Collaborative Research: Novel Corticosteroid Actions on Neurotransmitter Function

Intellectual merit: Acute activation of the hypothalamic-pituitary-adrenal (HPA) axis leading to the release of stress hormones (corticosteroids) into the circulation is crucial for dealing with emergencies. Paradoxically, persistent activation of this stress response can lead to impaired physiological or behavioral function. Thus, vertebrates depend upon a robust corticosteroid response to stressors as well as efficient termination of this response for long-term health and fitness. However, the acute neural actions of corticosteroids that facilitate organismal survival and initiate negative feedback mechanisms are poorly understood. Collaborative studies by the PIs point to an unusual mechanism of corticosteroid action that regulates the concentrations of a major group of neurotransmitters, the monoamines. The proposed studies investigate the hypothesis that corticosteroids acutely block clearance of monoamines, particularly serotonin, within the dorsomedial hypothalamus, a hypothalamic structure that integrates neuroendocrine, physiological, and behavioral responses to stress. The regulation of serotonin clearance during a stress response leading to enhanced serotonin signaling depends upon the inhibition of organic cation transporters (OCT) by corticosteroids. OCTs transport endogenous monoamines in a stresssensitive manner, but practically nothing is known about their function in the brain. OCTs are present, and corticosteroids regulate their activity in the dorsomedial hypothalamus (DMH) of rats and amphibians, suggesting that this newly discovered mechanism has been highly conserved in vertebrate evolution. Collaborative studies will use a rodent model to test this hypothesis at Arizona State University, University of Colorado at Boulder, and University of South Dakota. The specific aims are: 1) to investigate the functional significance of rapid corticosteroid actions on serotonergic signaling within the DMH, specifically its effects on HPA axis activity; 2) to determine the effects of stress and corticosteroid concentrations on extracellular serotonin concentrations in the DMH region and the dependence of these changes on OCTs; and 3) to investigate the cellular and molecular features that underlie clearance of extracellular serotonin in the DMH, and the inhibition of that process by corticosteroids during a stress response. The studies offer an exciting opportunity to investigate fundamental mechanisms underlying rapid actions of stress hormones with implications for understanding stress physiology and behavior. They should alter the way we think about stress hormones for several reasons: 1) OCT3 is a novel molecular target for corticosteroids in the brain; 2) ependymal and/or glial cells may have unsuspected roles in corticosteroid action; 3) stress-induced changes in monoamine concentrations, assumed to be due to neurotransmitter release, may instead be due to changes in monoamine clearance. Broader Impacts: A major goal of these studies is to train students (graduate, undergraduate, and high school) and post-docs in cutting-edge neuroscience research, state-of-the-art techniques, and critical thinking. These studies are well suited to generate enthusiasm for research in the next generation of scientists because each of the specific aims entails discovery about novel mechanisms of stress hormone action in the brain. The research training provided by the PIs is important to encourage undergraduate and high school students to not only appreciate the scientific process but, in many cases, pursue future careers in science. At the graduate and postdoctoral levels, the opportunity to work with high school and undergraduate students in a collaborative setting complements their research training by introducing an educational component which will carry over to the next stage in their careers. Each of the PIs has a long track record of dedication to undergraduate and graduate student educ