Microglial Dystrophy and Spatial Learning Impairments Following Exposure to Multiple Early-life Stressors in Rats.

Background: Adversities during perinatal critical windows act as a major risk factor for several psychopathologies during adolescence and adulthood. Protein malnutrition, infections, neurotoxicant exposure and social stressors are significant adverse factors encountered by neonates born to socio-economically compromised societies.

Purpose: The purpose of this study is to understand how the cumulative exposure to multiple perinatal stressors can result in conditions that mimic various neurological disorders in affected individuals later in life. The present study aimed to understand the involvement of microglia, their activation, priming and dystrophy due to multi-hit exposure in severe spatial learning and memory impairments.

Methods: Naïve female Wistar rats (n = 32; 140-150 gm) were divided into control and low protein (LP) groups and fed with 20% and 8% protein diets, respectively, starting from 15 days prior to breeding, followed by mating with healthy males. Pups from both control and LP groups, with their respective mothers, were maintained on their respective diets throughout the experimental regime. Both control and LP F1 Pups were injected intraperitoneally either with deltamethrin (DLT; 0.7 mg/kg body weight) from postnatal day (PND) 1-7 or lipopolysaccharide (LPS; 0.3 mg/kg body weight) at PND3 then a booster on PND5 or both in combination on specified days, forming eight groups: Control, Control+DLT, Control+LPS, Control+DLT+LPS, LP, LP+LPS, LP+DLT and LP+DLT+LPS (Multi-hit). Microglial priming was studied using immunohistochemical procedures, and spatial learning and memory were estimated by the Morris water maze test in F1 rats (1, 3, 6 months).

Results: Results revealed that LP F1-treated rats were more susceptible to stressors with reduced brain weight, long-term microglial activation specifying primed states with enhanced expression of CD11b/CR3, MHC-II/OX-6 and ED2.

Conclusion: Multi-hit exposure induced dystrophic changes in a large population of microglia, causing severe learning and memory impairments, suggesting that perinatal multi-hit exposure might become a significant risk factor for developmental disorders in adulthood.