Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J Comp Neurol. 2022 Aug;530(12):2100-2112. doi: 10.1002/cne.25322. Epub 2022 Apr 9.
The hippocampus has become a significant target of stress research in recent years because of its role in cognitive functioning, neuropathology, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite the pervasive impact of stress on psychiatric and neurological disease, many of the circuit- and cell-dependent mechanisms giving rise to the limbic regulation of the stress response remain unknown. Hippocampal excitatory neurons generally express high levels of glucocorticoid receptors (GRs) and are therefore positioned to respond directly to serum glucocorticoids. These neurons are, in turn, regulated by neighboring interneurons, subtypes of which have been shown to respond to stress exposure. However, GR expression among hippocampal interneurons is not well characterized. To determine whether key interneuron populations are direct targets for glucocorticoid action, we used two transgenic mouse lines to label parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. GR immunostaining of labeled interneurons was characterized within the dorsal and ventral dentate hilus, dentate cell body layer, and CA1 and CA3 stratum oriens and stratum pyramidale. While nearly all hippocampal SST+ interneurons expressed GR across all regions, GR labeling of PV+ interneurons showed considerable subregion variability. The percentage of PV+, GR+ cells was highest in the CA3 stratum pyramidale and lowest in the CA1 stratum oriens, with other regions showing intermediate levels of expression. Together, these findings indicate that, under baseline conditions, hippocampal SST+ interneurons are a ubiquitous glucocorticoid target, while only distinct populations of PV+ interneurons are direct targets. This anatomical diversity suggests functional differences in the regulation of stress-dependent hippocampal responses.
近年来，由于其在认知功能、神经病理学和下丘脑-垂体-肾上腺 (HPA) 轴调节中的作用，海马体已成为应激研究的重要目标。尽管压力对精神和神经疾病有普遍影响，但导致边缘系统对应激反应的调节的许多与回路和细胞相关的机制仍不清楚。海马体兴奋性神经元通常表达高水平的糖皮质激素受体 (GR)，因此能够直接对血清糖皮质激素做出反应。这些神经元反过来又受到邻近中间神经元的调节，其中一些亚型已被证明对应激暴露有反应。然而，海马体中间神经元中的 GR 表达尚未得到很好的描述。为了确定关键的中间神经元群体是否是糖皮质激素作用的直接靶标，我们使用两种转基因小鼠品系标记 Parvalbumin 阳性 (PV+) 和 Somatostatin 阳性 (SST+) 中间神经元。在背侧和腹侧齿状回的齿状回细胞体层以及 CA1 和 CA3 的放射状层和锥体层内，对标记的中间神经元进行 GR 免疫染色。虽然几乎所有海马 SST+中间神经元在所有区域都表达 GR，但 PV+中间神经元的 GR 标记显示出相当大的亚区变异性。在 CA3 锥体层中，PV+、GR+细胞的百分比最高，而在 CA1 放射状层中则最低，其他区域的表达水平居中。这些发现表明，在基础条件下，海马 SST+中间神经元是普遍的糖皮质激素靶标，而只有特定的 PV+中间神经元群体是直接靶标。这种解剖学多样性表明，应激依赖性海马体反应的调节存在功能差异。
