Vulnerabilidad a estrés del cerebro lesionado: el IGF-I como modulador de la sensibiblidad del eje HPA

Abstract

Post-traumatic stress disorder (PTSD), a condition afflicting millions of people worldwide, represents an increasing health burden. Responses to stress show a wide individual variation. For instance, only a subset of combatants develops PTSD after exposure to war. One factor negatively affecting development of PTSD in war veterans is exposure to traumatic brain injury. Intriguingly, it has also been observed that traumatic brain injury (TBI) may protect against PTSD symptoms when damage encompasses brain areas putatively involved in PTSD such as prefrontal cortex and amygdala. It is also known that circulating insulin-like growth factor 1 (IGF-I), a hormone that exerts a wide variety of neuromodulatory and neuroprotective actions, decrease in late periods of TBI. The aim of my thesis is to further explore this relationship. In order to do so, I studied the effects of a combined model of mild TBI and PTSD on the anxiety behaviour of C57BL/6 mice and liver IGF-I deficient (LID) mice. The results presented here show that TBI increased the vulnerability to stress only when serum IGF-I levels were low. Since it was known that IGF-I is accumulated in the injury site, I performed a series of experiments to determine the source of this increase and conclude that was mainly blood borne. These results gave more support to the idea that the peripherally produced IGF-I that enters the brain after a brain insult, could be responsible for the decrease in anxiety behaviour in C57BL/6 mice. In fact, the administration of IGF-I directly into the brain exerted the same effect that the injury in two anxiety test, the elevated plus maze and the open field test. Finally, I studied the effects of this hormone in the hypothalamic-pituitary-adrenal (HPA) axis, one of the main axis activated by stress. The experiments showed that the lack of circulating IGF-I increased the sensitivity of the HPA axis trough the modulation of the FKBP5, a gene that codifies for a co-chaperone that forms a complex with the glucocorticoid receptor, providing with a possible mechanism of how IGF-I was affecting the anxiety behaviour.