Cognition and Estrogen in Menopause:A Monkey Model

产品说明：（申请人提供）：更年期的卵巢激素缺乏症会带来变化，可能对女性未来的健康和福祉产生深远的影响。非痴呆绝经后妇女经常注意到认知功能的改变，特别是记忆和注意力。由于各种混杂因素，在女性中确定卵巢激素和更年期认知功能之间的关系可能很难研究。我们已经建立了一个更年期的猴子模型，使我们能够更严格地控制这些因素中的许多因素，此外，这使我们能够开始确定灵长类动物大脑中卵巢激素作用的胆碱能机制。我们最初的行为和神经生物学研究是在年轻的卵巢切除的猴子中进行的，这样我们就可以确定雌激素治疗（ERT）的效果，而不受其他混杂因素的影响，包括高龄。然而，仍有许多重要的问题尚未得到解答，包括雌激素加孕激素治疗（HRT）的效果和卵巢激素在年龄更接近中年绝经后妇女模型的猴子中的作用。这些问题将在本项目的中年猴中得到解决。具体目标1中的行为实验将使用一系列行为任务来确定卵巢激素替代疗法（ERT和HRT）的认知效应，这些行为任务测量依赖于胆碱能系统的几种不同的认知功能。具体目标2。将在特定目标1的猴中进行胆碱能系统的功能成像研究，同时对其进行行为评估，以确定突触前胆碱能活性的测量是否与用卵巢激素处理的猴的认知功能的测量相关。具体目标3。药理学研究将在猴的初始行为和成像研究之后在猴中进行，以确定胆碱能、毒蕈碱和烟碱受体阻断对用卵巢激素处理的猴的认知功能的影响。因此，本申请中提出的实验的总体目标是通过确定卵巢激素替代疗法对中年手术绝经恒河猴的认知功能和体内胆碱能系统功能的影响来扩展和拓宽我们在年轻猴子中的初步研究。在中年猴子中进行的这些新实验的发现将大大促进我们对卵巢激素治疗对灵长类动物认知和神经生物学特征影响的理解。

DESCRIPTION: (Provided by applicant): Ovarian hormone deficiency of menopause brings on changes that can have far reaching consequences on the future health and well being of women. Nondemented postmenopausal women frequently note alterations in cognitive functions, particularly memory and attention. Determining the relationship between ovarian hormones and cognitive function in menopause can be difficult to study in women because of a variety of confounding factors. We have developed a monkey model of menopause that allows us to more rigorously control many of these factors and additionally, that has allowed us to begin to identify cholinergic mechanisms of ovarian hormone action in the primate brain. Our initial behavioral and neurobiological studies were performed in young ovariectomized monkeys so that we could determine the effects of estrogen therapy (ERT) without the influence of other confounding factors, including advanced age. However, there are many important questions that remain unanswered, including the effects of estrogen plus progesterone therapy (HRT) and the effects of ovarian hormones in monkeys of an age that more closely models that of the middle-aged postmenopausal woman. These issues will be addressed in middle-aged monkeys in the present project. Behavioral experiments in Specific Aim 1 will determine the cognitive effects of ovarian hormone replacement therapy (ERT and HRT) using a series of behavioral tasks that measure several different cognitive functions that rely on the cholinergic system. In Specific Aim 2. functional imaging studies of the cholinergic system will be performed in the monkeys of Specific Aim 1 in parallel with their behavioral assessments to determine if measures of presynaptic cholinergic activity correlate with measures of cognitive function in monkeys treated with ovarian hormones. In Specific Aim 3. pharmacological studies will be performed in the monkeys following their initial behavioral and imaging studies to determine the effects of cholinergic, muscarinic and nicotinic receptor blockade on cognitive function in monkeys treated with ovarian hormones. Thus, the overall objectives of the experiments proposed in this application are to extend and broaden our initial investigations in young monkeys by determining the effects of ovarian hormone replacement therapy on cognitive function and in vivo cholinergic system function in middle-aged surgically menopausal rhesus monkeys. The findings from these novel experiments in middle-aged monkeys will significantly advance our understanding of the effects of ovarian hormone therapy on cognitive and neurobiological profiles of primates.