Department of Psychology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520, USA.
J Neurosci. 2010 Mar 24;30(12):4390-400. doi: 10.1523/JNEUROSCI.4333-09.2010.
We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17beta-estradiol (E(2)) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E(2) has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E(2) infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E(2)-induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E(2) infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E(2) infusion in middle-aged, but not aged, females. Intracerebroventricular E(2) infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E(2) to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E(2)-induced object recognition memory enhancement in young and middle-aged females and that the inability of E(2) to activate these pathways may underlie its failure to enhance object recognition in aged females.
我们之前的研究表明，背侧海马细胞外信号调节激酶（ERK）的激活对于 17β-雌二醇（E2）增强年轻去卵巢小鼠的新物体识别记忆是必需的（Fernandez 等人，2008）。在这里，我们想知道 E2 是否对中年和老年去卵巢小鼠具有类似的增强记忆作用，以及这些作用是否依赖于 ERK 和磷脂酰肌醇 3-激酶（PI3K）/Akt 的激活。我们首先证明，在新物体识别训练后立即给予脑室或海马内 E2 输注可增强中年女性的记忆巩固，但对老年女性没有影响。在中年女性中，E2 诱导的增强作用被海马内 ERK 或 PI3K 激活的抑制所阻断。在中年雌性动物中，脑室或海马内 E2 输注可在输注后 15 分钟而不是 5 分钟增加背侧海马中 p42 ERK 的磷酸化，这种作用被海马内 ERK 或 PI3K 激活的抑制所阻断。脑室或海马内 E2 输注可在中年女性中增加 5 分钟后增加背侧海马中的 PI3K 和 Akt 磷酸化，但在老年女性中没有。脑室内 E2 输注也可在 15 分钟后增加 PI3K 磷酸化，而这种作用被海马内 PI3K 抑制而不是 ERK 抑制所阻断。这些数据首次表明，背侧海马 PI3K/Akt 和 ERK 信号通路的激活对于 E2 增强中年雌性动物的新物体识别记忆是必需的。它们还表明，相似的背侧海马信号通路介导 E2 诱导的年轻和中年雌性动物的物体识别记忆增强，而 E2 无法激活这些通路可能是其无法增强老年雌性动物的物体识别记忆的原因。
