Asthma Induction During Development and Adult Lung Function, Behavior and Brain Gene Expression

Abstract

In developing youth, allergic asthma is the most common chronic condition, with 9%–10% of youth affected. Asthma onset during childhood and adolescence is further associated with other health issues, particularly psychiatric conditions. To understand causal mechanisms by which developmental asthma may lead to altered behavior, brain and health trajectories, we developed a mouse model of developmental allergic asthma. In the current study, we tested for potential long-term effects of developmental asthma on adult lung function and behavior and brain gene expression associated with emotion and stress regulation. We manipulated airway inflammation (AI) and methacholine (MCH)-induced bronchospasm (resulting in labored breathing, LB) in young male and female BALB/cJ mice and measured adult outcomes 3 months after final asthma manipulations. Results indicated that allergen exposure, used to cause AI, and which ended on post-natal day 56 (P56), led to persistent lung AI, mucus buildup and gene expression related to allergic asthma 3 months after final allergen exposure. In addition, at this same age, early allergen exposure led to altered brain gene expression related to stress regulation (prefrontal corticotropin releasing hormone receptor 1, Crhr1 and hippocampal glucocorticoid receptor, GR) and serotonin function (brainstem serotonin transporter, SERT). On the other hand, LB events during development led to altered anxiety-related behavior. Importantly, sex and pre-asthma fear-related behavior (ultrasonic vocalization, USV rates) modulated these adult outcomes. Asthma that develops during childhood/adolescence may have long-term impacts on emotion and stress regulation mechanisms, and these influences may be moderated by sex and pre-asthma temperament.

Individual differences in glucocorticoid regulation: Does it relate to disease risk and resilience?

“…Ones receiving just asthma had higher CORT and CRH mRNA expression compared to both COPD groups with no changes compared to controls (Cui et al, 2010). A similar downregulation in CORT concentration was observed in another asthma model, with this trend subsiding after asthma induction ends (Caulfield et al, 2018(Caulfield et al, , 2017. In an allergic mouse model, treatment with OVA alone or with metyrapone-RU486 (GC inhibitor) led to an increase in eosinophils, nasal rubs, and sneezes, as well as a decrease in circulating CORT, IL-4 and IL-5 compared to control and/or allergic untreated mice (Zhang et al, 2009).…”

Chronic allergic lung inflammation negatively influences neurobehavioral outcomes in mice

“…Developmental asthma and adult behavior has also been studied in mice. For example, sensitization with HDM in combination with repeated inhaled aerosolized methacholine challenge during development led to altered anxiety-related behavior with a higher serotonin transporter gene expression in the brainstem in mice [ 31 ]. Maternal asthma induced by ovalbumin and behavioral assessments of offspring revealed autism spectrum disorders-like behavioral outcomes in mice [ 32 ].…”