Chronic allergic lung inflammation negatively influences neurobehavioral outcomes in mice

Background: Asthma is a major public health problem worldwide. Emerging data from epidemiological studies show that allergies and allergic diseases may be linked to anxiety, depression and cognitive decline. However, little is known about the effect of asthma, an allergic lung inflammation, on cognitive decline/behavioral changes. Therefore, we investigated the hypothesis that allergic lung inflammation causes inflammation in the brain and leads to neurobehavioral changes in mice. Methods: Wild-type C57BL/6J female mice were sensitized with nasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. A series of neurocognitive tests for anxiety and/or depression were performed before and after the intranasal HDM administration. After the behavior tests, tissues were harvested to measure inflammation in the lungs and the brains. Results: HDM-treated mice exhibited significantly increased immobility times during tail suspension tests and significantly decreased sucrose preference compared with PBS controls, suggesting a more depressed and anhedonia phenotype. Spatial memory impairment was also observed in HDM-treated mice when assessed by the Y-maze novel arm tests. Development of lung inflammation after 6 weeks of HDM administration was confirmed by histology, bronchoalveolar lavage (BAL) cell count and lung cytokine measurements. Serum pro-inflammatory cytokines and Th2-related cytokines levels were elevated in HDM-sensitized mice. In the brain, the chemokine fractalkine was increased in the HDM group. The c-Fos protein, a marker for neuronal activity, Glial Fibrillary Acidic Protein (GFAP) and chymase, a serine protease from mast cells, were increased in the brains from mice in HDM group. Chymase expression in the brain was negatively correlated with the results of sucrose preference rate in individual mice. Conclusions: 6 weeks of intranasal HDM administration in mice to mimic the chronic status of lung inflammation in asthma, caused significant inflammatory histological changes in the lungs, and several behavioral changes consistent with depression and altered spatial memory. Chymase and c-Fos proteins were increased in the brain from HDM-treated mice, suggesting links between lung inflammation and brain mast cell activation, which could be responsible for depression-like behavior.