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。

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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总结更年期过渡是中年女性报告的许多认知障碍的原因。除了内源性激素自然丧失对认知造成的痛苦影响之外，因此，女性阿尔茨海默病和其他相关痴呆症的患病率高于男性， 45 岁时患阿尔茨海默病的终生风险增加一倍。激素疗法是最有效的治疗方法对于更年期伴随的血管舒缩和睡眠障碍，但干预的时机可能会有所不同对整体结果，特别是对认知能力的保存产生至关重要的影响。激素治疗干预没有任何好处，甚至可能有害，早期干预似乎会带来好处无论是否存在阿尔茨海默氏病病理，都能预防认知能力下降。心血管和代谢并发症与认知能力急剧下降直接相关，再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病的风险虽然高血压和代谢性疾病会损害血管性痴呆。神经血管耦合——将局部血液供应与神经元活动相匹配的微调机制—— 未知神经血管耦合破坏是否最终导致认知保护丧失鉴于控制神经血管耦合的机制受到内皮硝酸的严格调节。氧化物合酶，我们认为心脏代谢合并症会对一氧化氮的可用性产生负面影响它消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：绝经前的高血压和代谢性疾病阻碍了激素治疗的有益效果通过减弱神经血管耦合来预防与衰老相关的认知能力下降，这会导致局部受损。网络活动，因此，损害形成和稳定所需的突触可塑性创建功能性皮层回路所需的突触，因此我们还将检验该假设。增加内皮一氧化氮合酶活性和一氧化氮生物利用度将消除缺陷这项研究将确定高血压和肥胖引起的预先存在。卵巢切除术前的代谢性疾病抵消了中年雌二醇治疗对突触的积极作用可塑性和突触稳定性，损害皮质回路存储和管理信息的能力，以及将识别导致依赖经验的突触缺陷的皮质微电路的改变该研究还将检查线粒体在神经元活动中断中的作用并表征其特征。介导与神经血管耦合受损相关的分子机制雌激素的神经保护作用集中在我们可以全面研究和研究的皮质回路上。操纵，这项研究将为设计和改进个性化或旨在预防或治疗有认知障碍风险的绝经后妇女的精准干预措施阿尔茨海默病和血管性痴呆。