Neuroendocrine Entrainment of the Adrenal Clock

University Of Minnesota-Twin Cities, Minneapolis MN

Investigators

Abstract

Daily variation in glucocorticoids is critical for homeostatic regulation of metabolic, cardiovascular and neural processes. An adrenal clock generates glucocorticoid rhythmicity, but elements that entrain the clock are unknown. The overall hypothesis is that sympathetic neural activity (SNA) is a critical adrenal input that transmits rhythmic light-dark and feeding time signals to modulate glucocorticoid rhythms by interacting with ACTH to entrain the adrenal clock. Experiments will use mPER2:Luciferase knockin mice, in which luciferase is rhythmically expressed under the control of the Per2 clock gene. To assess SNA-mediated entrainment, the PER2Luc rhythm will be measured in adrenal explants from intact or adrenal-denervated mice on a 12:12 light:dark cycle and after light-dark phase shifts. Use of hypophysectomized mice replaced with constant ACTH will address whether ACTH rhythms entrain the adrenal clock or augment SNA-mediated entrainment. Using restricted feeding, studies will determine whether the rate of food entrainment is reduced by denervation. Using pharmacological approaches, experiments will determine whether ACTH acts through a cyclic AMP-dependent pathway. Examining responses to adrenergic receptor agonists and antagonists will determine if the adrenal medulla links SNA and the adrenal clock. Broader Impacts: The use of the PER2Luc mice provides an innovative experimental model that will stimulate students to challenge current understanding of neuroendocrine function. With the College of Biological Sciences, the PI will develop an evaluation tool to measure the effectiveness of the research experience to enhance academic achievement in the College; results will be reported in annual NSF reports. The PI and his students also will participate in outreach activities, including Brain Awareness Week for elementary students, Brain Bee for secondary students, and Brain U for middle school science teachers. Finally, to promote information dissemination, the PI will share data with collaborators, like Professor Horacio de la Iglesia, University of Washington to enhance mutual lab productivity and augment student development.