Research Paper Volume 11, Issue 1 pp 174—184

Loss of the interaction between estradiol and insulin-like growth factor I in brain endothelial cells associates to changes in mood homeostasis during peri-menopause in mice

Victor Munive1,2, , Jonathan A. Zegarra-Valdivia1,3, , Raquel Herrero-Labrador1,2, , Ana M. Fernandez1,2, , Ignacio Torres Aleman1,2, ,

  • 1 Cajal Institute, Madrid, Spain
  • 2 Ciberned, Madrid, Spain
  • 3 Universidad Nacional de San Agustín de Arequipa, Arequipa, Perú

Received: September 25, 2018       Accepted: December 19, 2018       Published: January 11, 2019
How to Cite

Copyright: © 2019 Munive et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


We recently reported that exercise increases resilience to stress in young female mice. Underlying mechanisms include an interaction of the ovarian hormone estradiol (E2) with insulin-like growth factor I (IGF-I), and an increase in the hippocampal levels of the latter. Since changes in mood regulation during aging may contribute to increasing incidence of affective disorders at older age, we determined whether the protective actions of exercise are maintained at later ages. We found that during peri-menopause, exercise no longer improves resilience to stress and even becomes anxiogenic. Furthermore, the interaction seen in young females between the E2 α receptor (ERα) and the IGF-I receptor (IGF-IR) is lost at middle-age. In addition, E2 no longer induces IGF-I uptake by brain endothelial cells, and consequently, hippocampal IGF-I levels do not increase. Treatment of middle-aged females with an ERα agonist did not recover the positive actions of exercise. Collectively, these data indicate that the loss of action of exercise during peri-menopause may be related to a loss of the interaction of IGF-IR with ERα in brain endothelial cells that cannot be ameliorated by estrogen therapy. Changes in regulation of mood by physical activity may contribute to increased appearance of affective disorders along age.


IGF-I: insulin-like growth factor I; E2: estrogen; ERα: estrogen receptor alpha; ERβ: estrogen receptor beta.