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

性类固醇和认知：狨猴作为新的灵长类动物模型

• 批准号: 8113839
• 负责人: Agnes Lacreuse
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-07 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113839
• 关键词: 5 year old; Affect; Animal Model; Animals; Behavioral; Biomedical Research; Brain; Callithrix; Callithrix jacchus jacchus; Characteristics; Cognition; Cognition Disorders; Cognitive; Complement; Complex; Conscious; Data; Development; Dose; Endocrine; Estradiol; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Exposure to; Female; Functional Magnetic Resonance Imaging; Gonadal Steroid Hormones; Health; Hippocampus (Brain); Hormonal; Human; Image; Impaired cognition; Investigation; Life; Long-Term Effects; Longevity; Longitudinal Studies; Macaca; Memory; Mental Health; Mental disorders; Modeling; Neurocognitive; Ovarian hormone; Pattern; Performance; Placebos; Primates; Process; Regimen; Reproductive Endocrinology; Research Design; Rodent; Role; Safety; Staging; Stimulus; Study models; Testing; Time; Visual; Woman; age related; awake; base; cognitive function; cost; efficacy testing; follow-up; innovation; male; mental age; middle age; model development; neuroimaging; nonhuman primate; novel; novel therapeutics; public health priorities; relating to nervous system; reproductive; response; sex; subcutaneous; translational study; visual stimulus

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.

描述（由申请人提供）：一生中性激素的变化会影响大脑功能和认知，并可能增加晚年罹患特定性别精神障碍和与年龄相关的衰退的可能性。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。虽然这个问题正在啮齿动物和猕猴中得到广泛研究，但这些模型存在局限性，限制了它们的转化影响。开发一种补充这些传统物种的新动物模型将有助于弥合动物和人类研究之间的差距，并为了解性类固醇对人类整个生命周期中大脑和认知功能的作用提供新的和有价值的数据。普通狨猴最近被确定为生物医学研究的有用替代灵长类动物模型。与传统猕猴物种相比，其优点包括体型小、寿命短、成本低、易于饲养、分布广泛且无生物安全问题。此外，这种小型灵长类动物的行为、内分泌和神经特征使其作为研究性类固醇对整个生命周期认知和大脑功能影响的新模型特别有吸引力。作为开发这种模型的第一步，我们建议重点关注雌激素对雌性狨猴认知和大脑功能的影响。接受低剂量 172 雌二醇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依赖性测试，以确定雌二醇是否有益于认知能力。认知电池完成后，狨猴将在接受海马依赖性任务期间使用功能性磁共振成像（fMRI）进行成像，以研究雌二醇对有意识动物大脑活动模式的影响。这些创新研究将（1）提供关于清醒非人类灵长类动物大脑活动的雌二醇调节的第一个数据，与女性的认知健康直接相关； (2) 建立狨猴作为新灵长类动物模型的有效性，以进一步了解性类固醇的神经认知作用。这些数据将构成对雄性和雌性狨猴进行纵向研究的基础，旨在了解性类固醇暴露的长期影响、不同激素疗法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，狨猴将成为理想的灵长类动物模型，用于测试新疗法在生命不同阶段针对激素依赖性精神和认知障碍的疗效。 公共健康相关性：普通狨猴是一种体型较小、寿命较短的灵长类动物，与生物医学研究的传统动物模型相比具有独特的优势。拟议的研究首次探讨了狨猴对于女性认知健康转化研究的价值。使用非侵入性认知评估和功能神经影像，我们将确定（1）雌激素是否有益于雌性狨猴的认知，以及（2）雌激素是否影响从事认知任务的清醒动物的大脑活动模式。这些发现将与女性的认知健康直接相关，并应验证狨猴作为一种新的灵长类动物模型，以进一步了解性类固醇在整个生命周期中的神经认知影响。