Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
Neuroendocrinology. 2024;114(11):1045-1065. doi: 10.1159/000541102. Epub 2024 Aug 23.
In perinatal female rats, the glutamine (Gln)-glutamate cycle (GGC) constitutively supplies Gln to neurons of the ventral lateral ventromedial nucleus of the hypothalamus (vlVMH) to sustain glutamatergic synaptic transmission (GST). In contrast, male pups may use Gln only during periods of elevated neuronal activity. Perinatal disruption of the GGC has sex-specific effects on the GST and morphology of vlVMH neurons during adulthood. Since (vl)VMH neuronal activities regulate mating behavior expression, we hypothesize that maintaining a perinatal intact GGC may be essential for the sexual differentiation of reproductive behaviors.
Using perinatal rats of both sexes, we pharmacologically killed astrocytes or blocked the GGC and supplemented them with exogenous Gln. Mating behavior, an open-field test and protein levels of GGC enzymes were examined during adulthood.
Killing astrocytes reduced mating behavior expression by 38-48% and 71-72% in male and female rats, respectively. Any blocker targeting the GGC consistently reduced female lordosis behavior by 52-73% and increased glutaminase protein levels in the hypothalamus, but blockers had no effect on the expression of or motivation for copulatory behavior in males. Exogenous Gln supplementation partly rescued the decline in Gln synthetase inhibitor-mediated sex behavior in females. Perinatal interruption of the GGC did not increase induced expression of female sexual behavior in hormone-primed castrated male rats or affect locomotion or anxiety-like behavior in either sex.
The intact GGC is necessary for behavioral feminization in female rats and may play little or no role in behavioral masculinization or defeminization in males.
在围产期雌性大鼠中，谷氨酰胺（Gln）-谷氨酸循环（GGC）持续向下丘脑腹外侧视前区（vlVMH）的神经元供应 Gln，以维持谷氨酸能突触传递（GST）。相比之下，雄性幼鼠可能仅在神经元活动增加期间使用 Gln。围产期 GGC 的破坏对成年后 vlVMH 神经元的 GST 和形态具有性别特异性影响。由于（vl）VMH 神经元的活动调节交配行为的表达，我们假设维持围产期完整的 GGC 对于生殖行为的性别分化可能是必不可少的。
使用两性围产期大鼠，我们用药理学方法杀死星形胶质细胞或阻断 GGC 并补充外源性 Gln。在成年期检查交配行为、旷场测试和 GGC 酶的蛋白质水平。
杀死星形胶质细胞分别使雄性和雌性大鼠的交配行为表达减少了 38-48%和 71-72%。任何针对 GGC 的阻断剂都一致地使雌性动物的发情行为减少了 52-73%，并增加了下丘脑的谷氨酰胺酶蛋白水平，但阻断剂对雄性的交配行为表达或动机没有影响。外源性 Gln 补充部分挽救了 Gln 合成酶抑制剂介导的雌性性行为下降。围产期 GGC 的中断不会增加激素预处理去势雄性大鼠中诱导的雌性性行为表达，也不会影响两性的运动或焦虑样行为。
完整的 GGC 对于雌性大鼠的行为女性化是必要的，而对于雄性大鼠的行为男性化或去女性化可能几乎没有作用或没有作用。
