The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-D-[1-14 C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1؊͞؊ mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-D-[1-14 C]glucose is significantly reduced in synaptosomes prepared from Igf1؊͞؊ brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine͞threonine kinase Akt͞ PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1؊͞؊ neurons. Phosphorylation of glycogen synthase kinase 3␤ and glycogen accumulation also are reduced in Igf1؊͞؊ neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism.mental retardation ͉ glycogen synthase kinase ͉ glucose transporter ͉ GLUT4 ͉ Akt T he brain requires enormous supplies of fuel to support neuroglial growth and process formation during early postnatal development. Murine and human brains consume over half the energy available to the organism as a whole during this critical period (1), when undernutrition may result in permanent intellectual deficit (2). How the developing brain competes so successfully with peripheral tissues for resources is unknown. Insulin preferentially enhances fuel and substrate utilization by peripheral tissues, but does not seem to be involved in the regulation of brain metabolism (3). Very little insulin is synthesized within the brain (4) and little circulating insulin crosses the blood-brain barrier (5). However, insulin-like growth factor 1 (Igf1), an insulin homologue, is abundant in the developing brain (6), where it is concentrated in large projection neurons (7-9). Igf1 and insulin receptors are also homologous, with nearly identical signal-transducing domains engaging many of the same intracellular pathways (10). The Igf1 receptor (Igf1R) is widely expressed in the brain (11)(12)(13)(14) where it is most abundant in Igf1-expressing neurons (15), suggesting a local autocrine͞paracrine mode of action for neuronal Igf1. Although Igf1's precise role in brain development is unknown, its importance seems clear because IGF1 gene deletion in humans results in mental retardation (16). Based on Igf1͞Igf1R expression patterns in the developing brain and on the functional homology with the insulin͞insulin receptor dyad, we hypothesized that neuronal Igf1 serves an anabolic, literally ''insulin-like'' role in brain development (17). To test this hypothesis, we investigated glucose utilization in Igf1-targeted gene deletion mice. Experimental ProceduresThe mice ...

Aged (20–22 months) male Fischer 344 rats were randomly assigned to sedentary (A-SED), environmentally enriched (A-ENR) or exercise (A-EX) conditions. After 10–12 weeks of differential experience, the three groups of aged rats and young sedentary controls were tested for physical and cognitive function. Spatial discrimination learning and memory consolidation, tested on the water maze, were enhanced in A-ENR compared to A-SED. A-EX exhibited improved and impaired performance on the cue and spatial task, respectively. Impaired spatial learning in A-EX was likely due to a bias in response selection associated with exercise training, as object recognition memory improved for A-EX rats. An examination of senescent hippocampal physiology revealed that enrichment and exercise reversed age-related changes in long-term depression (LTD) and long-term potentiation (LTP). Rats in the enrichment group exhibited an increase in cell excitability compared to the other two groups of aged animals. The results indicate that differential experience biased the selection of a spatial or a response strategy and factors common across the two conditions, such as increased hippocampal activity associated with locomotion, contribute to reversal of senescent synaptic plasticity.

The interactions of insulin-like growth factors (IGFs) with the type I IGF receptor are modulated by a family of high-affinity IGF binding proteins (IGFBPs). One of these, IGFBP2, demonstrates a striking spatiotemporal relationship with IGF-I during cerebellar and retinal development. IGF-I mRNA is transiently expressed in large projection neurons--cerebellar Purkinje and retinal ganglion cells--while IGFBP2 mRNA is selectively expressed by contiguous neuroglia--Bergmann glia in the cerebellum and Muller cells and astrocytes of the nerve fiber layer in the retina. IGF-I and IGFBP2 gene expression is not only neuroanatomically coordinated but also temporally synchronized, peaking together during the postnatal maturation of these structures. This pattern of IGF system expression suggests that IGFBP2 is closely related to IGF-I's action in the developing nervous system.

SummaryPeripheral nerves from aged animals exhibit features of degeneration, including marked fiber loss, morphological irregularities in myelinated axons and notable reduction in the expression of myelin proteins. To investigate how protein homeostatic mechanisms change with age within the peripheral nervous system, we isolated Schwann cells from the sciatic nerves of young and old rats. The responsiveness of cells from aged nerves to stress stimuli is weakened, which in part may account for the observed age-associated alterations in glial and axonal proteins in vivo . Although calorie restriction is known to slow the aging process in the central nervous system, its influence on peripheral nerves has not been investigated in detail. To determine if dietary restriction is beneficial for peripheral nerve health and glial function, we studied sciatic nerves from rats of four distinct ages (8, 18, 29 and 38 months) kept on an ad libitum (AL) or a 40% calorie restricted diet. Age-associated reduction in the expression of the major myelin proteins and widening of the nodes of Ranvier are attenuated by the dietary intervention, which is paralleled with the maintenance of a differentiated Schwann cell phenotype. The improvements in nerve architecture with diet restriction, in part, are underlined by sustained expression of protein chaperones and markers of the autophagylysosomal pathway. Together, the in vitro and in vivo results suggest that there might be an age-limit by which dietary intervention needs to be initiated to elicit a beneficial response on peripheral nerve health.