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

项目摘要/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 美国老年人。另一方面，产前饮酒的估计发病率 暴露(PAE)导致的精神残疾或疾病是每1000名活产儿中有10名。虽然 从理论上讲，PAE引发的精神疾病是可以预防的，PAE的患病率 据报道高达10%-16.3%。在广泛的PAE和AD中- 伴随的症状，进行性认知障碍已广泛存在 调查过了。然而，这些患者的症状缓解有限，可用 药物显示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(NPSS)。它被广泛接受 这种冷漠是PAE和AD中排名最高的NPS，是由于 遗传和环境因素。PAE被认为是对环境的侮辱 脑和阿尔茨海默病高危基因已被确定为促进 NPSS的开始。再加上美国人的预期寿命增加了8-10年 近50年来对PAE病史与AD高危因素相互作用的评价 在分子、突触、回路和行为水平上的基因是非常紧迫的。我们的 获奖家长R01专注于探索兴奋性突触的变化 突触缺失和低密度脂蛋白对伏隔核的传递 AD高危人群和PAE病史受试者的动机表型。除了 突触传递，评价一个脑区的功能输出是直接相关的 该区域投射神经元的兴奋性。因此，在本管理中 补充建议作为对PA-18-591的回应，我们将重点关注与兴奋性相关的 读数，包括全细胞膜片钳测量的动作电位数 测定了体内、外钙瞬变活性。

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.