Central Noradrenergic Neuron Subtype Development and Function

National Institute Of Environmental Health Sciences

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Abstract

Brainstem noradrenergic neurons comprise a small yet diverse population of 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 responseto 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 toxicants. Interestingly, it has been observed that subpopulations of noradrenergic neurons are differentially susceptible to disease and following exposure to certain toxicants. Given these observations, we suspect that the key to understanding noradrenergic system dysfunction will not be found by focusing on the system as a whole. Rather, this phenotypic complexity will only be understood by uncovering the developmental and genetic factors that define unique functional subtypes of noradrenergic neurons. In pursuit of this goal, we investigate the development, organization, and function of genetically defined subsets of noradrenergic neurons in the mouse central nervous system. Our central hypothesis is that genetic and environmental perturbation of distinct noradrenergic neuron subtypes early in development result in enhanced susceptibility to cognitive and affective disorders later in life. To address this hypothesis, we have adopted a recombinase-based genetic strategy using a unique set of genetically modified mice to: 1) identify molecularly distinct subsets of noradrenergic neurons; 2) determine their structural organization; 3) uncover their functional role in circuits underlying anxiety; and 4) perturb their function to uncover critical periods of noradrenergic neuron development and to determine the long-term effect of these perturbations on anxiety.