Physical exercise increases brain activity through mechanisms not yet known. We now report that in rats, running induces uptake of blood insulin-like growth factor I (IGF-I) by specific groups of neurons throughout the brain. Neurons accumulating IGF-I show increased spontaneous firing and a protracted increase in sensitivity to afferent stimulation. Furthermore, systemic injection of IGF-I mimicked the effects of exercise in the brain. Thus, brain uptake of IGF-I after either intracarotid injection or after exercise elicited the same pattern of neuronal accumulation of IGF-I, an identical widespread increase in neuronal c-Fos, and a similar stimulation of hippocampal brain-derived neurotrophic factor. When uptake of IGF-I by brain cells was blocked, the exercise-induced increase on c-Fos expression was also blocked. We conclude that serum IGF-I mediates activational effects of exercise in the brain. Thus, stimulation of the uptake of blood-borne IGF-I by nerve cells may lead to novel neuroprotective strategies.

Physical exercise ameliorates age-related neuronal loss and is currently recommended as a therapeutical aid in several neurodegenerative diseases. However, evidence is still lacking to firmly establish whether exercise constitutes a practical neuroprotective strategy. We now show that exercise provides a remarkable protection against brain insults of different etiology and anatomy. Laboratory rodents were submitted to treadmill running (1 km/d) either before or after neurotoxin insult of the hippocampus (domoic acid) or the brainstem (3-acetylpyridine) or along progression of inherited neurodegeneration affecting the cerebellum (Purkinje cell degeneration). In all cases, animals show recovery of behavioral performance compared with sedentary ones, i.e., intact spatial memory in hippocampal-injured mice, and normal or near to normal motor coordination in brainstem-and cerebellum-damaged animals. Furthermore, exercise blocked neuronal impairment or loss in all types of injuries. Because circulating insulin-like growth factor I (IGF-I), a potent neurotrophic hormone, mediates many of the effects of exercise on the brain, we determined whether neuroprotection by exercise is mediated by IGF-I. Indeed, subcutaneous administration of a blocking anti-IGF-I antibody to exercising animals to inhibit exercise-induced brain uptake of IGF-I abrogates the protective effects of exercise in all types of lesions; antibodytreated animals showed sedentary-like brain damage. These results indicate that exercise prevents and protects from brain damage through increased uptake of circulating IGF-I by the brain. The practice of physical exercise is thus strongly recommended as a preventive measure against neuronal demise. These findings also support the use of IGF-I as a therapeutical aid in brain diseases coursing with either acute or progressive neuronal death.

To initiate a system-level analysis of C. elegans DAF-7/TGF-beta signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-beta pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-beta pathway mutant animals, identified nine DAF-7/TGF-beta signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-beta signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-beta signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

No abstract

No abstract

No abstract

Specific changes in circulating levels of insulin-like growth factor I (IGF-I) and various IGF-binding proteins are known to occur in insulin-dependent diabetic patients and laboratory animals. However, little attention has been paid to the effects of this chronic metabolic disease on the IGF system of the central nervous system. Because various types of human cerebellar degeneration are accompanied by changes in the peripheral IGF-I system which are similar, although not identical, to those found in diabetes, we tested whether diabetes results in changes in the cerebellar IGF-I system. Streptozotocin-induced diabetic rats were divided into two groups: 1) well controlled diabetics, which received twice daily injections of insulin and had mean glucose levels in the normal range; and 2) poorly controlled diabetic animals, which received 1 U of insulin once a day and had glucose levels above 300 mg/dl. As previously described, there were significant decreases in circulating levels of IGF-I and IGFBP-3 (38-42 kDa band), and an increase in the 30-kDa IGFBP (likely corresponding to IGFBP-1) in poorly controlled diabetic animals. All these parameters were normal in well controlled diabetic rats. In addition, significant modifications in the cerebellar IGF-I system were found. Poorly controlled diabetic animals had significantly lower levels of IGF-I protein in the cerebellum, whereas no change in cerebellar IGF-I messenger RNA (mRNA) levels was found. A significant reduction in IGFBP-2 (31 kDa-band) protein and mRNA levels was also found in poorly controlled diabetics. Well controlled rats had normal cerebellar IGF-I levels, whereas levels of IGFBP-2 protein and mRNA were still significantly low. Finally, mRNA levels for the IGF-I receptor were similar in all experimental groups. These changes appear to be anatomically specific because other brain areas did not show the same alterations. The present results indicate that in the diabetic animal changes in circulating IGF-I and IGFBPs are accompanied by, and possibly implicated in, modifications of the IGF-I system in the cerebellum and possibly other brain regions. We suggest that modifications in the cerebellar, IGF-I system, which plays an important trophic role in postnatal life, may underlie, at least in part, specific neuronal losses known to occur in diabetic patients.

Undernutrition reduces circulating concentrations of insulin-like growth factor (IGF)-I, but how it affects the brain IGF system, especially during development, is largely unknown. We have studied IGF-I, IGF-II, IGF receptor and IGF binding protein (BP)-2 mRNA expression in the hypothalamus, cerebellum and cerebral cortex of neonatal rats that were food restricted beginning on gestational day 16. One group was refed starting on postnatal day 14. Rats were killed on postnatal day 8 or 22. Undernutrition did not produce an overall reduction in brain weight at either age but, at 22 days, both the cerebellum and hypothalamus weighed significantly less. At 8 days, no change was detected in the central IGF axis in response to undernutrition. However, in 22-day-old undernourished rats, IGF-I and IGF receptor mRNA expression were increased in both the hypothalamus and cerebellum, while IGFBP-2 was decreased, but only in the hypothalamus. Refeeding had no effect on any of these parameters. These results suggest that the hypothalamus and cerebellum respond to malnutrition and the decrease in circulating IGF-I, a peptide fundamental for growth and development, by increasing the local production of both the growth factor and its receptor in attempt to maintain normal development.