Endogenous barcoding to determine complex dynamics of adult neurogenesis in aging and Alzheimer's disease

1篇摘要 2 3艾滋病毒感染者逐渐老化，部分原因是抗逆转录病毒药物的有效性。 4疗法（ART），显着提高了受感染者的预期寿命。人口老龄化 5不可避免地面临发展神经退行性疾病包括阿尔茨海默病（AD）的风险增加。 6这些问题是 7这些缺陷可能完全是由于HIV-1感染; 然而，这也可能表明长期ART本身也会导致损伤。后一种可能性是 9特别令人关切的是，越来越多的未感染者使用抗逆转录病毒药物， 10暴露前预防（PrEP）。ART引起的变化的机制及其对脑的影响 抗逆转录病毒药物长期治疗可能影响的回路尚不清楚;对这种作用的了解更少。 12抗逆转录病毒药物在衰老和AD折磨的大脑。ART引起的变化和脑回路的机制 13可能受到长期抗逆转录病毒药物治疗影响的疾病尚不清楚; 14抗逆转录病毒药物治疗老年痴呆症患者的大脑. [15]我们建议应用我们最近开发的一系列新工具来分析神经发生， 16构建、比较和分析小鼠大脑中神经元激活的3D全脑图，以揭示 图17受代表性抗逆转录病毒药物影响的关键神经回路。我们的假设是，神经元的3D模式 18在暴露于抗逆转录病毒药物并参与挑战性行为任务的衰老和AD模型动物中， 19都揭示了定义这些效应的关键电路，并作为治疗的独特标志。 20种效果此外，我们最近的研究结果表明，抗逆转录病毒治疗可以影响成年海马 21神经发生，从而表明ARV暴露的衰老和AD大脑的另一个潜在的脆弱性。这 22提案与R 01补助金直接相关，R 01补助金也关注衰老和AD大脑。 23在具体目标1中，我们将确定代表性抗逆转录病毒药物延长治疗对干细胞的影响。 24细胞和成年出生的神经元在衰老和AD模型小鼠的海马。具体目标2： 25确定神经回路的关键共享组件受长期暴露于选定的抗逆转录病毒药物的影响。我们 图26将生成衰老和AD模型小鼠中神经元激活的介观全局图，呈现相关的 接触抗逆转录病毒药物后的27项认知挑战。然后，我们将逐步选择映射数据集 28个管道来识别治疗改变的关键大脑区域和神经回路。我们的实验将 29揭示了抗逆转录病毒药物对海马神经发生的影响，并将为抗逆转录病毒药物的作用创造一个电路图空间。 30种抗逆转录病毒药物，其他回路映射在其上，描述了在衰老背景下对治疗的各种反应， 31 AD可以预测和比较。 32 进一步加剧了认知缺陷的患病率观察到的实质性 接受抗逆转录病毒治疗的艾滋病毒1感染者的比例。

1 ABSTRACT 2 3 The population of people living with HIV gradually ages, in part due to the efficiency of antiretroviral 4 therapy (ART) which has significantly improved the life expectancy of infected individuals. This aging population 5 inevitably faces an increased risk of developing neurodegenerative disorders including Alzheimer's disease (AD). 6 These concerns are 7 These deficits may be due solely to the HIV-1 infection; 8 however, this may also indicate that long-term ART itself contributes to the impairments. The latter possibility is 9 of particular concern given that a growing number of uninfected individuals employ use antiretrovirals (ARVs) as 10 pre-exposure prophylaxis (PrEP). The mechanisms underlying ART-induced changes and their impact on brain 11 circuitry that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action 12 of ARVs in the aging and AD-afflicted brain. The mechanisms of ART-induced changes and the brain circuitry 13 that may be affected by prolonged treatment with ARVs are unclear; even less is known about the action of 14 ARVs in the aging and AD -afflicted brain. 15 We propose to apply our recently developed array of new tools for analyzing neurogenesis and for 16 constructing, comparing, and analyzing 3D whole-brain maps of neuronal activation in the mouse brain to reveal 17 the critical neural circuitry affected by representative ARVs. Our hypothesis is that 3D patterns of neuronal 18 activation in aging and AD model animals exposed to ARVs and involved in challenging behavioral tasks can 19 both reveal the crucial circuitry defining these effects and serve as unique signatures of the treatments’ 20 effects. Furthermore, our recent results demonstrate that treatment with ARVs can affect adult hippocampal 21 neurogenesis, thus indicating another potential vulnerability of the ARV-exposed aging and AD brain. This 22 proposal is directly related to the parent R01 grant which also focuses on the aging and AD brain. 23 In specific aim 1, we will determine the effect of prolonged treatment with representative ARVs on stem 24 cells and adult-born neurons in the hippocampus of aging and AD model mice. In specific aim 2, we will 25 determine the critical shared components of neural circuitry affected by prolonged exposure to select ARVs. We 26 will generate mesoscopic global maps of neuronal activation in aging and AD model mice presented with relevant 27 cognitive challenges after exposure to ARVs. We will then subject the mapping datasets to our stepwise selection 28 pipeline to identify the critical brain regions and neural circuits altered by the treatments. Our experiments will 29 reveal the effect of ARVs on hippocampal neurogenesis and will create a circuitry map space for the action of 30 ARVs upon which other circuitry maps that describe various responses to treatments in the context of aging and 31 AD can be projected and compared. 32 further compounded by the prevalence of cognitive deficits observed in a substantial proportion of HIV-1-infected individuals undergoing ART.