Effect of Testosterone Replacement on Spatial Working Memory of Hypogonadal Aged

描述（由申请人提供）：认知能力下降是衰老的常见组成部分，尤其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。男性的睾丸激素水平随着年龄的增长而稳步下降，70岁以上的男性中有多达65%的人性腺功能低下。关于雄激素替代疗法对性腺功能低下的老年男性的认知益处，过去的研究产生了相互矛盾的结果，这表明需要一个动物模型来实验测试睾丸激素对空间记忆的影响。本实验将以阉割的老年雄性大鼠作为性腺功能低下的老年男性的模型，系统地测试睾酮诱导的空间学习和记忆变化的生理机制。本实验的具体目的是确定：1)睾酮对性腺功能低下的老年男性空间记忆是否具有剂量依赖性；2)睾酮对空间记忆的影响是雌激素依赖性还是雄激素依赖性；3)睾酮是否通过直接作用于大脑来影响空间记忆；4)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变化。为了实现这些目标，将进行三项涉及成年雄性大鼠的主要实验。每个实验都包括给阉割的雄性大鼠注射激素。在实验1和2中，空间记忆将使用工作参考记忆版本的八臂径向迷宫进行评估。在实验1a中，老年雄性大鼠将与年轻雄性大鼠进行比较，以确定去势在两个年龄组中是否具有相同的记忆损害作用。在实验1b中，将向老年男性注射大范围的睾酮剂量，以评估可能的剂量依赖性效应。实验2将通过注射不同剂量的双氢睾酮或雌二醇来检测雄激素依赖通路和雌激素依赖通路在大鼠空间记忆中的相对作用。这些途径将使用雄激素拮抗剂和芳香酶抑制剂进一步评估。在实验3中，睾酮对空间记忆的直接影响将通过颅内输注高剂量和低剂量睾酮来测试。注射到海马体后将进行海马体依赖任务的记忆测试，注射到纹状体后将进行纹状体依赖任务的记忆测试。在所有的实验中，将检测血清激素水平，并测量脑关键区域的BDNF水平。综上所述，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的一步。

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.