Editorial: Ultradian, Circadian, and Stress-Related Hypothalamic-Pituitary-Adrenal Axis Activity--A Dynamic Digital-to-Analog Modulation

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis helps to maintain basal and stress-related homeostasis of central nervous system (CNS), cardiovascular, metabolic, and immune functions (1, 2). Disregulation of this axis is involved in several behavioral, circulatory, endocrine/metabolic and immune disorders. In this issue of the journal, Windle et al. (3) report a detailed assessment of the ultradian rhythmicity of corticosterone secretion in the rat. Using an automated, frequent blood sampling technique, they demonstrated that the end-hormone of the HPA axis was secreted in an ultradian pulsatile fashion, with secretory episodes occurring in a constant frequency but with a variable amplitude. The nocturnal circadian rise of corti-costerone secretion resulted from increases in the amplitude of the pulses, whereas a brief stressor increased or failed to stimulate the secretion of corticosterone, depending on its timing, during or after a secretory episode, respectively. These findings make a lot of sense and merit commentary. The main regulation of the ultradian, circadian, and stress-related activity of the HPA axis occurs at the level of the hypothalamus, in particular the parvocellular components of the paraventricular (PVN) nuclei (1, 2). There, a finite number of neurons produce and secrete CRH and arginine vasopressin (AVP) into the hypophyseal portal system (Fig. 1). The majority of these neurons secrete CRH or AVP, whereas a minority secretes both neuropeptides. CRH and AVP appear to enhance the activity of each other and they synergistically stimulate ACTH secretion by cor-ticotroph cells (4-6). In certain situations, AVP secreted by collateral neuronal fibers of magnocellular neurons from the PVN and/or supraoptic (SON) nuclei participates in ACTH stimulation (7). Studies from experimental animals and humans have suggested that both parvocellular CRH and AVP are secreted in an ultradian pulsatile fashion and participate in the generation of a circadian ACTH and cortisol rhythm and in the elevation of the concentrations of these hormones during acute stress, by increasing the amplitude rather than the frequency of their ultradian secretory episodes (8-15). In the early 1980s, when ovine (o) and human (h) CRH became available for clinical studies and development of specific RIAs, Schulte et al. (12) administered large doses of oCRH as a continuous infusion to normal male volunteers. The circulating levels of oCRH attained were approximately 10 times higher than the concentrations of this neuropeptide in the hypophyseal portal system of rats. In response to these constantly elevated levels of oCRH, the frequently measured plasma ACTH and cortisol concentrations were increased, however, they retained their ul-tradian pulsatile and circadian patterns of secretion. These data suggested that a second CRF was secreted in an ultradian pulsatile and circadian fashion, which allowed retention of the typical secretory pattern of these hormones , in spite of the constant exposure of the corticotroph to high concentrations of CRH. Subsequent studies in rats (9, 11), sheep (10), horses (8), monkeys (14), and humans (13, 15) suggested that CRH and AVP are both secreted episodically at the relatively constant and similar frequencies of 1 to 3 secretory episodes per hour, with a temporal overlap of approximately 80% (Fig. 2A). The synchrony and amplitudes of these pulsations increase, the latter severalfold, in a circadian fashion and during stress (Fig. 2B). Thus, the generation of the baseline ultradian pattern of the activity of the HPA axis depends on a relatively constant oscillation of the parvocellular CRH, AVP, and CRH/AVP neurons, with the superimposition of several constitutive inputs, all expressed primarily as changes in amplitude (1, 2). These include: positive circadian input(s) from one or more pacemakers, tonic positive input from the locus caeruleus/norepinephrine (LC/NE) and dopam-inergic mesocorticolimbic systems, tonic negative input from the hippocampus and prefrontal cortex and negative feedback input from the arcuate nucleus-POMC-peptider-gic system and the end-hormone of the HPA axis cortisol or corticosterone, depending on the species. It appears that the CRH component of the HPA axis is more sensitive to the suppressive effect of glucocorticoids than the AVP component, and this includes not only the secretion of CRH vs. AVP but also the ability of these hormones to stimulate ACTH secretion; the hypothalamic magnocel-lular AVP-secreting neurons, on the other hand, may not be suppressed by glucocorticoids (16, 17). The generation of the stress-related increase in the activity of the HPA axis also depends on the relatively constant ultradian oscillation of the parvocellular CRH, AVP, and CRH/AVP neurons, and the superimposition of stress-related inputs, resulting in amplitude increases (1, 2). These are exerted directly and/or via activation of the locus caeruleus/norepinephrine (LC/NE) system and include: emotional stress inputs from the amygdala and the dopaminergic mesocorticolimbic system and prefrontal cortex, circulatory stress signals from changes in blood volume or pressure through vagal afferent nerves, os-motic, and chemical signals sensed humorally and