Hough D, Bellingham M, Haraldsen I R, McLaughlin M, Robinson J E, Solbakk A K, Evans N P
Institute of Biodiversity Animal Health and Comparative Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G61 1QH, UK.
Department of Medical Neurobiology, Division of Clinical Neuroscience, Oslo University Hospital - Rikshospitalet, 0027 Oslo, Norway.
Psychoneuroendocrinology. 2017 Mar;77:1-8. doi: 10.1016/j.psyneuen.2016.11.029. Epub 2016 Nov 30.
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.
慢性促性腺激素释放激素激动剂（GnRHa）给药适用于下丘脑 - 垂体 - 性腺轴活动抑制有益的情况，如类固醇依赖性癌症、早发性性别焦虑症、中枢性性早熟，以及在兽医学中作为可逆性避孕药。然而，GnRH受体在生殖轴以外表达，例如在对学习和记忆过程至关重要的海马体等脑区。先前使用绵羊模型的研究表明，在青春期前阻断GnRH信号（GnRHa：醋酸戈舍瑞林）后，成年公羊（45周龄）的长期空间记忆会降低，且这与性腺类固醇信号的相关丧失无关。本研究调查了GnRHa治疗停止后这种影响是否会逆转。结果表明，青春期前GnRHa治疗抑制了公羊的生殖功能，在44周龄停止GnRHa治疗后生殖功能得以恢复，81周龄时GnRHa恢复组和对照组公羊的睾丸大小（相对于体重）相似即表明了这一点。在85周龄和99周龄进行空间定向和学习评估时，停止GnRHa治疗的公羊（GnRHa恢复组）与对照组的空间迷宫穿越时间相当。在83周龄和99周龄时，先前的GnRHa治疗改变了公羊在空间迷宫中超过特定点的速度，且这种影响的方向取决于性腺类固醇暴露情况，即与对照组相比，GnRHa恢复组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，停止GnRHa治疗后，GnRHa恢复组公羊的长期空间记忆表现仍然降低（P<0.05，慢1.5倍）。这一结果表明，正常青春期发生的时间可能代表海马体可塑性的关键时期。在这个青春期前阶段扰乱正常的海马体形成也可能对其他脑区和认知功能方面产生长期影响。
