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

• 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
• 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' 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

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）：认知能力下降是衰老的常见组成部分，尤其是空间记忆会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。男性睾酮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% 患有性腺功能减退症。过去的研究对于性腺功能减退的老年男性的雄激素替代疗法的认知益处产生了相互矛盾的结果，表明需要一种动物模型来通过实验测试睾酮对空间记忆的影响。拟议的实验将使用阉割的老年雄性大鼠作为性腺功能减退老年男性的模型，系统地测试睾酮引起的空间学习和记忆变化的生理机制。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影响，2）睾酮对空间记忆的影响是否依赖于雌激素或雄激素，3）睾酮是否影响空间记忆通过对大脑的直接作用来影响记忆，4）脑源性神经营养因子（BDNF）的变化是否与睾酮引起的空间记忆变化有关。为了实现这些目标，将进行涉及成年雄性大鼠的三项主要实验。每个实验都会涉及对阉割的老年雄性大鼠进行激素注射。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来评估空间记忆。在实验1a中，将老年雄性大鼠与年轻雄性大鼠进行比较，以确定阉割是否对两个年龄组具有相同的记忆损害作用。在实验 1b 中，将向老年男性注射多种睾酮剂量，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二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，将通过颅内输注高剂量和低剂量的睾酮来测试睾酮对空间记忆的直接影响。输注到海马体后将进行海马依赖性任务的记忆测试，输注到纹状体后将进行纹状体依赖性任务的记忆测试。对于所有实验，将检测血清激素水平，并测量关键大脑区域的 BDNF 水平。结合起来，这些实验将为确定雄激素替代疗法治疗与年龄相关的记忆障碍的治疗价值提供关键的一步。

项目成果

Dose-dependent effects of testosterone on spatial learning strategies and brain-derived neurotrophic factor in male rats.

睾酮对雄性大鼠空间学习策略和脑源性神经营养因子的剂量依赖性影响。

• 发表时间: 2020
• 影响因子: 3.7
• 作者: Zhang, Kevin J;Ramdev, Rajan A;Tuta, Nicholas J;Spritzer, Mark D
• 通讯作者: Spritzer, Mark D

Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats.

睾酮替代导致老年雄性大鼠空间记忆的剂量依赖性改善。

• 发表时间: 2020
• 影响因子: 3.7
• 作者: Jaeger, Eliza C B;Miller, L Erin;Goins, Emily C;Super, Chloe E;Chyr, Christina U;Lower, John W;Honican, Lauren S;Morrison, Daryl E;Ramdev, Rajan A;Spritzer, Mark D
• 通讯作者: Spritzer, Mark D