Chronic allergic lung inflammation is associated with brain mast cell-mediated suppression of neuronal activity and behavioral changes in mice

We have previously observed depressive-like behaviors in mice following the development of chronic allergic lung inflammation that potentially involved brain mast cell activation. However, the specific brain regions that might be responsible for the observed behavioral changes were not identified. The anterior cingulate cortex (ACC) has been implicated in depression, and hypoactivity of this region is seen in the electroencephalogram of patients with depression. In the current study, we tested our hypothesis that chronic allergic lung inflammation causes mast cell activation that affects neuronal activity in the ACC, leading to depressive-like behavioral changes in mice. We further explored whether preventing mast cell activation during allergen administration modulates neuronal activity and attenuates behavioral changes. Wild-type C57BL/6 J and Thy1-GCaMP6 mice were sensitized with intranasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. Intraperitoneal injection of cromolyn sodium was performed during HDM sensitization. Neurocognitive tests were carried out before and after the sensitization. In vivo cortical calcium imaging was performed through cranial windows in head-restrained awake mice, and spontaneous calcium activity was measured. Brain and lung tissues were harvested for assessment of inflammatory changes. Coronal sections of frontal cortex showed that mast cell-derived protease chymase expression was substantially increased in the ACC after 6 weeks of HDM treatment compared with PBS controls. The frequency of somatic calcium activity in ACC pyramidal neurons was reduced in HDM compared with PBS. Intraperitoneal administration of cromolyn sodium, a mast cell stabilizing agent, during HDM sensitization inhibited this frequency reduction observed in HDM sensitized mice. Behavioral changes observed in HDM sensitized mice by open field, light–dark and sucrose preference tests, were attenuated in mice that received cromolyn sodium during HDM sensitization. Cerebral mast cell degranulation and decreased somatic calcium activity of pyramidal neurons were observed in the ACC of mice with allergic lung inflammation. Co-administration of mast cell stabilizer cromolyn prevented this allergen-induced hypoactivity and behavioral changes. The activation of mast cells in ACC and decreased pyramidal neuronal activity may play a role in the depressive behaviors observed in mice after chronic HDM sensitization.