Regional Molecular Changes in Chronic Lipopolysaccharide-Induced Neuroinflammation

Abstract

Background

Neuroinflammation is linked to the development of depression. Exposure to the proinflammatory endotoxin lipopolysaccharide (LPS) is associated with a depressive-like phenotype in rodents. However, acute LPS exposure may reflect sickness behavior, and thus the molecular mechanisms and neurobehavioral changes associated with chronic neuroinflammation warrant investigation.

Methods

Using male Sprague Dawley rats (N = 37) we investigated the impact of systemic inflammation, following a single or multiple doses of LPS on neurobehavioral outcomes and brain regional gene expression of inflammatory, neurotrophic and apoptotic markers in the prefrontal cortex, striatum, hippocampus, hypothalamus, midbrain, cortex, and cerebellum.

Results

LPS administration induced systemic inflammation and subsequent neuroinflammation, as evidenced by increased circulating concentrations and regional expression of proinflammatory cytokines (Tnf-α and Il1β) in both short-term (ST) and long-term (LT) groups. Single LPS administration reduced the time spent in the center of the open field test after one week, while sucrose consumption was reduced with repeated LPS exposure. LPS showed a time- and region-specific effect on the expression of neurotrophins, as evidenced by increased messenger RNA expression of Ngf and Nt-3 in both the ST-LPS and LT-LPS groups, while Bdnf and Il6 expression was increased only in the LT-LPS group, and Creb expression was increased only in the ST-LPS group.

Conclusions

Taken together, our findings suggest that in LPS-induced systemic inflammation, Tnf-α and Il1β drive region-specific neurodegeneration via apoptotic processes, while Il6 and its regulatory interaction with neurotrophins may serve as a protective mechanism in neuroinflammation.