Effects of Prenatal Alcohol Exposure on Alzheimer's Disease-associated Neuropsychiatric Symptoms

产前酒精暴露对阿尔茨海默病相关神经精神症状的影响

• 批准号: 10743681
• 负责人: Yao-Ying Ma
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743681
• 关键词: Acceleration; Action Potentials; Administrative Supplement; Adolescent; Adult; Affect; Alcohol-Related Disorders; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Atrophic; Attention; Award; Behavioral; Brain; Brain region; Calcium; Caregiver Burden; Caregivers; Cells; Clinic; Dementia; Disease; Elderly; Environmental Risk Factor; Evaluation; Exhibits; Fetal Alcohol Exposure; Fetal alcohol effects; Genetic; Goals; Grant; Human; Impaired cognition; Incidence; Institutionalization; Investigation; Laboratory Animals; Life; Life Expectancy; Live Birth; Measures; Molecular; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Oral; Output; Parents; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Psyche structure; Quality of life; Rattus; Recording of previous events; Reporting; Role; Slice; Sucrose; Symptoms; Synapses; Synaptic Transmission; Testing; United States; alcohol exposure; associated symptom; behavioral phenotyping; care costs; design; disability; exposed human population; high risk; improved; in vivo; maternal alcohol use; middle age; neuronal excitability; neuropsychiatric symptom; novel; patch clamp; premature; response; risk variant; success

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia, affecting 3–11% of the United States elderly. On the other hand, the estimated incidence of prenatal alcohol exposure (PAE)-induced mental disability or disease is 10 per 1000 live births. Although theoretically PAE-induced mental diseases are preventable, the prevalence of PAE has been reported to be as high as 10%-16.3%. Among a broad spectrum of PAE and AD- associated symptoms, progressive impairment of cognition has been extensively investigated. However, limited symptomatic relief in these patients by available medications demonstrates lack of understanding of the neuronal substrates, especially the PAE and/or AD-associated neuropsychiatric symptoms (NPSs). It is well accepted that apathy, the top ranked NPS in both PAE and AD, arises through interactions between genetic and environmental factors. PAE has been considered an environmental insult to the brain and AD high risk genes have been identified as top genetic factors facilitating the onset of NPSs. Together with the increased life expectancy by 8-10 years in the USA in the last 50 years, the evaluation of interactions between PAE history and AD high-risk genes at the molecular, synaptic, circuit, and behavioral levels is highly urgent. Our awarded parent R01 grant focused on exploring changes of excitatory synaptic transmission to the nucleus accumbens (NAc) underlying the synaptic loss and the low motivation phenotype in subjects with high risk of AD and a history of PAE. Besides the synaptic transmission, evaluation of a brain region’s functional output is directly related to the excitability of the projecting neurons in that region. Thus, in this Administrative Supplement proposal as a response to PA-18-591, we will focus on the excitability-related readouts, including the number of action potentials measured by whole-cell patch clamp and the calcium transient activity measured in vivo and ex vivo.

项目总结/摘要 阿尔茨海默病（AD）是痴呆症的最常见原因，影响3-11%的老年人。 美国老人另一方面，产前饮酒的估计发生率 接触（PAE）引起的精神残疾或疾病的死亡率为每1 000名活产10人。虽然 从理论上讲，PAE引起的精神疾病是可以预防的， 据报道高达10%-16.3%。在广泛的PAE和AD中， 伴随症状，认知的进行性损害已被广泛地 研究了然而，这些患者的症状缓解有限， 药物治疗表明缺乏对神经基质的理解，特别是 PAE和/或AD相关神经精神症状（NPS）。这是公认的 冷漠，在PAE和AD中排名第一的情感障碍，是通过以下因素之间的相互作用产生的： 遗传和环境因素。PAE被认为是对环境的一种侮辱， 大脑和AD高危基因已被确定为促进AD发生的最重要的遗传因素。 NPSs的出现。加上美国人的预期寿命增加了8-10年， 在过去的50年里，PAE病史和AD高危之间的相互作用的评价 在分子、突触、电路和行为水平上研究基因是非常紧迫的。我们 授予父母R 01基金，专注于探索兴奋性突触的变化 传递到突触丢失和低水平的突触传递的基础是突触核（NAc）。 动机表型在具有AD高风险和PAE病史的受试者中的作用。除了 突触传递，评估大脑区域的功能输出直接相关 与该区域投射神经元的兴奋性有关。因此，在本行政 作为对PA-18-591的回应，我们将重点关注兴奋性相关的 读数，包括全细胞膜片钳测量的动作电位数量 以及在体内和离体测量的钙瞬时活性。