Predictive Modeling of the Hypothalamic-Pituitary-Adrenal (ΗΡΑ) Function. Dynamic Systems Theory Approach by Stoichiometric Network Analysis and Quenching Small Amplitude Oscillations

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress

“…Thus, ultradian oscillations occur under defined conditions, without the need for circadian rhythm driven CRH pulse generation [17][18][19]. This very important characteristic of the model is in agreement with experimental findings showing that ultradian rhythmicity of cortisol does not cease after surgically disconnecting the hypothalamus from the pituitary [40], leaving the pituitary corticotrophs unstimulated by the hypothalamic CRH.…”

“…This low-dimensional model, described in detail in our previous studies [17][18][19], comprises CRH (corticotropin-releasing hormone), ACTH (adrenocorticotropic hormone), ALDO (aldosterone) and CORT (cortisol) as dynamic variables. Reactions (R1)-(R9) epitomize the following complex pathways: (R1) describes basal CRH production from the hypothalamic paraventricular nucleus; (R2) describes aldosterone production under the renin-angiotensin system control; (R3) describes the CRH stimulated ACTH production from the pituitary; (R4) and (R5) describe ACTH stimulated production of cortisol and aldosterone from the adrenal cortex; (R6) describes the positive feedback actions of cortisol, acting through hippocampal GR to enhance CRH, and consequently ACTH and its own production; (R7) exemplifies cortisol negative feedback through hippocampal MR where both aldosterone and cortisol compete for the same receptor, as well as through hypothalamic and pituitary GR; (R8) and (R9) describe ACTH and cortisol elimination, respectively.…”

“…A key feature of the model presented in Table 1 is the spontaneous evolution of ultradian oscillations, arising as a consequence of an intrinsic instability in the model [17][18][19]25]. Thus, ultradian oscillations occur under defined conditions, without the need for circadian rhythm driven CRH pulse generation [17][18][19].…”

“…Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.Key words: HPA axis, Stress, Cortisol, Predictive modeling, Circadian and ultradian rhythmicity acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4-6] superimposed on circadian oscillations, with a period of about 24 h. The importance of circadian rhythms for adequate functioning of the HPA axis has been recognized for years [7, 8]; in addition, new experimental [9-15] and theoretical [16][17][18][19][20][21][22][23][24][25][26][27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology. Since ultradian and circadian oscillations operate on different time scales, their effects are manifested in different biological realms.…”

“…acteristic frequencies: ultradian oscillations, with a period of 20-120 min [4][5][6] superimposed on circadian oscillations, with a period of about 24 h. The importance of circadian rhythms for adequate functioning of the HPA axis has been recognized for years [7,8]; in addition, new experimental [9][10][11][12][13][14][15] and theoretical [16][17][18][19][20][21][22][23][24][25][26][27] results offer enough evidence to support the indispensable roles of ultradian oscillatory dynamics of HPA hormones levels for normal physiology. Since ultradian and circadian oscillations operate on different time scales, their effects are manifested in different biological realms.…”