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.

项目概要/摘要 阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，影响 3-11% 的人 另一方面，美国老年人产前饮酒的估计发生率。 每 1000 名活产婴儿中就有 10 人因暴露 (PAE) 导致精神残疾或疾病。 理论上PAE引起的精神疾病是可以预防的，PAE的患病率已经下降 据报道，在广泛的 PAE 和 AD 中，这一比例高达 10%-16.3%。 相关症状，尤其是进行性认知障碍 然而，研究发现这些患者的症状缓解有限。 药物表明缺乏对神经元底物的了解，尤其是 PAE 和/或 AD 相关的神经精神症状 (NPS) 已被广泛接受。 冷漠是 PAE 和 AD 中排名最高的 NPS，是通过之间的相互作用而产生的 PAE 被认为是对环境的侮辱。 大脑和 AD 高风险基因已被确定为促进的首要遗传因素 NPS 的出现以及美国的预期寿命增加了 8-10 年。 过去 50 年中，PAE 病史与 AD 高风险之间的相互作用评估 分子、突触、回路和行为水平上的基因非常紧迫。 获得母公司 R01 资助，专注于探索兴奋性突触的变化 传输到伏隔核（NAc），导致突触损失和低 AD 高风险和 PAE 病史受试者的动机表型。 突触传递，大脑区域功能输出的评估直接相关 因此，在该管理中，该区域的投射神经元的兴奋性。 补充提案作为对 PA-18-591 的回应，我们将重点关注与兴奋性相关的问题 读数，包括通过全细胞膜片钳测量的动作电位数量 以及体内和离体测量的钙瞬时活性。