Developing neurons under stress: glucocorticoids as modulators of neuronal plasticity in the prenatal lung

Abstract

The exposure to environmental factors during the perinatal period of development is associated with long-term changes in the organism. Exposure to stress and glucocorticoids (GCs) during this period can lead to several pathologies and systems malfunction. To accelerate lung maturation and reduce neonatal respiratory distress syndrome (RDS), synthetic GC receptor (GR) agonists (sGCs), as dexamethasone (DEX), are given to pregnant women in anticipation to preterm birth. Despite the clear benefit of sGCs on protecting from RDS related mortality, the administration of such drugs is not absent from long-term risks. Specially in several of such predicted pre-term infants whom are actually born within the correct timeframe, being devoid of any positive benefits of sGCs treatment. Several studies points that such treatment is associated with later life hyperglycemia, behavior disorders and allergic asthma.Given that GCs are strong inducers of neuronal plasticity, administration of synthetic analogues that cross the placenta can reach significant concentrations in the fetal tissues. The development of extrinsic neurons that reach the lungs begin during the latter half of pregnancy and extends up to afterbirth. During this sensitive period, synthetic GCs could potentially determinate the development of this network and push the lungs towards a disease prone state. It is well established now that efferent and afferent neurons in the airways are crucial players in the development of lung diseases, as asthma. Indeed, in the previous BEPE project, we have established a novel mechanism via TrkB signaling that drives cholinergic neuroplasticity in asthma. In this BEPE, we aim to: 1) study how early DEX exposure affects cholinergic neuron development and 2) establish the impact of DEX treatment on the capacity of such neurons to respond to asthma-related cytokines. For this, we propose to use in vitro models of: 1) cholinergic differentiated SH-SY5Ycells and 2) human pluripotent stem cell derived airway cholinergic neurons. As outcomes, we will perform calcium imaging, electrophysiology via microelectrode array (MEA) and RNA-seq for differential gene expression.