Estrogen depletion as a risk factor for Neuropsychiatric Symptoms associated with aging

与阿尔茨海默病和相关痴呆相关的神经精神症状（Neuropsychiatric Symptoms，简称CNS） （ADRD）包括激越、幻觉、意识模糊和抑郁，并与疾病严重程度相关， 通常会导致向辅助生活设施的过渡。尽管广泛流行，但有效 对疟疾的治疗仍然难以捉摸。在辅助生活设施中，约40%的痴呆患者接受了以下治疗： 抗精神病药物（标签外）来治疗精神分裂症，尽管疗效有限，安全性和 生活质量受损。据报道，性别差异的患病率和严重程度，但 造成这种情况的因素还没有得到很好的理解。症状类似于标志性阳性，阴性和 认知症状以及与精神分裂症相关的睡眠障碍。这些行为和 ADRD和精神分裂症患者的功能相似性提示病因学上的相似性 和风险因素。精神分裂症病因的一个主要假设是谷氨酸功能减退， 特异性降低离子型谷氨酸N-甲基-D-天冬氨酸受体（NMDAR）功能。在人类和 在动物中，NMDAR拮抗作用产生拟精神病和抑郁样症状，损害认知， 并扰乱睡眠，模拟这两种情况的所有症状群。调查与下列因素有关的因素： 影响NMDAR功能的衰老为理解神经生物学和治疗阿尔茨海默病提供了希望。 雌激素被假设在女性中具有神经保护作用。绝经后雌激素耗竭 是认知能力下降、精神分裂症、抗精神病药物疗效降低和可能的精神分裂症的危险因素。 与ADRD有关。雌激素还影响NMDAR亚基的组成和功能。我们建议 研究雌激素耗竭对认知、脑功能和NMDAR亚单位表达和功能影响 结合更年期和精神分裂症样症状的啮齿动物模型来模拟ADRD中的抑郁症，以及 对非典型抗精神病药物奥氮平的反应性，奥氮平通常用于治疗已知 绝经后妇女的疗效降低。将采用脑电图（EEG）， 提供了一个跨物种的大脑功能和睡眠的翻译测量。在人类和动物中 NMDAR拮抗作用诱导高频γ振荡过度增加， 认知障碍和类似精神分裂症的影响。研究雌激素耗竭对 认知，NMDAR功能和抗精神病样作用，我们将使用卵巢切除大鼠（Ovx），一种模型， 手术绝经，其中性腺激素耗尽，在存在或不存在17 β-雌二醇的情况下， 雌激素类固醇衍生物，用作绝经后妇女的激素替代疗法。使用 翻译认知评估和脑电图，我们将测试假设，雌激素是保护性的， NMDAR拮抗剂诱导的破坏，赋予对抗精神病药样活性的敏感性， NMDAR功能归因于NR2A/B亚基表达的雌激素依赖性改变。

Neuropsychiatric Symptoms (NPS) associated with Alzheimer’s Disease and related dementias (ADRD) include agitation, hallucinations, confusion and depression and are associated with disease severity, often precipitating the transition to assisted living facilities. Despite widespread prevalence, efficacious treatments for NPS remain elusive. ~40% of patients with dementia in assisted living facilities are treated with antipsychotic medications (off-label) to manage NPS despite limited efficacy, concerns regarding safety and compromised quality of life. Sex differences in the prevalence and severity of NPS are reported yet the contributing factors are not well understood. NPS symptoms resemble hallmark positive, negative and cognitive symptoms as well as sleep disturbances associated with schizophrenia. These behavioral and functional commonalities between NPS in ADRD and schizophrenia suggest plausible similarities in etiology and risk factors. One primary hypothesis for the etiology of schizophrenia is glutamate hypofunction, specifically decreased ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) function. In humans and animals, NMDAR antagonism produces psychotomimetic- and depression-like symptoms, impairs cognition and disrupts sleep, modelling all symptom clusters of both conditions. Investigating factors associated with aging that influence NMDAR function holds promise for understanding neurobiology and treatment of NPS. Estrogen is hypothesized to have neuroprotective effects in females. Estrogen depletion post menopause represents a risk factor for cognitive decline, schizophrenia, reduced antipsychotic efficacy and likely NPS associated with ADRDs. Estrogen also influences NMDAR subunit composition and function. We propose to investigate estrogen depletion on cognition, brain function, and NMDAR subunit expression and function combining rodent models of menopause and schizophrenia-like symptoms to model NPS in ADRD, as well as responsivity to the atypical antipsychotic medication, olanzapine, commonly used to treat NPS with known reductions in efficacy in post-menopausal women. Electroencephalography (EEG) will be employed which provides a translational measure of brain function and sleep across species. In both human and animals NMDAR antagonism induced excessive increases in high frequency gamma oscillations which correlates with cognitive impairments and psychotomimetic-like effects. To examine the impact of estrogen depletion on cognition, NMDAR function and antipsychotic-like effects, we will use ovariectomized rats (Ovx), a model of surgical menopause where gonadal hormones are depleted, in the presence or absence of 17β-estradiol, an estrogen steroid derivative used as a hormone replacement therapy in post-menopausal women. Using translational cognitive assessments and EEG, we will test the hypothesis that estrogen is protective against NMDAR antagonist-induced disruptions, confers sensitivity to antipsychotic-like activity and that altered NMDAR function is attributed to estrogen-dependent alterations in NR2A/B subunit expression.