Dulka Eden A, Moenter Suzanne M
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Endocrinology. 2017 Nov 1;158(11):3943-3953. doi: 10.1210/en.2017-00768.
Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype.
促性腺激素释放激素（GnRH）神经元通过脉冲式激素释放来调节生殖。多囊卵巢综合征（PCOS）以及年轻的高雄激素血症女孩中，通过黄体生成素（LH）脉冲测量发现GnRH释放受到破坏。在表现出PCOS诸多特征的成年产前雄激素化（PNA）小鼠中，LH升高与GnRH神经元动作电位发放增加有关。GnRH神经元活动在青春期前如何发展，以及其是否因性别或产前雄激素处理而改变尚不清楚。我们假设GnRH神经元在青春期前就活跃，且这种活动存在性别差异并受PNA影响。在交配后第16至18天给母鼠注射二氢睾酮（DHT）以产生PNA小鼠。监测来自1周龄、2周龄、3周龄、4周龄和成年小鼠脑片中绿色荧光蛋白（GFP）标记的GnRH神经元的动作电位发放。在所有测试年龄的小鼠中，GnRH神经元均有活性。在对照雌性小鼠中，活动在3周龄前随年龄增加，之后降至成年水平。相比之下，PNA雌性小鼠的活动没有变化，且在3周龄时降低。在2至3周龄时，对照雌性小鼠的活动高于雄性小鼠。PNA在任何年龄都不影响雄性小鼠的GnRH神经元发放率。短期动作电位模式也受年龄和PNA处理的影响。因此，GnRH神经元在青春期前通常比成年期更活跃，PNA降低了雌性小鼠青春期前的活动。青春期前的活动可能在GnRH神经元上游建立性别分化的神经网络中起作用；在此期间雄激素诱导的变化可能导致成年PNA小鼠以及可能的PCOS表型。
