Impact of hypertension and high-fat diet on mechanisms by which estradiol affects cortical synaptic plasticity.

高血压和高脂肪饮食对雌二醇影响皮质突触可塑性机制的影响。

• 批准号: 10579241
• 负责人: Ricardo Mostany
• 金额: $ 47.4万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579241
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Animals; Behavior; Biological Availability; Blood Vessels; Brain; Cardiovascular system; Cells; Cerebrovascular system; Chronic; Cognition; Cognitive; Cognitive aging; Dementia; Discrimination; Early Intervention; Electron Spin Resonance Spectroscopy; Electrophysiology (science); Equilibrium; Estradiol; Estrogens; Female; Frequencies; Genus Hippocampus; Health; High Fat Diet; Hormone use; Hormones; Hypertension; Image; Impaired cognition; Impairment; Information Management; Interneurons; Intervention; Knowledge; Mediating; Menopause; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Microscopy; Mitochondria; Molecular; Mus; NOS3 gene; Neurons; Nitric Oxide; Obesity; Outcome; Ovariectomy; Patients; Penetration; Performance; Perfusion; Perimenopause; Periodicity; Peroxonitrite; Postmenopause; Prevalence; Probability; Production; Reporting; Respiration; Risk; Role; Sensory; Sleep disturbances; Somatosensory Cortex; Synapses; Synaptic plasticity; Testing; Texture; Therapeutic Intervention; Vascular Dementia; Vascular blood supply; Vasomotor; Vibrissae; Woman; arteriole; awake; barrel cortex; brain cell; cardiometabolism; comorbidity; design; effective therapy; excitatory neuron; experience; high risk; hippocampal pyramidal neuron; hormone therapy; improved; in vivo; in vivo imaging; inhibitory neuron; interdisciplinary approach; lifetime risk; men; middle age; neural; neuroprotection; neurovascular coupling; novel; personalized intervention; pharmacologic; preservation; prevent; protective effect; response; restoration; structural imaging; two-photon

Project 2 Summary The menopausal transition is responsible for many of the cognitive impairments reported by women at midlife. In addition to the detrimental effects of the natural loss of endogenous hormones on cognition, and as a probable consequence, the prevalence of Alzheimer’s disease and other related dementias is higher in women than men, with double the lifetime risk of Alzheimer’s disease at age 45. Hormone therapy is the most effective treatment for the vasomotor and sleep disruptions that accompany menopause, but timing of the intervention may have a crucial impact on overall outcome, particularly on the preservation of cognitive capabilities. Whereas late hormone therapy interventions have no benefit, or may even be harmful, early interventions seem to bestow protection against cognitive decline, regardless of the presence of Alzheimer’s disease pathology. In addition, cardiovascular and metabolic complications are directly associated with sharper cognitive decline, which together with the loss of endogenous estrogens, may further increase the risk of developing Alzheimer’s disease and vascular dementia. While it has been described that hypertension and metabolic disease impair neurovascular coupling—the fine-tuned mechanism that matches local blood supply with neuronal activity—it is unknown if disrupted neurovascular coupling is ultimately responsible for the loss of cognitive protection by estrogen. Given that the mechanisms governing neurovascular coupling are tightly regulated by endothelial nitric oxide synthase, we believe that cardiometabolic comorbidities negatively impact the availability of nitric oxide to the extent that it abolishes the estrogen-induced neuroprotection. Therefore, our working hypothesis is that hypertension and metabolic disease prior to menopause impede the beneficial effects of hormone therapy in preventing aging-related cognitive decline by blunting neurovascular coupling. This leads to impaired local network activity, and therefore, to impaired synaptic plasticity required for the formation and stabilization of synapses needed to create functional cortical circuits and therefore for cognition. We will also test the hypothesis that increasing endothelial nitric oxide synthase activity and nitric oxide bioavailability will eliminate the deficits in neurovascular coupling. This study will determine that the preexistence of hypertension and obesity-induced metabolic disease prior to ovariectomy nullifies the positive effects of midlife estradiol treatment on synaptic plasticity and synaptic stabilization, impairing the ability of cortical circuits to store and manage information, and will identify alterations in the cortical microcircuitry responsible for the deficient experience-dependent synaptic plasticity. The study will also examine the role of mitochondria in disrupted neuronal activity and characterize the molecular mechanisms mediating the impaired neurovascular coupling that is associated with the loss of estrogen’s neuroprotective effects. Focusing on a cortical circuit that we can comprehensively study and manipulate, this study will create foundational knowledge for the design and improvement of personalized or precision interventions aimed to prevent or treat cognitive disturbances in postmenopausal women at risk for Alzheimer’s disease and vascular dementia.

项目2摘要 绝经过渡负责中年妇女报告的许多认知障碍。 除了内源荷尔蒙自然丧失对认知的有害影响以及有问题 结果，在女性中，阿尔茨海默氏病和其他相关痴呆症的患病率高于男性 45岁时，阿尔茨海默氏病的寿命风险是两倍。激素治疗是最有效的治疗方法 对于容纳更年期的血管舒缩和睡眠中断，但干预的时机可能有一个 对整体结果的关键影响，尤其是在保存认知能力方面。而迟到 Horseone治疗干预措施没有好处，甚至可能有害，早期干预似乎赋予了 不论阿尔茨海默氏病病理学的存在如何，可以防止认知能力下降。此外， 心血管和代谢并发症与认知敏锐的下降直接相关，而认知能力下降 加上内源性雌激素的丧失，可能会进一步增加患阿尔茨海默氏病的风险 和血管痴呆。虽然已经描述了高血压和代谢疾病障碍 神经血管耦合 - 与局部血液供应与神经元活动相匹配的微调机制 - 未知的神经血管耦合是否最终导致了认知保护的丧失 雌激素。鉴于管理神经血管夫妇的机制受到内皮氮的严格调节 氧化物合酶，我们认为心脏代谢合并症对一氧化氮的可用性负面影响 废除雌激素诱导的神经保护作用的程度。因此，我们的工作假设是 更年期之前的高血压和代谢性疾病阻碍了马酮治疗的有益作用 通过钝化神经血管耦合来防止与衰老相关的认知下降。这导致本地障碍 网络活动，因此，以损害形成和稳定所需的突触可塑性 创建功能性皮质电路所需的突触，因此需要进行认知。我们还将检验假设 内皮一氧化氮合酶活性和一氧化氮生物利用度增加将消除缺陷 在神经血管耦合中。这项研究将确定高血压和肥胖诱导的 卵巢切除术之前的代谢疾病无效雌二醇治疗对突触的积极影响 可塑性和突触稳定，损害了皮质圈存储和管理信息的能力，并且 将确定负责默认经验依赖性突触的皮质微电路的变化 可塑性。该研究还将检查线粒体在神经元活性中断的作用，并表征 分子机制介导与丧失有关的神经血管耦合受损 雌激素的神经保护作用。专注于我们可以全面研究的皮质电路 操纵这项研究将为设计和改进个性化或改进的基础知识或 精确干预措施旨在预防或治疗有可能有风险的绝经后妇女的认知障碍 阿尔茨海默氏病和血管痴呆。