Regulation of synaptic plasticity in amygdala mediated by neuron-synthetized sexual hormones (sex neurosteroids)

神经元合成的性激素（性神经类固醇）介导的杏仁核突触可塑性的调节

• 批准号: 384870444
• 负责人: Professor Dr. Roland A. Bender
• 金额: --
• 依托单位: Institut für Neuroanatomie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/384870444?language=en
• 关键词: Regulation; synaptic; plasticity; amygdala; mediated

Neurons are capable of synthesizing sex steroid hormones which are released as neurosteroids and influence neuronal connectivity. The functions of these sex neurosteroids have been intensely studied in hippocampus, where endogenously synthesized 17beta-estradiol (E2) and dihydrotestosterone (DHT) have been shown to regulate the stability and properties of excitatory synapses in a sex-specific manner. We recently showed that similar mechanisms are also effective in amygdala. We found in basolateral amygdala (BLA) a robust expression of the E2-synthesizing enzyme aromatase (AROM) and showed that inhibition of AROM results sex-specifically in altered spine synapse density and LTP. In addition, robust AROM expression was found in the lateral part of the central amygdala (CeAl), which together with BLA is pivotal for the fear response. This raises the questions what mechanisms underlie the sex-specific regulation of synaptic plasticity by E2, and whether they influence fear behavior sex-dependently. In the present proposal, we suggest experiments aimed at comprehensively addressing these questions. As 5alpha-reductase type 2 (5alpha-R2), the enzyme that generates DHT, is also strongly expressed both in BLA and CeAl, we further include studies addressing the function of DHT into our proposal. Experimental models include: a) Analysis of AROM- and androgen receptor (AR)-deficient mice, and b) intraventricular infusion of inhibitors of AROM and 5alpha-R2 (letrozole and finasteride, respectively) into adult gonadectomized rats. Animals are subsequently analyzed for altered synaptic plasticity in BLA and CeAl, and for altered fear-related behavior. c) Organotypic cultures including amygdala, which will be used to identify the molecular mechanisms of sex neurosteroid signaling in BLA. In addition, we will d) determine expression profiles of neurons which express AROM, 5alpha-R2, estrogen and/or androgen receptors in BLA and CeAl. We believe that these studies will provide valuable information that may help to better understand certain sex differences in mood disorders as well as side effects of the inhibitors, which are frequently used for cancer therapy (breast and prostate cancer, respectively).

神经元能够合成作为神经类固醇释放并影响神经元连通性的性类固醇激素。这些性神经固醇的功能已在海马中进行了深入研究，在海马中，内源合成的17beta-雌二醇（E2）和二氢睾丸激素（DHT）已被证明以性别特异性的方式调节了兴奋性突触的稳定性和特性。我们最近表明，类似的机制在杏仁核中也有效。我们在基底外侧杏仁核（BLA）中发现了E2合成酶芳香酶（AROM）的鲁棒表达，并表明抑制AROM在脊柱突触密度和LTP中的抑制作用特异性变化。此外，在中央杏仁核（CEAL）的侧面发现了稳健的芳香族表达，与BLA一起，这对于恐惧反应至关重要。这提出了疑问哪些机制是e2对性别可塑性的特定性别调节的基础，以及它们是否依赖性地影响恐惧行为。在本提案中，我们建议实验旨在全面解决这些问题。由于5Alpha-reductase 2型（5alpha-R2）（生成DHT的酶）在BLA和CEAL中也得到了强烈表达，我们进一步包括针对DHT功能的研究。实验模型包括：a）分析芳香族和雄激素受体（AR）缺陷小鼠，b）脑室室内注入AROM和5alpha-R2（Letrozole和finasteride）分别为成年性卵切切除大鼠。随后，对动物分析了BLA和CEAL中突触可塑性的改变，并改变了与恐惧相关的行为改变。 c）包括杏仁核在内的器官培养物，该培养物将用于鉴定BLA中性神经固醇信号的分子机制。此外，我们将d）确定在BLA和CEAL中表达芳香，5alpha-R2，雌激素和/或雄激素受体的神经元的表达谱。我们认为，这些研究将提供有价值的信息，这些信息可能有助于更好地了解情绪障碍的某些性别差异以及抑制剂的副作用，这些抑制剂经常用于癌症治疗（乳腺癌和前列腺癌）。