Centre for Neuroendocrinology, Department of Anatomy, University of Otago School of Biomedical Sciences, Dunedin, New Zealand.
Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Biomedical Sciences, Dunedin, New Zealand.
J Neuroendocrinol. 2023 Jun;35(6):e13302. doi: 10.1111/jne.13302. Epub 2023 Jun 6.
Polycystic ovary syndrome (PCOS) is a female endocrine disorder that is associated with prenatal exposure to excess androgens. In prenatally androgenized (PNA) mice that model PCOS, GABAergic neural transmission to and innervation of GnRH neurons is increased. Evidence suggests that elevated GABAergic innervation originates in the arcuate nucleus (ARC). We hypothesized that GABA-GnRH circuit abnormalities are a direct consequence of PNA, resulting from DHT binding to androgen receptor (AR) in the prenatal brain. However, whether prenatal ARC neurons express AR at the time of PNA treatment is presently unknown. We used RNAScope in situ hybridization to localize AR mRNA (Ar)-expressing cells in healthy gestational day (GD) 17.5 female mouse brains and to assess coexpression levels in specific neuronal phenotypes. Our study revealed that less than 10% of ARC GABA cells expressed Ar. In contrast, we found that ARC kisspeptin neurons, critical regulators of GnRH neurons, were highly colocalized with Ar. Approximately 75% of ARC Kiss1-expressing cells also expressed Ar at GD17.5, suggesting that ARC kisspeptin neurons are potential targets of PNA. Investigating other neuronal populations in the ARC we found that ~50% of pro-opiomelanocortin (Pomc) cells, 22% of tyrosine hydroxylase (Th) cells, 8% of agouti-related protein (Agrp) cells and 8% of somatostatin (Sst) cells express Ar. Lastly, RNAscope in coronal sections showed Ar expression in the medial preoptic area (mPOA), and the ventral part of the lateral septum (vLS). These Ar-expressing regions were highly GABAergic, and 22% of GABA cells in the mPOA and 25% of GABA cells in the vLS also expressed Ar. Our findings identify specific neuronal phenotypes in the ARC, mPOA, and vLS that are androgen sensitive in late gestation. PNA-induced functional changes in these neurons may be related to the development of impaired central mechanisms associated with PCOS-like features.
多囊卵巢综合征（PCOS）是一种女性内分泌疾病，与产前暴露于过量雄激素有关。在模拟 PCOS 的产前雄激素化（PNA）小鼠中，GABA 能神经传递到 GnRH 神经元和支配 GnRH 神经元的神经支配增加。有证据表明，升高的 GABA 能神经支配起源于弓状核（ARC）。我们假设，GABA-GnRH 回路异常是 PNA 的直接后果，是由于 DHT 与产前大脑中的雄激素受体（AR）结合所致。然而，目前尚不清楚 PNA 治疗时产前 ARC 神经元是否表达 AR。我们使用 RNAScope 原位杂交技术在健康妊娠第 17.5 天（GD）的雌性小鼠大脑中定位 AR mRNA（Ar）表达细胞，并评估特定神经元表型的共表达水平。我们的研究表明，不到 10%的 ARC GABA 细胞表达 Ar。相比之下，我们发现 ARC kisspeptin 神经元是 GnRH 神经元的关键调节因子，高度与 Ar 共表达。大约 75%的 ARC Kiss1 表达细胞在 GD17.5 时也表达 Ar，这表明 ARC kisspeptin 神经元可能是 PNA 的潜在靶点。在 ARC 中研究其他神经元群体时，我们发现约 50%的前阿黑皮素原（Pomc）细胞、22%的酪氨酸羟化酶（Th）细胞、8%的刺鼠相关蛋白（Agrp）细胞和 8%的生长抑素（Sst）细胞表达 Ar。最后，冠状切片的 RNAscope 显示 Ar 在中前脑（mPOA）和外侧隔核（vLS）的腹侧部分表达。这些表达 Ar 的区域高度 GABA 能，mPOA 中的 22%的 GABA 细胞和 vLS 中的 25%的 GABA 细胞也表达 Ar。我们的研究结果确定了 ARC、mPOA 和 vLS 中在妊娠晚期对雄激素敏感的特定神经元表型。这些神经元中 PNA 诱导的功能变化可能与 PCOS 样特征相关的中枢机制受损有关。
