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

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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.