The Selfish Brain: A new model of the LHPA-system

The limbic-hypothalamic-pituitary-adrenal (LHPA) system plays a crucial role in energy metabolism. The activity of the LHPA-system is indicated by serum cortisol concentration. Cortisol acts as feedback signal on the activity of the LHPA system on various hierarchical levels of the system: the limbic system, the hypothalamus, the pituitary and the adrenal glands. In the limbic system cortisol binds to cytosolic high- and low-affine corticosteroid receptors, which are known as Mineralo- (MR) and Glucocorticoid receptors (GR). The cortisol bound MR and GR can traverse into the cell nucleus where they form homo- and heterodimers with one another. MR-MR homodimers, MR-GR heterodimers and GR-GR homodimers interact with each other and bind to the glucocorticoid responsive element thereby controlling cell response and activity of the LHPA-system. Based on the concept of the “Selfish Brain“ we developed a mathematical model that describes the setpoint, the feedback and the control cycle of the LHPA-system. This model includes latest results of research like dimerization and autoregulation of MR and GR. By using systems of differential equations our model allows to simulate complex cortisol kinetics over the time. Previous models of the LHPA system failed to explain the regulation of the LHPA system under special circumstances and even lead to paradoxes. Considering the complex limbic MR-GR-feedback in our model we were now able to solve and explain these paradoxes. Findings derived from our model may elucidate how the LHPA system can lose its balance and contribute to diseases like depression or diabetes.