Sex steroids and cognition: the marmoset as a new primate model

描述(由申请人提供)：性激素在一生中的变化影响大脑功能和认知，并可能增加对性别特有的精神障碍和晚年与年龄相关的下降的易感性。动物模型对于了解性激素在生命不同阶段影响大脑和认知功能的机制至关重要。虽然这个问题在啮齿动物和猕猴身上得到了广泛的研究，但这些模型存在局限性，限制了它们的翻译影响。开发一种新的动物模型来补充这些传统物种，将有助于弥合动物和人类研究之间的差距，并为理解性类固醇在人类一生中对大脑和认知功能的作用提供新的有价值的数据。常见的绒猴最近被确定为生物医学研究的一种有用的替代灵长类动物模型。与传统猕猴物种相比，其优势包括体型小、寿命短、成本低、易于饲养、可广泛获得以及缺乏生物安全方面的考虑。此外，这种小型灵长类动物的行为、内分泌和神经特征使其成为研究性类固醇对终生认知和大脑功能影响的新模型特别有吸引力。作为发展这一模型的第一步，我们建议重点研究雌激素对雌性绒猴认知和脑功能的影响。接受低剂量雌激素或安慰剂治疗的卵巢切除的中年女性将接受一系列额叶和海马区依赖测试，以确定雌激素是否有助于认知能力。在认知电池完成后，在接受海马体依赖的任务期间，将使用功能磁共振成像(FMRI)对绒猴进行成像，以研究雌二醇对清醒动物大脑活动模式的影响。这些创新的研究将(1)提供第一个关于雌激素对清醒的非人类灵长类动物大脑活动的调节的数据，与女性的认知健康直接相关；(2)建立绒猴作为新的灵长类动物模型的有效性，以加深我们对性类固醇的神经认知影响的理解。这些数据将成为对雄性和雌性绒猴进行纵向研究的基础，目的是了解性类固醇暴露的长期影响，不同激素方案的影响，以及性类固醇对灵长类动物大脑功能和认知的作用机制。最终，绒猴将成为一种理想的灵长类动物模型，用于测试新疗法对不同生命阶段激素依赖型精神和认知障碍的疗效。 与公共卫生相关：常见的绒猴是一种小的、短暂的灵长类动物，在生物医学研究中表现出比传统动物模型独特的优势。这项拟议的研究首次检验了绒猴对女性认知健康的翻译研究的价值。使用非侵入性认知评估和功能神经成像，我们将确定(1)雌激素是否有助于雌性绒猴的认知，以及(2)雌激素是否影响参与认知任务的清醒动物的大脑活动模式。这一发现将与女性的认知健康直接相关，并将验证绒猴作为一种新的灵长类动物模型，以加深我们对性类固醇在一生中对神经认知的影响的理解。

DESCRIPTION (provided by applicant): Changes in sex hormones across the lifespan influence brain function and cognition and may increase vulnerability to sex-specific mental disorders and age-related decline later in life. Animal models are essential to understand the mechanisms by which sex hormones affect the brain and cognitive function at different stages of life. While this issue is being extensively studied in rodents and macaques, these models have limitations that constrain their translational impact. The development of a new animal model that complements these traditional species will help bridge the gap between animal and human studies and provide new and valuable data for understanding the role of sex steroids on brain and cognitive function across the lifespan in humans. The common marmoset has recently been identified as a useful alternative primate model for biomedical research. Advantages compared to traditional macaque species include small size, short lifespan, low cost, ease of husbandry, widespread availability, and lack of bio-safety concerns. In addition, the behavioral, endocrine and neural characteristics of this small primate make it particularly attractive as a new model for studying the effects of sex steroids on cognitive and brain function throughout the lifespan. As a first step towards the development of such a model, we propose to focus on the effects of estrogens on cognition and brain function in female marmosets. Ovariectomized middle-aged females treated with a low-dose 172 estradiol or a placebo will be tested on a battery of frontal and hippocampal-dependent tests to determine whether estradiol benefits cognitive performance. Following completion of the cognitive battery, the marmosets will be imaged with functional Magnetic Resonance Imaging (fMRI) during exposure to a hippocampal-dependent task to investigate the effects of estradiol on patterns of brain activity in conscious animals. These innovative studies will (1) provide the first data on estradiol-modulation of brain activity in awake nonhuman primates, with direct relevance for women's cognitive health; (2) establish the validity of the marmoset as a new primate model to further our understanding of the neurocognitive effects of sex steroids. These data will form the basis for longitudinal investigations in male and female marmosets aimed at understanding the long-term effects of sex steroid exposure, the effects of different hormonal regimens, and the mechanisms of action of sex steroids on primate brain function and cognition. Ultimately, the marmoset will be an ideal primate model for testing the efficacy of new treatments against hormonally-dependent psychiatric and cognitive disorders at different stages of life. PUBLIC HEALTH RELEVANCE: The common marmoset is a small, short-lived primate that presents unique advantages over traditional animal models for biomedical research. The proposed studies examine for the first time the value of the marmoset for translational studies on women's cognitive health. Using noninvasive cognitive assessments and functional neuroimaging, we will determine (1) whether estrogens benefit cognition in female marmosets and (2) whether estrogens affect patterns of brain activity in awake animals engaged in a cognitive task. The findings will be of direct relevance for women's cognitive health and should validate the marmoset as a new primate model for furthering our understanding of the neurocognitive effects of sex steroids across the lifespan.