Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

睡眠障碍在衰老过程中很常见。与年幼的动物相比，年老小鼠的睡眠结构发生了变化，皮层脑电图 (ECoG) 活动的速度和速度都发生了变化，睡眠和清醒阶段之间的转换也更少。胰岛素样生长因子 I (IGF-I) 参与衰老过程中的适应性变化，之前已被证明可以增加幼鼠和猴子的 ECoG 活性。此外，IGF-I 通过调节小鼠下丘脑外侧 (LH) 食欲素神经元的活动来塑造睡眠结构。我们现在报告说，在老年小鼠中，系统性 IGF-I 对 ECoG 激活和食欲素神经元的激发都被消除了。此外，在年轻小鼠中，全身或局部 IGF-I 促进了 LH 神经元的正向反应，但在老年小鼠中则不然。由于老年小鼠的食欲素神经元显示 IGF-I 受体 (IGF-IR) 表达失调，表明 IGF-I 敏感性受到干扰，我们用 AIK3a305（一种新型 IGF-IR 敏化剂）治疗老年小鼠，并观察到对 IGF-I 的反应恢复和恢复活力睡眠模式。因此，衰老小鼠睡眠结构紊乱可能与食欲素神经元上的 IGF-I 信号受损有关，反映出衰老小鼠大脑中 IGF-I 活性的广泛丧失。