Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Instituto de Investigación Biomédica de Málaga-IBIMA, 29590 Málaga, Spain.
Int J Mol Sci. 2023 May 31;24(11):9565. doi: 10.3390/ijms24119565.
Cortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as its dysregulation is associated with debilitating conditions such as Alzheimer's Disease, chronic stress, anxiety and depression. Among other brain regions, cortisol importantly influences the function of the hippocampus, a structure central for memory and emotional information processing. The mechanisms fine-tuning the different synaptic responses of the hippocampus to steroid hormone signaling remain, however, poorly understood. Using ex vivo electrophysiology and wild type (WT) and miR-132/miR-212 microRNAs knockout (miRNA-132/212) mice, we examined the effects of corticosterone (the rodent's equivalent to cortisol in humans) on the synaptic properties of the dorsal and ventral hippocampus. In WT mice, corticosterone predominantly inhibited metaplasticity in the dorsal WT hippocampi, whereas it significantly dysregulated both synaptic transmission and metaplasticity at dorsal and ventral regions of miR-132/212 hippocampi. Western blotting further revealed significantly augmented levels of endogenous CREB and a significant CREB reduction in response to corticosterone only in miR-132/212 hippocampi. Sirt1 levels were also endogenously enhanced in the miR-132/212 hippocampi but unaltered by corticosterone, whereas the levels of phospo-MSK1 were only reduced by corticosterone in WT, not in miR-132/212 hippocampi. In behavioral studies using the elevated plus maze, miRNA-132/212 mice further showed reduced anxiety-like behavior. These observations propose miRNA-132/212 as potential region-selective regulators of the effects of steroid hormones on hippocampal functions, thus likely fine-tuning hippocampus-dependent memory and emotional processing.
皮质醇是一种强效的人类类固醇激素，在中枢神经系统中发挥关键作用，影响大脑神经元突触可塑性等过程，并调节情绪和行为反应的表达。皮质醇在疾病中的相关性尤为突出，因为其失调与阿尔茨海默病、慢性应激、焦虑和抑郁等衰弱性疾病有关。在其他大脑区域中，皮质醇重要地影响海马体的功能，海马体是记忆和情绪信息处理的中枢结构。然而，调节海马体对类固醇激素信号不同突触反应的机制仍知之甚少。使用离体电生理学和野生型（WT）和 miR-132/miR-212 微 RNA 敲除（miRNA-132/212）小鼠，我们研究了皮质酮（啮齿动物与人皮质醇等效物）对背侧和腹侧海马体突触特性的影响。在 WT 小鼠中，皮质酮主要抑制背侧 WT 海马体的代谢可塑性，而在 miR-132/212 海马体的背侧和腹侧区域，皮质酮显著扰乱了突触传递和代谢可塑性。Western blot 进一步显示，仅在 miR-132/212 海马体中，内源性 CREB 水平显著增加，而对皮质酮的反应则显著减少。仅在 WT 海马体中，Sirt1 水平也内源性增强，但不受皮质酮影响，而 phospo-MSK1 水平仅在 WT 海马体中受皮质酮降低，而在 miR-132/212 海马体中不受影响。在使用高架十字迷宫的行为研究中，miRNA-132/212 小鼠进一步显示出焦虑样行为减少。这些观察结果表明，miRNA-132/212 可能是类固醇激素对海马体功能影响的潜在区域选择性调节剂，从而可能精细调节海马体依赖的记忆和情绪处理。
