Emergent Patterns of HPA Hormone Pulsatility and Diurnal Variability in silico: Part 3 of 3
Jay Michael Otero and Hans B. Sieburg*
Laboratory for Biological Informatics and Theoretical Medicine
Department of Psychiatry, Department of Mathematics
University of California, San Diego
La Jolla, California 92093-0112 USA
*Author to whom all correspondence should be addressed.
Pulsatility in CRF, ACTH, and CORT secretion arose in HPA axes stimulated by regular, constant pulse stimulation. Early experiments produced pulsatile and variable CRF and ACTH levels (Exp. #12; Fig. 7). These secretion patterns emerged in simulations employing small adrenal populations, small-to-intermediate hypothalamic and pituitary populations, low-to-medium secretion rates, dual feedback inhibition, and constitutive CORT secretion. CORT levels tended to be elevated and sustained.
Figure 7. Experiment #12. Diurnal variability in CRF and ACTH secretion with steady-state CORT secretion produced in a simulation using regular pulse stimulation; small HPA populations; dual feedback inhibition; intermediate CRF and ACTH secretion rates; low CORT secretion rate; constitutive CORT secretion; and CRF, ACTH, and CORT eigenlifes of 30, 17, and 80 minutes (generation cycles), respectively. The figure uses symbols to graphically depict the parameters of a virtual HPA axis. The pulse generator stimulates "100%" of the hypothalamic cells for a one generation cycle duration at a regular interval of 63 cycles (minutes). Gland size is proportional to circle size. Secretion rate is proportional to the thickness of the arrows extending from each gland. Positive signs represent tropic (stimulatory) action on target glands. Constitutive (baseline) secretion is depicted by an open arrowhead. Feedback inhibition is represented by curved arrows extending to the hypothalamic and/or pituitary. Here, dual feedback inhibition is represented by recursive arrows marked with negative signs. The eigenlife of each hormone is proportional to the number of straight lines (and fractions thereof) adjacent to the hormone label.
Removal of inhibition to the hypothalamus caused regular CRF pulsatility without diurnal variability. Overall ACTH pulsatility was diminished and CORT levels were sustained (Exp. #13; Fig. 8).
Figure 8. Experiment #13. Diurnal variability in CRF and ACTH secretion with steady-state CORT secretion produced in a simulation using regular pulse stimulation; small HPA populations; short feedback inhibition; intermediate CRF and ACTH secretion rates; low CORT secretion rate; constitutive CORT secretion; and CRF, ACTH, and CORT eigenlifes of 30, 17, and 80 minutes (generation cycles), respectively.
Larger adrenal populations relative to hypothalamic and pituitary populations resulted in steady-state cortisol secretion and near total shutdown of CRF and ACTH secretion with only single breakthrough spikes (Exp. #16; Fig. 9).
Figure 9. Experiment #16. Single-spike CRF and ACTH secretion with steady-state CORT secretion produced in a simulation using regular pulse stimulation; small hypothalamic and pituitary populations; medium adrenal populations; dual feedback inhibition; intermediate CRF and ACTH secretion rates; low CORT secretion rate; constitutive CORT secretion; and CRF, ACTH, and CORT eigenlifes of 30, 17, and 80 minutes (generation cycles), respectively.
Simulations using larger hypothalamic and pituitary populations relative to adrenal populations showed regular pulsatility of CRF and ACTH with little diurnal variation (Exp. #19; Fig. 10). Overall cortisol secretion tended to be diminished but mirrored the pulsatility of the other two hormones.
Figure 10. Experiment #19. Pulsatile CRF, ACTH and CORT secretion produced in a simulation using regular pulse stimulation; large hypothalamic and pituitary populations; small adrenal populations; dual feedback inhibition; intermediate CRF and ACTH secretion rates; low CORT secretion rate; constitutive CORT secretion; and CRF, ACTH, and CORT eigenlifes of 30, 17, and 80 minutes (generation cycles), respectively.
Diurnal variability in CORT secretion was produced using small HPA populations, low CORT secretion, intermediate CRF and ACTH secretion, constitutive CRF secretion, and hypothalamic (long) feedback inhibition (Exp. #6; Fig. 11).
Figure 11. Experiment #6. Diurnal variability in simulated CRF, ACTH, and CORT secretion produced with regular pulse stimulation; small HPA populations; constitutive CRF secretion; intermediate CRF and ACTH secretion rates; low CORT secretion rate; hypothalamic (long) feedback inhibition; and CRF, ACTH, and CORT eigenlifes of 30, 17, and 80 minutes (generation cycles), respectively. Note amplitude modulation with regular pulse frequency. 34 discrete synchronous pulses arose in a one-to-one correspondence for CRF, ACTH, and CORT. Stimulated and constitutive CRF secretion produces periodicity in HPA secretion when long (hypothalamic) feedback inhibition is in place.
Computer simulations modeling basic aspects of HPA functioning can produce patterns of hormonal variability that are qualitatively similar to those observed in vivo. Pulsatility emerging from simple HPA axes driven by regular pacing in silico provides a basis for modeling circadian secretion patterns occurring clinically. Figure 12, adapted from Refetoff, et al. (1985), shows ACTH and cortisol pulses from representative clinical time series data (30 minute sampling from a normal subject).
Figure 12. ACTH and cortisol secretion in a normal human. These time series graphs (30 minute sampling) depict typical secretion patterns showing nine "significant" ACTH pulses and eight "significant" cortisol pulses. Adapted from Refetoff, et al (1985).
The diurnal pulsatility of the secretion patterns of Figure 12 is typical of the approximately 18-40 ACTH pulses and six to 15 secretory CORT episodes per day. Our simulations demonstrated that HPA pulsatility arises through interaction of multiple mechanisms at work in the HPA axis. By modulating HPA parameters and allowing the neuroendocrine simulator to recursively evolve, we produced diurnal patterns of hormone secretion in silico. Pulsatility in CRF and ACTH secretion and variability in amplitude occurred with regular stimulus pacing. Additionally, feedback mechanisms and constitutive CRF secretion appear important for the in silico establishment of "diurnal" patterns of CORT secretion. Experiment #6 (Fig. 11; Table II), with 34 discrete synchronous CRF, ACTH, and CORT pulses, produced periodicity when CRF was secreted at a baseline (constitutive) level and hypothalamic feedback alone was present. Since constitutive CRF secretion and hypothalamic feedback inhibition oppose each other, non-linear mechanisms appear to be involved. The synergism of long CORT eigenlife, hypothalamic feedback inhibition, and overall increased CRF secretion produced a stable configuration resulting in regular pulsatility and amplitude modulation. Interestingly, in Experiment #13 (Fig. 8; Table II), exclusively short (pituitary) loop feedback inhibition maintained CRF pulsatility but abolished CORT pulsatility. Steady state CORT levels emerged. Hence, the pituitary appears to serve as a "brake" on CORT pulsatility when pituitary feedback predominates. In vivo , this effect may manifest itself through changes in pituitary feedback sensitivity during the day. Additionally, animal studies showing regular pulsatility in CRF secretion and variability in frequency and amplitude of ACTH and cortisol secretion suggest that factors outside the hypothalamus are important in controlling adrenal hormone secretion (Mershon, Sehlhorst et al. 1992). Future experiments superimposing irregular boost stimulation patterns on regular stimulation pulsatility will aid in exploring the role of multiple pacemakers regulating circadian and diurnal patterns of HPA hormone secretion.
In Experiment #19 (Fig. 10; Table II), constitutive secretion of CORT and larger hypothalamic/pituitary populations resulted in steady CORT levels with superposition of pulsatile patterns mirroring CRF and ACTH activity. This is consistent with in vivo studies suggesting that pulsatile secretion of cortisol is superimposed on circadian patterns of secretion (Liu, Kazer et al. 1987). Clinically, cortisol-secreting tumors of the adrenal gland produce near complete suppression of ACTH and loss of diurnal variation in cortisol (McCutcheon and Oldfield ). We found in silico (Experiment #16; Fig. 9; Table II) that a larger ratio of adrenal to hypothalamic and pituitary cells resulted in high steady-state CORT levels with minimal CRF and ACTH secretion. Constitutive CORT secretion in this setting mirrors the autonomous secretion of cortisol-secreting tumors. It also seems that the relatively longer eigenlife of CORT, and its feedback inhibition on both hypothalamic and pituitary populations, saturates the system with CORT and paralyzes tropic hormone secretion. Due to the increased cell-to-effector ratio, simulations using larger hypothalamic and pituitary populations reduce the net magnitude of feedback inhibition and off-set the longer eigenlife of CORT.
Computer simulations of neuroendocrine functioning using the CDM-DS provide opportunities to explore complex in vivo dynamics. This paper shows that basic neuroendocrine dynamics can be simulated in silico. The patterns of hormonal secretion arising in the simulations indicate that diurnal variability can arise de novo from isolated and simple dynamic interactions. Expanding simulations to include multiple pulse generators is likely to cause more complex patterns of hormonal secretion. Alterations in feedback sensitivities with additional sources of inhibition and tropic influences can also be modeled to more realistically portray in vivo dynamics. Direct application of in vivo data will require scaling of in silico parameters to accurately translate real-world dynamics into the corresponding virtual world. Computer simulations allow opportunities to efficiently draw conclusions from available data and provide insight into possible directions for hypotheses exploration. in silico data may also support justification in procuring limited resources for particular scientific exploration.
This work was supported by MH18399 to JMO, and MH45688 and CDA9404655 to HBS.
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