Cognition and Estrogen in Menopause:A Monkey Model

描述：(申请人提供)：更年期卵巢激素缺乏引起的变化可能会对女性未来的健康和福祉产生深远的影响。非精神错乱的绝经后妇女经常注意到认知功能的变化，特别是记忆和注意力。由于多种混杂因素，确定更年期卵巢激素和认知功能之间的关系可能很难在女性身上进行研究。我们开发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，这还使我们能够开始识别灵长类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去卵巢猴子身上进行的，这样我们就可以确定雌激素治疗(ERT)的效果，而不会受到其他混杂因素的影响，包括高龄。然而，还有许多重要的问题仍然没有答案，包括雌激素加黄体酮治疗(HRT)的效果，以及卵巢激素对年龄更接近绝经后中年女性的猴子的影响。在本项目中，这些问题将在中年猴子身上解决。特定目标1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)的认知效果，这些任务测量依赖胆碱能系统的几种不同认知功能。在特定目标2中，将在对特定目标1的猴子进行行为评估的同时，对胆碱能系统进行功能成像研究，以确定突触前胆碱能活动的测量是否与使用卵巢激素治疗的猴子的认知功能测量相关。在最初的行为和成像研究之后，将在猴子身上进行药理学研究，以确定胆碱能、毒碱和尼古丁受体阻滞剂对卵巢激素治疗猴子认知功能的影响。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治疗对中年手术绝经期恒河猴认知功能和体内胆碱能系统功能的影响，扩大和扩大我们对年轻猴子的初步研究。这些在中年猴子身上进行的新颖实验的发现将极大地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的影响的理解。

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.