Goshen Inbal, Kreisel Tirzah, Ounallah-Saad Hadile, Renbaum Paul, Zalzstein Yael, Ben-Hur Tamir, Levy-Lahad Efrat, Yirmiya Raz
Department of Psychology, The Hebrew University, Jerusalem 91905, Israel.
Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):1106-15. doi: 10.1016/j.psyneuen.2007.09.004. Epub 2007 Oct 31.
Ample research demonstrates that pathophysiological levels of the pro-inflammatory cytokine interleukin-1 (IL-1) produces detrimental effects on memory functioning. However, recent evidence suggests that IL-1 may be required for the normal physiological regulation of hippocampal-dependent memory. To substantiate the physiological role of IL-1 in learning and memory we examined the induction of IL-1 gene expression following a learning experience, and the effects of IL-1 signaling blockade, by either genetic or pharmacological manipulations, on memory functioning. We show that IL-1 gene expression is induced in the hippocampus 24h following fear-conditioning in wild type mice, but not in two mouse strains with impaired IL-1 signaling. Moreover, we report that mice with transgenic over-expression of IL-1 receptor antagonist restricted to the CNS (IL-1raTG) display impaired hippocampal-dependent and intact hippocampal-independent memory in the water maze and fear-conditioning paradigms. We further demonstrate that continuous administration of IL-1ra via osmotic minipumps during prenatal development disrupt memory performance in adult mice, suggesting that IL-1 plays a critical role not only in the formation of hippocampal-dependent memory but also in normal hippocampal development. Finally, we tested the dual role of IL-1 in memory by intracerebroventricular (ICV) administration of different doses of IL-1beta and IL-1ra following learning, providing the first systematic evidence that the involvement of IL-1 in hippocampal-dependent memory follows an inverted U-shaped pattern, i.e., a slight increase in brain IL-1 levels can improve memory, whereas any deviation from the physiological range, either by excess elevation in IL-1 levels or by blockade of IL-1 signaling, results in impaired memory.
大量研究表明，促炎细胞因子白细胞介素-1（IL-1）的病理生理水平会对记忆功能产生有害影响。然而，最近的证据表明，IL-1可能是海马依赖性记忆正常生理调节所必需的。为了证实IL-1在学习和记忆中的生理作用，我们研究了学习经历后IL-1基因表达的诱导情况，以及通过基因或药理学操作阻断IL-1信号传导对记忆功能的影响。我们发现，野生型小鼠在恐惧条件反射后24小时海马中会诱导IL-1基因表达，但在两种IL-1信号传导受损的小鼠品系中则不会。此外，我们报告说，IL-1受体拮抗剂转基因过表达仅限于中枢神经系统（IL-1raTG）的小鼠在水迷宫和恐惧条件反射范式中表现出海马依赖性记忆受损和海马非依赖性记忆完整。我们进一步证明，在产前发育期间通过渗透微型泵持续给予IL-1ra会破坏成年小鼠的记忆表现，这表明IL-1不仅在海马依赖性记忆的形成中起关键作用，而且在正常海马发育中也起关键作用。最后，我们通过在学习后脑室内（ICV）给予不同剂量的IL-1β和IL-1ra来测试IL-1在记忆中的双重作用，提供了第一个系统性证据，即IL-1参与海马依赖性记忆呈倒U形模式，即脑内IL-1水平略有升高可改善记忆，而任何超出生理范围的偏差，无论是IL-1水平过度升高还是IL-1信号传导受阻，都会导致记忆受损。
