Sex specific effects of estrogen on the neural substrates of episodic and fear memory

大量证据表明，最重要的雌激素-雌二醇（E2）可以改变动物海马体的可塑性。行为学上，E2影响海马体依赖性记忆。神经活性E2由海马神经元局部合成，并以旁分泌和细胞内方式起作用。最近，E2对其他与记忆相关的大脑区域，即鼻周皮层和杏仁核的调节也被描述。此外，E2通过与多巴胺能系统相互作用影响神经元的可塑性，多巴胺能系统反过来调节记忆的形成。对于男性大脑，E2对男性和女性海马体的类似影响已经在体外描述过。然而，目前关于E2在体内作用的数据模式并不一致。目前的项目旨在通过将功能磁共振成像（fMRI）与E2的药理应用相结合，将这些关于E2中枢效应的发现从动物转化为人类。至关重要的是，血清E2水平的增加会触发促性腺激素释放激素（GnRH）的中枢释放，进而调节大脑中E2的合成，从而导致两性血清和神经元E2水平呈正相关。因此，血清E2水平的药理学增加将导致大脑中E2浓度的增加。此外，现有的神经影像学文献表明，功能磁共振成像可以检测激素水平短暂而微妙波动的神经相关性。为了将动物研究的结果与我们在人脑中的工作相结合，我们将研究E2对三种记忆现象及其神经相关性的影响。特别是，我们将研究杏仁核中E2对恐惧消退记忆巩固的影响。其次，我们将确定E2在鼻周皮层和海马体中对可塑性的不同调节，以及在这些区域计算的特定遗忘过程。第三，E2对多巴胺能调节记忆形成的影响及其与奖励加工的相互作用将被确定。此外，我们的目标是系统地表征E2对人类大脑的性别特异性影响。特别是，E2水平在年轻女性和男性志愿者中都将增加，并且将在两性中研究相同的记忆范式。总的来说，目前的项目将是第一个系统地和不同地描述E2对人类女性和男性大脑和行为的影响。我们的实验结果对基础研究很有兴趣，因为它们与动物的发现密切相关，并将反过来刺激进一步的动物研究。此外，这些实验具有临床相关性，因为人类情感和成瘾障碍的临床前模型，即恐惧条件反射和奖励处理，将被研究，显示出与E2影响一致的性别依赖性流行。

A large body of evidence accumulated showing that the most important estrogen, 17beta-estradiol (E2), modifies plasticity in the animal hippocampus. Behaviourally, E2 impacts on hippocampus-dependent memory. Neuroactive E2 is synthesised locally by hippocampal neurons and acts in a paracrine but also intracellular manner. More recently, the modulation by E2 of other memory-related brain areas, i.e. the perirhinal cortex and the amygdala, has also been described. In addition, E2 affects neuronal plasticity by interacting with the dopaminergic system, which modulates in turn memory formation. With respect to the male brain, similar effects of E2 on the male and female hippocampus have been described in vitro. However, the pattern of data on in vivo effects of E2 is currently inconsistent. The current project aims to translate these findings on central effects of E2 from animals to humans by combining functional magnetic resonance imaging (fMRI) with the pharmacological application of E2. Crucially, an increase in serum E2 levels triggers the central release of Gonadotropin-releasing hormone (GnRH) which in turn regulates E2-synthesis in the brain, resulting in a positive correlation of serum and neuronal E2 levels in both sexes. Hence, a pharmacological increase in serum E2 levels will result in enhanced E2 concentrations in the brain. Moreover, the existing neuroimaging literature shows that fMRI is feasible to detect the neural correlates of brief and subtle fluctuations in hormone levels. To translate the results from animal studies as well as to connect to our own work in the human brain, we will investigate the effect of E2 on three mnestic phenomena and their neural correlates. In particular, we will study the effect of E2 in the amygdala on the consolidation of fear extinction memory. Secondly, we will identify differential modulations of plasticity by E2 in the perirhinal cortex and hippocampus as well as on the specific mnestic processes computed in these areas. Thirdly, the effect of E2 on the dopaminergic modulation of memory formation and also its interaction with reward processing will be determined. In addition, we aim to systemically characterize the sex-specific effects of E2 on the human brain. In particular, E2 levels will be increased pharmacologically in young female but also male volunteers, and the same memory paradigms will be studied in both sexes. Altogether, the current project will be the first systematic and differential characterization of the effects of E2 on human female and male brains and behavior. The results of our experiments are of interest to basic research as they closely connect to findings in animals and will in turn stimulate further animal research. In addition, the experiments are of clinical relevance, since preclinical models of human affective and addictive disorders, i.e. fear conditioning and reward processing, will be studied that show a sex-dependent prevalence consistent with an influence of E2.