Central Noradrenergic Neuron Subtype Development and Function

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Brainstem noradrenergic neurons comprise a small yet diverse population of norepinephrine-synthesizing cells that project to virtually all areas of the central nervous system. Through the release of norepinephrine, these neurons modulate functions as diverse as attention, emotion, appetite, memory, and response to stress. Consistent with this functional diversity, norepinephrine signaling is disrupted in a spectrum of neurodegenerative and neurodevelopmental disorders and following exposure to a number of environmental insults. Interestingly, it has been observed that subpopulations of noradrenergic neurons are differentially susceptible to disease-related cell death and vary in sensitivity to environmental insults. Given these observations, we suspect that the key to understanding noradrenergic system dysfunction will be the genetic and epigenetic factors across development that define unique functional subtypes of noradrenergic neurons. Using molecular, cellular, behavioral, and systems-based approaches we are investigating two critical and interrelated questions: 1) How does molecular and functional heterogeneity of noradrenergic neurons vary across the lifespan? 2) What is the impact of altered norepinephrine signaling during development on phenotypes associated with neurodevelopmental and neurodegenerative disorders? To address these questions, we employ a combination of mouse models, mouse and human neuroblastoma cell lines and hESCs. Our choice of model system is guided by a core principle in biological research that the appropriate experimental model is critically dependent on the specific biological question being addressed. To determine how molecular and functional heterogeneity of noradrenergic neurons vary across the lifespan, we developed a cost-effective pipeline to transcriptionally profile noradrenergic neurons from male and female mice at multiple developmental timepoints. In addition, we developed a mouse model and a set of new AAVs that allow us to determine how differential gene expression during development contributes to functional heterogeneity of adult noradrenergic neurons. We also initiated experiments to begin to uncover epigenetic factors that may underlie individual variation in norepinephrine levels and drive noradrenergic neuron function. To accomplish this, we used mouse and human neuroblastoma cell lines to characterize an evolutionarily conserved putative enhancer in intron one of the gene encoding dopamine β-hydroxylase, which catalyzes the conversion of dopamine to norepinephrine. Lastly, to determine the impact of altered norepinephrine signaling during development on phenotypes associated with neurodevelopmental and neurodegenerative disorders, we initiated experiments to examine the effects of prenatal pesticide exposure on noradrenergic neuron development and function.