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

Abstract

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.

Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons

“…Indeed, numerous reports relate IGF-I with affective disorders [ 7 , 13 , 58 – 61 ], and specific potential mechanisms have started to unfold. For example, recent observations indicate that IGF-I participates in depression through its role in the serotonin system [ 6 ], while others related it to its involvement in adult hippocampal neurogenesis [ 62 ] or blood-brain-barrier function [ 63 , 64 ]. Thus, our observations widen the number of potential mechanisms whereby IGF-I intervenes in mood homeostasis, including coping responses through the orexinergic system, which emphasizes the system level (i.e.,: mood) of actions of this growth factor in the brain.…”

Insulin and insulin-like growth factor-I receptors in astrocytes exert different effects on behavior and Alzheimer´s-like pathology

“…Barnes maze. To assess spatial learning and memory, animals received reinforcement to escape from an open circular platform (92 cm Ø with 20 holes of 5 cm Ø) to the "escape chamber", as described (Ortiz et al, 2010;Zegarra-Valdivia et al, 2019). All animals received appropriate training (four trials per day), and trials were separated by 15 min.…”

“…Exploratory behavior and locomotion were assessed by introducing the animal to an open field arena (42 cm  42 cm  30 cm, Versamax; AccuScan Instruments, Inc.) for 10 min. All parameters were quantified as described (Zegarra-Valdivia et al, 2019). Time spent exploring specific areas of the arena was measured.…”

Interoceptive Information of Physical Vigor: Orexin Neurons Gauge Circulating Igf-I for Motivational Motor Output

“…Mice with low serum IGF-I levels (LID mice, Figure 1A) display a disparity of brain deficits and abnormal behaviors (Trejo et al, 2007;Zegarra-Valdivia et al, 2019).…”

“…The animals keep swimming until they give up, or they alternated between swimming and floating. A 6 min test session was video recorded and the last 4 min were scored (immobility time; (Munive et al, 2019). Evaluation of muscle mass.…”