The Circadian Regulation Of Glucocorticoid Release In Rodents

Abstract

Nearly all organisms living near the surface of the Earth contain circadian (circa - "about"; diem- "day") clocks functioning as an endogenous timekeeping mechanism by which the organism can coordinate biological processes with 24h cycles in the external environment (such as the daily light:dark cycle). In nature, the ~24h free-running oscillation of circadian clocks is synchronized or entrained with the precisely 24h solar day cycle. In mammals, the master circadian pacemaker is located in the hypothalamic suprachiasmatic nucleus (SCN) which regulates ~24h rhythms of biological activity. The master circadian pacemaker within the SCN modulates adrenal gland release of glucocorticoids (GCs). GCs are a class of steroids critical for the mobilization of energy throughout the organism. GCs are released from the adrenal cortex and exhibit a circadian oscillation anticipating the onset of locomotor activity. In addition to humoral input to the adrenal cortex via adrenocorticotropic hormone (ACTH), the functional anatomy of the adrenal cortex demonstrates extensive sympathetic input. These signal transduction cascades are largely dependent on cyclic adenosine monophosphate (cAMP)-associated signaling. Recent studies demonstrate cAMP is a core clock component required for the maintenance of cellular circadian activity. Circadian GC release might be regulated by 2 independent pathways: 1) via circadian modulation of ACTH release from the pituitary gland in the hypothalamic-pituitary-adrenal (HPA) axis; 2) via a multisynaptic neural pathway between the SCN and adrenal cortex. The studies of this dissertation demonstrate behaviorally split golden hamsters exhibit a dissociation of circadian oscillations of cortisol (the major hamster GC) and ACTH, suggesting the circadian release of GCs is regulated by modes independent of the HPA axis, such as multisynaptic innervation. Additionally, phase coordination of the adrenal circadian clock with the external environment can be controlled by temporal fluxes in cAMP signaling in the adrenal gland, which is ultimately responsible for resetting the adrenal circadian clock, as well as the generation of ~24h oscillations in the concentration of circulating plasma GCs. Chapter 3 of this dissertation demonstrates phase specific responsiveness to temporary and reversible interference with rhythmic adrenal cAMP signaling, a hallmark of entrainment processes.