Exercise Increases Insulin Signaling in the Hippocampus: Physiological Effects and Pharmacological Impact of Intracerebroventricular Insulin Administration in Mice

Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocam- pus, insulin improves synaptic plasticity, memory formation, and learn- ing via direct modulation of GABAergic and glutamatergic receptors. Separately, physical exercise and central insulin administration exert rel- evant roles in cognitive function. We here use CF1 mice to investigate (i) the effects of voluntary exercise on hippocampal insulin signaling and memory performance and (ii) whether central insulin administration alters the effects of exercise on hippocampal insulin signaling and mem- ory performance. Adult mice performed 30 days of voluntary exercise on running wheel and afterward both, sedentary and exercised groups, received intracerebroventricular (icv) injection of saline or insulin (0.5- 5 mU). Memory performance was assessed using the inhibitory avoid- ance and water maze tasks. Hippocampal tissue was measured for (U- 14 C) glucose oxidation and the immunocontent of insulin receptor/ signaling (IR, pTyr, pAktser473). Additionally, the phosphorylation of the glutamate NMDA receptor NR2B subunit and the capacity of gluta- mate uptake were measured, and immunohistochemistry was used to determine glial reactivity. Exercise significantly increased insulin periph- eral sensitivity, spatial learning, and hippocampal IR/pTyrIR/pAktser473 immunocontent. Glucose oxidation, glutamate uptake, and astrocyte number also increased relative to the sedentary group. In both memory tasks, 5 mU icv insulin produced amnesia but only in exercised animals. This amnesia was associated a rapid (15 min) and persistent (24 h) increase in hippocampal pNR2B immunocontent that paralleled the increase in glial reactivity. In conclusion, physical exercise thus increased hippocampal insulin signaling and improved water maze per- formance. Overstimulation of insulin signaling in exercised animals, however, via icv administration impaired behavioral performance. This effect was likely the result of aberrant phosphorylation of the NR2B subunit. V C 2010 Wiley-Liss, Inc.