Modeling of the Interaction Between the Serotonin Regulation Pathway and the Stress Response, Mediated by the Hypothalamic-Pituitary-Adrenal Axis, Using a Boolean Approximation: a Novel Study for Depression

Modeling of the Interaction between the Serotonin Regulation Pathway and the Stress Response, mediated by the Hypothalamic-Pituitary-Adrenal Axis, using a Boolean Approximation: a Novel Study for Depression.

Oscar Moreno-Ramos^1,2, Mar'a Claudia Lattig¹, AndrŽs Fernando Gonz‡lez²

^1. Laboratorio de GenŽtica Humana, Departamento de Microbiolog'a, Universidad de los Andes

^2. Grupo de Dise–o de Productos y Procesos, Departamento de Ingenier'a Qu'mica, Universidad de los Andes

Depression is a disease with a high incidence in world population and who suffer it, tend to bear different symptoms that can disable them to have a normal life. According to different studies performed into twins, the heritability of it is about 40%. Beside of this fact, the heritability gets higher if another member of the family suffers this disease or another neurological disorder. Thus, it has been hypothesized that depression has a strong genetic background because different genetic polymorphisms, of the serotonin metabolic pathway, have been found to be associated. Same, it has been found an association to have the disease if the patient suffered different stressor events in his childhood so; it shows that depression is highly related to stress and its response pathways as well. According to the interaction between the stress response and the serotonin metabolism, the principal aim of this work was to model the interaction between the serotoninergic pathway and the stress response pathway mediated by the hypothalamic-pituitary-adrenal axis using a Boolean approximation; in order to observe how is the interaction between both paths and examine if the system is stable. Also, we wanted to study which genes, when are mutated in-silico, causes the highest impact on the model stability. In this model, we also simulate the impact that anti-depressive drugs have on the biological pathway. The results obtained show that the network is stable with or without stress, but that stability is reached faster when the pathway is run without stress than when it is taking into account. Also we observed that the biological model generated predicts steady states (attractors) for each of the different runes done. Those attractors change in shape, especially when anti-depressive drugs were also included in the simulation. We also found that when the patient is depressive and is stressed too, anti-depressive drugs do not have the expected effect.