title: Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis.
abstract: Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.
authors.affiliation: Department of Catalysis and Chemical Engineering, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.
authors.forename: Željko
authors.initials: Ž
authors.lastname: Čupić
authors.affiliation: Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Marković
authors.affiliation: Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia.
authors.forename: Stevan
authors.initials: S
authors.lastname: Maćešić
authors.affiliation: Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Stanojević
authors.affiliation: Institute of Endocrinology, Diabetes and Metabolic Diseases, School of Medicine, University of Belgrade, Dr Subotica 13, 11000 Belgrade, Serbia.
authors.forename: Svetozar
authors.initials: S
authors.lastname: Damjanović
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, CMM L8:01, 17176 Stockholm, Sweden.
authors.forename: Vladana
authors.initials: V
authors.lastname: Vukojević
authors.affiliation: Department of Catalysis and Chemical Engineering, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia.
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Kolar-Anić
mesh_terms: D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008954:Models, Biological; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*