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 (ADRD)包括激动、幻觉、困惑和抑郁，并与疾病严重程度有关， 往往会加速向辅助生活设施的过渡。尽管流行广泛，但有效 治疗NPS的方法仍然难以捉摸。在辅助生活设施中，约40%的痴呆症患者接受了 抗精神病药物(标签外)用于管理NPS，尽管疗效有限，对安全性和 降低了生活质量。据报道，NPS的患病率和严重程度存在性别差异 造成这一现象的因素还不是很清楚。NPS症状类似于标志性阳性、阴性和 与精神分裂症相关的认知症状以及睡眠障碍。这些行为和 ADRD和精神分裂症患者NPS的功能共同点提示在病因学上可能有相似之处 和风险因素。精神分裂症病因学的一个主要假设是谷氨酸功能低下， 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 动物，NMDAR拮抗剂会产生类似精神分裂和抑郁的症状，损害认知 并扰乱睡眠，模拟这两种情况的所有症状群。调查与以下方面相关的因素 影响NMDAR功能的衰老为了解神经生物学和NPS的治疗提供了希望。 雌激素被认为对女性有神经保护作用。绝经后雌激素耗竭 是认知功能减退、精神分裂症、抗精神病药物疗效降低以及可能的NPS的危险因素 与ADRD相关。雌激素还影响NMDAR亚单位的组成和功能。我们建议 研究雌激素缺乏对认知、脑功能以及NMDAR亚单位表达和功能的影响 结合更年期和精神分裂症样症状的啮齿动物模型在ADRD中建立NPS模型，以及 对非典型抗精神病药物奥氮平的反应性，通常用于治疗已知的NPS 绝经后妇女的疗效降低。将采用脑电图仪(EEG) 提供了一种跨物种的大脑功能和睡眠的翻译测量。在人类和动物中 NMDAR拮抗导致高频伽马振荡过度增加，这与 认知障碍和类似精神分裂的影响。为了研究雌激素耗竭对 在认知、NMDAR功能和抗精神病药样效应方面，我们将使用卵巢切除大鼠(OVX)，一个 性腺激素耗尽的外科绝经期，在17β-雌二醇存在或不存在的情况下， 雌激素类固醇衍生物用于绝经后妇女的激素替代治疗。vbl.使用 翻译认知评估和EEG，我们将检验雌激素对 NMDAR拮抗剂诱导的干扰，赋予抗精神病药样活动的敏感性，并改变 NMDAR的功能归因于雌激素依赖性的NR2A/B亚单位表达的改变。

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.