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Effect of Testosterone Replacement on Spatial Working Memory of Hypogonadal Aged

睾酮替代对性腺功能减退老年人空间工作记忆的影响

基本信息

批准号：
8689617
负责人：
Mark D. Spritzer
金额：
$ 32.16万
依托单位：
MIDDLEBURY COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689617
关键词：
Adult Affect Age Age-associated memory impairment Aging Agonist Alzheimer&apos s Disease Androgen Antagonists Androgen Receptor Androgens Animal Model Aromatase Inhibitors Binding Biological Assay Brain Brain region Brain-Derived Neurotrophic Factor Castration Cognitive Conflict (Psychology)Corpus striatum structure Dose Estradiol Estrogen Receptors Estrogens Flutamide Hippocampus (Brain)Hormones Human Hypogonadism Impaired cognition Incidence Individual Infusion procedures Injection of therapeutic agent Learning Letrozole Measures Mediating Memory Memory Loss Modeling Neuronal Plasticity Pathway interactions Performance Physiological Play Population Process Radial Rattus Relative (related person)Replacement Therapy Reporting Risk Factors Rodent Role Series Serum Short-Term Memory Stanolone System Testing Testosterone Therapeutic Work age group age related aged arm frontal lobe improved male men neurotrophic factor older men public health relevance research study response testosterone replacement therapy two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Cognitive decline is a common component of aging, and spatial memory in particular is negatively affected by increasing age. One possible cause of impaired spatial memory is an age-related decline in circulating testosterone. Testosterone levels among men decline steadily with increasing age, and as many as 65% of men over age 70 are hypogonadal. Past studies have produced conflicting results regarding the cognitive benefits of androgen replacement therapies given to hypogonadal aged men, indicating a need for an animal model to experimentally test the effects of testosterone on spatial memory. The proposed experiments will systematically test the physiological mechanisms underlying testosterone-induced changes in spatial learning and memory, using castrated aged male rats as a model for hypogonadal aged men. The specific aims of the proposed experiments are to determine: 1) whether testosterone has dose-dependent effects on spatial memory in hypogonadal aged males, 2) whether the effects of testosterone on spatial memory are estrogen or androgen dependent, 3) whether testosterone influences spatial memory through direct actions on the brain, and 4) whether changes in brain-derived neurotrophic factor (BDNF) are involved in testosterone-induced changes in spatial memory. Three major experiments involving adult male rats will be performed to achieve these aims. Each experiment will involve hormone injections given to castrated aged male rats. For Experiments 1 and 2, spatial memory will be assessed using a working-reference memory version of the 8-arm radial maze. In Experiment 1a, aged males will be compared to young male rats to determine whether castration has the same memory impairing effects in both age groups. In Experiment 1b, a broad range of testosterone doses will be injected into aged males to assess possible dose-dependent effects. Experiment 2 will test the relative roles of androgen-dependent and estrogen-dependent pathways on spatial memory by injecting rats with various dihydrotestosterone or estradiol doses. These pathways will be further assessed using an androgen antagonist and an aromatase inhibitor. In Experiment 3, the direct effects of testosterone on spatial memory will be tested using intracranial infusions of high and low testosterone doses. Infusions into the hippocampus will be followed by memory testing on a hippocampus-dependent task, and infusions into the striatum will be followed by memory testing on a striatum-dependent task. For all experiments, serum hormone levels will be assayed, and BDNF levels will be measured in key brain regions. In combination, these experiments will provide a critical step in determining the therapeutic value of androgen replacement therapies for treating age-associated memory impairment.

描述（由申请人提供）：认知衰退是衰老的常见组成部分，特别是空间记忆受到年龄增长的负面影响。空间记忆受损的一个可能原因是与年龄相关的循环睾酮下降。男性的睾酮水平随着年龄的增长而稳步下降，70岁以上的男性中多达65%的人性腺功能减退。过去的研究已经产生了相互矛盾的结果，关于雄激素替代疗法给予性腺功能减退的老年男性的认知益处，表明需要一种动物模型来实验测试睾酮对空间记忆的影响。本实验拟以去势老年雄性大鼠作为性腺功能减退的老年男性模型，系统地研究睾酮诱导的空间学习记忆改变的生理机制。拟议实验的具体目的是确定：1）睾酮对性腺功能减退的老年男性的空间记忆是否具有剂量依赖性作用，2）睾酮对空间记忆的作用是雌激素依赖性还是雄激素依赖性的，3）睾酮是否通过对大脑的直接作用来影响空间记忆，脑源性神经营养因子（BDNF）的变化是否参与睾酮诱导的空间记忆改变。为实现这些目标，将进行三项涉及成年雄性大鼠的主要实验。每一项实验都将涉及给阉割的老年雄性大鼠注射激素。对于实验1和2，将使用8臂径向迷宫的工作参考记忆版本评估空间记忆。在实验1a中，将老年雄性大鼠与年轻雄性大鼠进行比较，以确定去势是否对两个年龄组具有相同的记忆损害效应。在实验1b中，将向老年男性注射广泛的睾酮剂量，以评估可能的剂量依赖性效应。实验2将通过给大鼠注射不同剂量的双氢睾酮或雌二醇来测试雄激素依赖性和雌激素依赖性途径对空间记忆的相对作用。将使用雄激素拮抗剂和芳香酶抑制剂进一步评估这些途径。在实验3中，睾酮对空间记忆的直接影响将使用高和低睾酮剂量的颅内输注来测试。向海马体中输注后将进行海马体依赖性任务的记忆测试，向纹状体中输注后将进行纹状体依赖性任务的记忆测试。对于所有实验，将测定血清激素水平，并测量关键脑区的BDNF水平。这些实验将为确定雄激素替代疗法治疗年龄相关记忆障碍的治疗价值提供关键步骤。