairments in sensorimotor and cognitive functions.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Perinatal infection is a key risk factor for diffuse white matter injury (dWMI) in preterm infants.
- dWMI affects oligodendrocyte lineage cells and gray matter neurons, causing neurological disability.
- The study investigates whether neuroinflammation disproportionately impacts white or gray matter cellularity.
Purpose of the Study:
- To determine the preferential impact of neuroinflammation on white versus gray matter cellular composition.
- To elucidate the neuropathological and behavioral consequences of early-life neuroinflammation.
Main Methods:
- Neuroinflammation was induced in rat pups using intracerebral lipopolysaccharide (LPS) administration on postnatal day 5.
- Neurobiological changes and behavioral outcomes were assessed from postnatal day 6 to 21.
- Key markers for cell differentiation, axonal injury, dendritic maturation, and neurogenesis were analyzed.
Main Results:
- LPS challenge activated microglia and astrocytes, inhibiting oligodendrocyte and neuron differentiation, leading to myelination deficits.
- Neuroinflammation reduced immature oligodendrocytes, caused axonal injury, and impaired dendritic maturation in the cortex.
- Deficits in neurogenesis were observed in the hippocampus, alongside sensorimotor, neuromuscular, and cognitive impairments.
Conclusions:
- Early postnatal neuroinflammation can independently induce the primary neuropathological features of diffuse white matter injury.
- This model highlights the significant impact of neuroinflammation on both white and gray matter development.
- The findings underscore the critical role of early-life inflammatory events in long-term neurological dysfunction.
Background:
Perinatal infection is a major risk factor for diffuse white matter injury (dWMI), which remains the most common form of neurological disability among very preterm infants. The disease primarily targets oligodendrocytes (OL) lineage cells in the white matter but also involves injury and/or dysmaturation of neurons of the gray matter. This study aimed to investigate whether neuroinflammation preferentially affects the cellular compositions of the white matter or gray matter.
Method:
Neuroinflammation was initiated by intracerebral administration of lipopolysaccharide (LPS) to rat pups at postnatal (P) day 5, and neurobiological and behavioral outcomes were assessed between P6 and P21.
Results:
LPS challenge rapidly activates microglia and astrocytes, which is associated with the inhibition of OL and neuron differentiation leading to myelination deficits. Specifically, neuroinflammation reduces the immature OLs but not progenitors and causes acute axonal injury (β-amyloid precursor protein immunopositivity) and impaired dendritic maturation (reduced MAP2+ neural fiber density) in the cortical area at P7. Neuroinflammation also reduces the expression of doublecortin in the hippocampus, suggesting compromise in neurogenesis. Utilizing a battery of behavioral assessments, we found that LPS-exposed animals exhibited deficits in sensorimotor, neuromuscular, and cognitive domains.
Conclusion:
Our overall results indicate that neuroinflammation alone in the early postnatal period can produce cardinal neuropathological features of dWMI.
