Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor
Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor
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DOI：
10.1210/en.2004-1285
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发表时间：
2005-09-01
期刊：
影响因子：
4.8
通讯作者：
Baram, TZ
中科院分区：
文献类型：
--
作者：
Fenoglio, KA;Brunson, KL;Baram, TZ
早期生活经历，包括母亲护理，会影响一生中依赖海马体的学习和记忆。在产后 d2-9 (P2-9) 期间处理幼崽可以刺激母亲护理，并改善记忆功能和压力应对能力。潜在的分子机制可能涉及下丘脑促肾上腺皮质激素释放因子（CRF）表达的早期（到P9）和持久减少以及随后（到P45）海马糖皮质激素受体（GR）表达的增加。然而，下丘脑 CRF 水平是否通过减少 CRF 受体激活和随后降低的血浆糖皮质激素水平影响海马 GR 表达（和记忆功能）的变化尚不清楚。在这项研究中，我们从 P10-17 起事后对未处理的大鼠施用 1 型 CRF 受体的选择性拮抗剂 NBI 30775，并使用两种独立的范例检查海马依赖性学习和记忆（P50-70），与初始和媒介物治疗的未处理大鼠以及初始和拮抗剂治疗的处理大鼠进行比较。还检查了海马 GR 和下丘脑 CRF mRNA 水平以及应激诱导的血浆皮质酮水平。短暂、部分选择性阻断未处理的大鼠中的 CRF1，可改善莫里斯水迷宫和物体识别测试的记忆功能，其水平显着优于未处理的大鼠和媒介物处理的对照组，并且与处理过的（未处理的、媒介物处理的和拮抗剂处理的）大鼠的记忆功能没有区别。 CRF1拮抗剂处理的未处理大鼠的海马CA1和齿状回中GR mRNA表达增加至与处理组相当的水平。因此，CRF1 激活的程度可能涉及下丘脑 CRF 水平和释放的变化，有助于海马 GR 表达以及学习和记忆功能的变化。
Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d2-9 (P2-9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression. However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear. In this study we administered selective antagonist for the type 1 CRF receptor, NBI 30775, to nonhandled rats post hoc from P10-17 and examined hippocampus-dependent learning and memory later (on P50-70), using two independent paradigms, compared with naive and vehicle-treated nonhandled, and naive and antagonist-treated handled rats. Hippocampal GR and hypothalamic CRF mRNA levels and stress-induced plasma corticosterone levels were also examined. Transient, partial selective blockade of CRF1 in nonhandled rats improved memory functions on both the Morris watermaze and object recognition tests to levels significantly better than in naive and vehicle-treated controls and were indistinguishable from those in handled (naive, vehicle-treated, and antagonist-treated) rats. GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF1-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts. Thus, the extent of CRF1 activation, probably involving changes in hypothalamic CRF levels and release, contributes to the changes in hippocampal GR expression and learning and memory functions.