A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.
A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.
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DOI：
10.1016/j.psyneuen.2016.11.029
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发表时间：
2017-03
影响因子：
3.7
通讯作者：
Evans NP
中科院分区：
文献类型：
--
作者：
Hough D;Bellingham M;Haraldsen IR;McLaughlin M;Robinson JE;Solbakk AK;Evans NP
青春期前GnRHa损害长期空间记忆。这种损害在停止GnRHa治疗后未逆转。GnRHa停药后，空间定向和学习表现不受影响。停止GnRHa后，这些空间任务的进展速度发生了变化。GnRH在发育的关键窗口期不可逆地改变这些认知功能。长期促性腺激素释放激素激动剂（GnRHa）给药适用于抑制下丘脑-垂体-性腺轴活动有益的情况，如类固醇依赖性癌症、早发性性别焦虑、中枢性性早熟，以及用作兽医学中的可逆避孕药。然而，GnRH受体在生殖轴之外表达，例如大脑区域，如海马体，这对学习和记忆过程至关重要。以前的工作，使用绵羊模型，已经证明，长期空间记忆减少成年公羊（45周龄），以下围青春期阻断GnRH信号（GnRHa：醋酸戈舍瑞林），这是独立的性腺类固醇信号的相关损失。目前的研究调查了这种效应是否在GnRHa治疗停止后逆转。结果表明，青春期前后GnRHa处理抑制了公羊的生殖功能，在44周龄停止GnRHa处理后恢复，如在81周龄GnRHa恢复和对照公羊中相似的睾丸大小（相对于体重）所示。在85和99周龄的空间定向和学习评估期间，停止GnRHa治疗（GnRHa恢复）的公羊的空间迷宫穿越时间与对照组相当。以前的GnRHa治疗改变了公羊在83和99周龄时超越空间迷宫中特定点的进展速度，这种影响的方向取决于性腺类固醇暴露，即与对照组相比，GnRHa恢复公羊在繁殖季节进展更快，在非繁殖季节进展更慢。与对照组相比，GnRHa-恢复公羊的长期空间记忆性能在GnRHa停药后仍降低（P < 0.05，慢1.5倍）。这一结果表明，青春期正常发生的时间可能代表了海马可塑性的关键时期。在青春期前后扰乱正常的海马结构也可能对其他大脑区域和认知功能产生长期影响。
Peripubertal GnRHa impaired long-term spatial memory. This impairment was not reversed after discontinuing GnRHa-treatment. Spatial orientation and learning performance remained unaffected following GnRHa withdrawal. Speed of progression through these spatial tasks was altered after discontinuing GnRHa. GnRH irreversibly alters these cognitive functions during critical window of development. Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P < 0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function.