Insulin-like growth factor I modulates sleep through hypothalamic orexin neurons.

Although sleep disturbances are common co-morbidities of metabolic diseases, the underlying processes linking both are not yet fully defined. Changes in the duration of sleep are paralleled by changes in the levels of insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activity-dependent entrance in the brain. However, the specific role, if any, of IGF-I in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle and arousal, is modulated by IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electro-corticographic patterns with predominant slow wave activity, and reduced onset-sleep latency. Collectively, these results extend the role in the brain of this pleiotropic growth factor to shaping sleep architecture through the regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

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.

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.

Acute exercise does not modify brain activity and memory performance in APP/PS1 mice.

Age is the main risk factor for Alzheimer´s disease (AD). With an increasingly aging population, development of affordable screening techniques to determine cognitive status will help identify population-at-risk for further follow-up. Because physical exercise is known to modulate cognitive performance, we used it as a functional test of cognitive health. Mice were submitted to treadmill running at moderate speed for 30 min, and their brain activity was monitored before and after exercise using electrocorticogram (ECG) recordings. After exercise, normal, but not APP/PS1 mice, a well established AD model, showed significantly increased ECG theta rhythm. At the same time normal, but not AD mice, showed significantly enhanced performance in a spatial memory test after exercise. Therefore, we postulate that a running bout coupled to pre- and post-exercise brain activity recordings will help identify individuals with cognitive alterations, by determining the presence or absence of exercise-specific changes in brain activity. Work in humans using a bout of moderate exercise plus electroencephalography, a clinically affordable procedure, is warranted.

A Concerted Action Of Estradiol And Insulin Like Growth Factor I Underlies Sex Differences In Mood Regulation By Exercise.

Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, exercise enhanced resilience to stress and physical arousal, two other important components of mood, only in females. Because exercise increases brain input of circulating insulin-like growth factor I (IGF-I), a potent modulator of mood, we explored whether sex-specific actions of exercise on mood homeostasis relate to changes in brain IGF-I input. We found that exercise increased hippocampal IGF-I levels only in cycling females. Underlying mechanism involved activation of estrogen (E2) receptors in brain vessels that led to increased uptake of serum IGF-I as E2 was found to stimulate IGF-I uptake in brain endothelial cells. Indeed, modulatory effects of exercise on mood were absent in female mice with low serum IGF-I levels or after either ovariectomy or administration of an E2 receptor antagonist. These results suggest that sex-specific brain IGF-I responses to physiological stimuli such as exercise contribute to dimorphic mood homeostasis that may explain sex differences in affective disorders.

A free radical-generating system regulates AßPP metabolism/processing: involvement of the ubiquitin/proteasome and autophagy/lysosome pathways.

Oxidative stress is an early event in the pathogenesis of Alzheimer's disease (AD). We previously reported that, in SK-N-MC cells, the xanthine/xanthine oxidase (X-XOD) free radical generating system regulates the metabolism/processing of the amyloid-ß protein precursor (AßPP). Oxidative stress alters the two main cellular proteolytic machineries, the ubiquitin/proteasome (UPS) and the autophagy/lysosome systems, and recent studies have established connections between the malfunctioning of these and the pathogenesis of AD. The aim of the present work was to examine the involvement of these proteolytic systems in the regulation of AßPP metabolism by X-XOD. The proteasome inhibitor MG132 was found to accelerate the metabolism/processing of AßPP promoted by X-XOD because it significantly enhances the secretion of α-secretase-cleaved soluble AßPP and also the levels of both carboxy-terminal fragments (CTFs) produced by α- and ß-secretase. Further, MG132 modulated the intracellular accumulation of holo-AßPP and/or AßPP CTFs. This indicates that the X-XOD modulation of AßPP metabolism/processing involves the UPS pathway. With respect to the autophagy/lysosome pathway, the AßPP processing and intracellular location patterns induced by X-XOD treatment closely resembled those produced by the lysosome inhibitor ammonium chloride. The present results suggest that the regulation of AßPP metabolism/processing by mild oxidative stress requires UPS activity with a simultaneous reduction in that of the autophagy/lysosome system.