Estrogen Receptor α Functions in the Regulation of Motivation and Spatial Cognition in Young Male Rats

Estrogenic functions in regulating behavioral states such as motivation, mood, anxiety, and cognition are relatively well documented in female humans and animals. In males, however, although the entire enzymatic machinery for producing estradiol and the corresponding receptors are present, estrogenic functions have been largely neglected. Therefore, and as a follow-up study to previous research, we sub-chronically applied a specific estrogen receptor α (ERα) antagonist in young male rats before and during a spatial learning task (holeboard). The male rats showed a dose-dependent increase in motivational, but not cognitive, behavior. The expression of hippocampal steroid receptor genes, such as glucocorticoid (GR), mineralocorticoid (MR), androgen (AR), and the estrogen receptor ERα but not ERβ was dose-dependently reduced. The expression of the aromatase but not the brain-derived neurotrophic factor (BDNF) encoding gene was also suppressed. Reduced gene expression and increased behavioral performance converged at an antagonist concentration of 7.4 µmol. The hippocampal and blood serum hormone levels (corticosterone, testosterone, and 17β-estradiol) did not differ between the experimental groups and controls. We conclude that steroid receptors (and BDNF) act in a concerted, network-like manner to affect behavior and mutual gene expression. Therefore, the isolated view on single receptor types is probably insufficient to explain steroid effects on behavior. The steroid network may keep motivation in homeostasis by supporting and constraining the behavioral expression of motivation.

雌激素在调控动机、情绪、焦虑及认知等行为状态中的功能，在人类女性与实验动物中已有较为充分的研究记载。然而在雄性个体中，尽管合成雌二醇的全套酶促系统及相应受体均存在，但雌激素的功能却长期被极大忽视。因此，作为前期研究的后续工作，我们在年轻雄性大鼠开展空间学习任务（洞板实验，holeboard）的前后及任务期间，亚慢性给予特异性雌激素受体α（ERα）拮抗剂。结果显示，雄性大鼠的动机相关行为呈剂量依赖性增强，但认知行为未出现此类变化。海马体类固醇受体基因，如糖皮质激素受体（GR）、盐皮质激素受体（MR）、雄激素受体（AR）以及雌激素受体ERα（而非ERβ）的表达均呈剂量依赖性下调。编码芳香化酶的基因表达同样受到抑制，但脑源性神经营养因子（BDNF）的基因表达未受影响。基因表达下调与行为表现提升在拮抗剂浓度为7.4 µmol时达到交汇点。实验组与对照组的海马体及血清激素水平（皮质酮、睾酮及17β-雌二醇）并无显著差异。我们得出结论：类固醇受体（及BDNF）以协同的网络样方式共同影响行为及彼此的基因表达。因此，仅针对单一受体类型的孤立研究，或许不足以解释类固醇对行为的调控作用。该类固醇网络可能通过支持与约束动机的行为表达，维持动机的稳态平衡。