Impact of brain estrogens on cognition and brain aging in a non-human primate

总结 芳香酶抑制剂（AIs）是抑制雌激素合成的药物，用于预防 雌激素反应性乳腺癌的复发。然而，人工智能，如常用的来曲唑 (LET)，与严重的副作用有关，这些副作用进一步加重了生活质量，包括失眠，热 闪光、抑郁症状和认知缺陷。认可机构可能引致 这些中枢神经系统症状仍然不清楚，难以在人类中进行研究， 缺乏疾病严重程度、治疗史和经历过的压力。此外，建议进行AI治疗 然而，人们对长期使用人工智能对大脑和行为的影响知之甚少， 与年龄相关的认知能力下降和阿尔茨海默病（AD）风险。我们打算培育一种灵长类动物 AI诱导的CNS效应的模型，以推进我们在这一领域的知识，并促进新的设计， 治疗学 这个应用程序使用了绒猴（Callithrix jacchus），一种小型灵长类动物， 模式，认知能力，情绪反应和体温调节模式，可与那些 人类（1）研究长期使用LET对大脑和行为的影响，（2）测试DHED，一种 选择性地将E2递送到大脑的前药，可以有效和安全地预防LET相关的不良反应。 方面的影响. 为了实现这些目标，中年雄性和雌性绒猴用LET、LET + DHED或 将纵向研究溶剂给药3年的睡眠/觉醒模式、认知表现， 情绪调节和体温调节。这些猴子将配备一个睡眠/清醒活动监测器 模式分析认知功能将通过自动计算机化电池进行评估。热成像 将用于测量热挑战期间面部皮肤温度的变化。情绪调节将 通过测量猴子的心率变异性和面部皮肤温度进行评估， 中立视频在这些体内行为评估之后，对来自底层脑的脑组织进行分析。 区域（下丘脑、海马、前额叶皮质、蓝斑）进行定量基因表达。 所选基因的表达、tau蛋白病、β-淀粉样蛋白沉积和神经元兴奋性。 这些结果将通过以下方式对AI治疗的患者具有重要的转化应用：（1）表征 AI对多种神经和行为结果的影响;（2）确定长期雌激素是否 抑制促进AD样表型的发展和（3）是否为大脑提供了 雌激素的替代来源可以抵消AI对大脑和行为的不利影响。

SUMMARY Aromatase inhibitors (AIs) are drugs that inhibit estrogen synthesis and that are prescribed to prevent the recurrence of estrogen responsive breast cancers. However, AIs, such as the commonly prescribed Letrozole (LET), are associated with severe side-effects that further burden the quality of life, including insomnia, hot flashes, depressive symptoms and cognitive deficits. The precise mechanisms by which AIs may give rise to these CNS symptoms remain unclear and difficult to study in humans, as control for individual differences in disease severity, treatment history and experienced stress is lacking. Furthermore, AI treatment is recommended for 3 to 5 years, yet little is known about the effects of long-term AI use on the brain and behavior, especially with regards to age-related cognitive decline and Alzheimer's disease (AD) risk. We propose to develop a primate model for AI-induced CNS effects to advance our knowledge in this area and facilitate the design of novel therapeutics. This application uses the marmoset (Callithrix jacchus), a small primate with a brain architecture, sleep patterns, cognitive abilities, emotional responses and thermoregulation patterns that are comparable to those of humans (1) to study the effects of chronic LET use on the brain and behavior and (2) to test whether DHED, a prodrug that delivers E2 selectively to the brain, can effectively and safely prevent LET-associated adverse effects. To achieve these aims, middle-aged male and female marmosets treated with LET, LET + DHED or Vehicle for 3 years will be studied longitudinally for changes in sleep/wake patterns, cognitive performance, emotional regulation, and thermoregulation. The monkeys will be outfitted with an activity monitor for sleep/wake patterns analysis. Cognitive function will be assessed via an automated computerized battery. Thermal imaging will be used to measure changes in facial skin temperature during a thermal challenge. Emotional regulation will be assessed by measuring heart rate variability and facial skin temperature in monkeys viewing emotional and neutral videos. Following these in vivo behavioral assessments, analyses of brain tissues from underlying brain regions (hypothalamus, hippocampus, prefrontal cortex, locus coeruleus) will be carried out to quantify gene expression of selected genes, tauopathies, β-amyloid deposition and neuronal excitability. The results will have important translational applications for AI-treated patients by (1) characterizing the effects of AIs on multiple neural and behavioral outcomes; (2) determining whether long-term estrogen suppression promotes the development of an AD-like phenotype and (3) whether providing the brain with an alternate source of estrogen can counteract the adverse effects of AIs on the brain and behavior.