Modulation of fear behavior and neuroimmune alterations in house dust mite exposed A/J mice, a model of severe asthma

Abstract

Fear-associated conditions such as posttraumatic stress disorder (PTSD) and panic disorder (PD) are highly prevalent. There is considerable interest in understanding contributory risk and vulnerability factors. Accumulating evidence suggests that chronically elevated inflammatory load may be a potential risk factor for these disorders. In this regard, an association of asthma, a chronic inflammatory condition, with PTSD and PD has been reported. Symptoms of PD and PTSD are more prevalent in severe asthmatics, compared to those with mild or moderate asthma suggesting that factors that influence the severity of asthma, may also influence susceptibility to the development of fear-related disorders. There has been relatively little progress in identifying contributory factors and underlying mechanisms, particularly, the translation of severe asthma-associated lung inflammation to central neuroimmune alterations and behavioral manifestations remains unclear. The current study investigated the expression of behaviors relevant to PD and PTSD (CO2 inhalation and fear conditioning/extinction) in A/J mice using a model of severe allergic asthma associated with a mixed T helper 2 (Th2) and Th17 immune response. We also investigated the accumulation of Th2- and Th17-cytokine expressing cells in lung and brain tissue, microglial alterations, as well as neuronal activation marker, delta FosB (ΔFosB)) in fear and panic regulatory brain areas. HDM-exposed mice elicited higher freezing during fear extinction. CO2-associated spontaneous and conditioned freezing, as well as anxiety or depression-relevant exploratory and coping behaviors were not altered by HDM treatment. A significant increase in brain Th17-associated inflammatory mediators was observed prior to behavioral testing, accompanied by microglial alterations in specialized blood brain barrier-compromised circumventricular area, subfornical organ. Post extinction measurements revealed increased ΔFosB staining within the medial prefrontal cortex and basolateral amygdala in HDM-treated mice. Collectively, our data show modulation of brain immune mechanisms and fear circuits by peripheral airway inflammation, and is relevant to understanding the risk and comorbidity of asthma with fear-associated disorders such as PTSD.