Loss of sensitivity to insulin-like growth factor I in orexin neurons is associated to perturbed sleep patterns during aging.

Abstract

Sleep disturbances are common during aging. Old mice show altered sleep structure, with changes in both slow and fast electro-corticographic (ECG) activity, and less transitions between sleep and wake stages, as compared to young animals. Insulin-like growth factor I (IGF-I), that is involved in hormonal changes during aging, was previously shown to increase ECG patterns in young mice and monkeys. More recently, we observed that IGF-I shapes sleep architecture through modulation of the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both stimulation of ECG patterns and activation of orexin neurons by systemic IGF-I were abrogated in old mice. Further, activation of orthodromically stimulated LH neurons by either systemic or local IGF-I in young mice was absent in old mice. As orexin neurons of old mice show markedly increased IGF-I receptor (IGF-IR) levels, suggesting loss of sensitivity to IGF-I, we treated them with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of ECG patterns. Thus, disturbed sleep structure in aging mice may be related to IGF-I resistance in orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.