Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging

更年期激素的变化：对认知和大脑衰老的影响

• 批准号: 10417066
• 负责人: HEATHER A. BIMONTE-NELSON
• 金额: $ 32.16万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417066
• 关键词: Address; Affect; Age; Aging; Androgens; Androstenedione; Animal Model; Anti-Cholinergics; Anti-Progestin; Area; Attenuated; Automobile Driving; Behavior; Behavioral; Biological Availability; Blinded; Brain; Choline O-Acetyltransferase; Cholinergic Receptors; Clinic; Clinical; Cognition; Cognitive; Cognitive aging; Complex; Conjugated Equine Estrogens; Drops; Endometrial Carcinoma; Endometrial Hyperplasia; Enzymes; Estradiol; Estrogens; Estrus; Evaluation; Excision; Feedback; Female; Funding; Goals; Grant; Hippocampus (Brain); Histology; Hormone use; Hormones; Hyperplasia; Hysterectomy; Impaired cognition; Individual; Intervention; Learning; Levonorgestrel; Link; Literature; Maps; Memory; Memory impairment; Menopausal Status; Menopausal Symptom; Menopause; Modeling; Neurobiology; Neurocognitive; Neurons; Neurotransmitters; Operative Surgical Procedures; Oral Contraceptives; Outcome; Output; Ovarian; Ovarian Follicle; Ovariectomy; Ovary; Perimenopause; Periodicity; Pharmaceutical Preparations; Physiological; Progesterone; Progestins; Proteins; Publications; Randomized; Rattus; Regimen; Research; Research Project Grants; Rodent; Scopolamine; Secondary to; Serum; Short-Term Memory; Signal Transduction; Steroids; Surgical Models; Synthetic Progestogens; System; Testing; Time; Tissues; Uterus; Variant; Woman; Work; aging brain; androgenic; antagonist; basal forebrain; cancer risk; cholinergic; clinical biomarkers; clinical practice; cognitive benefits; cognitive change; cognitive testing; dementia risk; estrogenic; frontal lobe; gamma-Aminobutyric Acid; hormone therapy; human model; immunoreactivity; middle age; neurocognitive test; novel; ovarian failure; prevent; programs; reproductive senescence; reproductive tract; stem; steroid hormone

The broad goal of our continued program of research is to decipher the cognitive and brain effects of transitional and surgical variants of menopause, including optimizing cognitive aging by discovering efficacious hormone therapy (HT) options in the context of menopause variations seen in women. This incorporates determining memory and brain changes as transitional menopause ensues when ovaries are undergoing follicular depletion, as well as the optimal parameters for interventions subsequent to transitional and surgical menopause variants. Menopause has been associated with cognitive decline and increased dementia risk. However, factors driving these outcomes, and which HT parameters alter effects, are undetermined. Importance is underscored given that most women are living at least one-third of their lives in a menopausal state encompassed by numerous variations (with or without a uterus, follicular deplete ovaries, or HT). In the current grant period, we had 23 publications; using the rat model, we showed that transitional menopause detrimentally impacted memory, that effects were most pronounced during perimenopause when follicles were undergoing early depletion, that higher androstenedione levels were associated with worse memory outcomes, and that short-term hysterectomy (uterus removal) alone impaired memory. We found that progesterone impaired memory, and that these effects were modulated by the GABAergic system. We also showed that several clinically-used synthetic progestins impaired memory, and identified one that enhanced memory: Levonorgestrel (Levo). When taking oral contraceptives or HT, a woman with a uterus must include a progestin along with estrogens to offset estrogen-induced hyperplasia. Thus, we performed an individual versus combination study, and showed that 17β-estradiol (E2) and Levo each enhanced memory when given alone, but impaired memory when given in combination. We also found that E2- induced cognitive benefits were associated with cholinergic integrity, building on literature showing estrogen- cholinergic interactions. This renewal addresses critical questions stemming from these collective findings. Aim 1 tests whether varied E2 regimens attenuate memory impairments associated with the perimenopausal transition, and assesses novel progestins that are anti-androgenic or have minimal androgenicity, with a goal to find options that do not reverse beneficial E2 effects on cognition and the brain. Aim 2 determines how variations in menopause type, including hysterectomy, impact cognition and the brain, testing effects of a temporal window, age, and follicular depletion state. Aim 3 defines how menopause variants and clinically-used HTs interact with candidate neurotransmitter systems in mechanistic detail, systematically examining GABAergic signaling and cholinergic circuitry. We combine behavioral, physiological, and neurobiological approaches in the framework of a blinded and randomized animal model research program to disentangle the complexity of menopause variants and HT opportunities for neurocognitive enhancement, extrapolating directives explicitly from the clinic.

我们持续的研究计划的广泛目标是破译过渡的认知和大脑影响 和更年期的手术变体，包括通过发现有效的激素来优化认知衰老 在女性中发现的更年期变化的情况下，治疗（HT）选择。这并确定 当卵巢耗尽时，记忆和大脑随着过渡更年期的变化而变化， 以及过渡和外科绝经后的干预措施的最佳参数。 更年期与认知能力下降和痴呆症风险增加有关。但是，驾驶因素 这些结果以及哪些HT参数改变效果，尚不确定。重要性是强调的 大多数妇女至少生活在三分之一的一生中 变化（有或没有子宫，卵泡卵巢或HT）。在当前的赠款期，我们有23 出版物；使用大鼠模型，我们表明过渡更年期对记忆有害的记忆，这表明 卵泡发生早期消耗时，效果最为明显，较高 雄性固定水平与较差的记忆结局有关，而短期子宫切除术（子宫） 删除）单独的记忆障碍。我们发现孕酮的记忆力受损，这些影响是 由GABA能系统调节。我们还表明，几种临床中使用的合成孕激素受损 记忆，并确定了增强内存的一个：左臂菌（Levo）。服用口服避孕药或 HT，具有子宫的女性必须包括孕激素以及雌激素，以抵消雌激素诱导的增生。 那我们进行了一个单独的与组合研究，并表明17β-雌二醇（E2）和Levo分别 单独给予时会增强内存，但组合给出时记忆会损害。我们还发现E2- 诱导的认知益处与胆碱能完整性有关，基于文献，表明雌激素 胆碱能相互作用。这种续签解决了这些集体发现引起的关键问题。目的 1测试是否各种E2方案减弱了与围绝经的记忆障碍 过渡并评估抗雄激素或具有最小雄激素的新型孕激素，其目标是 查找对认知和大脑的影响不会影响E2的选项。 AIM 2确定如何变化 在更年期类型中，包括子宫切除术，撞击认知和大脑，临时窗口的测试效果， 年龄和卵泡耗尽状态。 AIM 3定义了更年期的变体和临床中的HTS如何与 机械细节的候选神经递质系统，系统地检查GABA能信号和 胆碱能电路。我们将行为，身体和神经生物学方法结合在 一个盲目的随机动物模型研究计划，旨在解散更年期变体的复杂性 和HT的神经认知增强的机会，从诊所明确推断指令。

项目成果

Surgical Menopause and Estrogen Therapy Modulate the Gut Microbiota, Obesity Markers, and Spatial Memory in Rats.

• DOI: 10.3389/fcimb.2021.702628
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Zeibich L;Koebele SV;Bernaud VE;Ilhan ZE;Dirks B;Northup-Smith SN;Neeley R;Maldonado J;Nirmalkar K;Files JA;Mayer AP;Bimonte-Nelson HA;Krajmalnik-Brown R
• 通讯作者: Krajmalnik-Brown R

Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity.

• DOI: 10.3389/fnbeh.2021.610078
• 发表时间: 2021
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Bernaud VE;Hiroi R;Poisson ML;Castaneda AJ;Kirshner ZZ;Gibbs RB;Bimonte-Nelson HA
• 通讯作者: Bimonte-Nelson HA

A component of Premarin(®) enhances multiple cognitive functions and influences nicotinic receptor expression.

• DOI: 10.1016/j.yhbeh.2010.09.002
• 发表时间: 2010-11
• 期刊: HORMONES AND BEHAVIOR
• 影响因子: 3.5
• 作者: Talboom, Joshua S.;Engler-Chiurazzi, Elizabeth B.;Whiteaker, Paul;Simard, Alain R.;Lukas, Ronald;Acosta, Jazmin I.;Prokai, Laszlo;Bimonte-Nelson, Heather A.
• 通讯作者: Bimonte-Nelson, Heather A.

Harmine treatment enhances short-term memory in old rats: Dissociation of cognition and the ability to perform the procedural requirements of maze testing.

• DOI: 10.1016/j.physbeh.2014.09.001
• 发表时间: 2015-01
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Mennenga SE;Gerson JE;Dunckley T;Bimonte-Nelson HA
• 通讯作者: Bimonte-Nelson HA

Tonic Premarin dose-dependently enhances memory, affects neurotrophin protein levels and alters gene expression in middle-aged rats.

• DOI: 10.1016/j.neurobiolaging.2009.09.005
• 发表时间: 2011-04
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Engler-Chiurazzi E;Tsang C;Nonnenmacher S;Liang WS;Corneveaux JJ;Prokai L;Huentelman MJ;Bimonte-Nelson HA
• 通讯作者: Bimonte-Nelson HA