Role of adolescent stress in the acceleration of Alzheimer's disease related-cognitive impairment

青少年压力在加速阿尔茨海默病相关认知障碍中的作用

• 批准号: 10494601
• 负责人: Minae Niwa
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494601
• 关键词: APP-PS1; Acceleration; Address; Adolescence; Adolescent; Affect; Alzheimer' s Disease; Amyloid; Anterior; Behavior; Behavioral; Biological; Brain; Childbirth; Cognition; Cognitive; Cognitive deficits; Corticosterone; DNA Sequence Alteration; Data; Development; Disease Progression; Dorsal; Exposure to; Female; Foundations; Functional disorder; Future; Generations; Glucocorticoid Receptor; Glucocorticoids; Glutamates; Goals; Human; Hydrocortisone; Image; Impaired cognition; Impairment; Insula of Reil; Lead; Life; Life Experience; Maternal Behavior; Measures; Mediating; Mediation; Microscope; Molecular; Moods; Mothers; Mus; National Institute of Mental Health; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neurosecretory Systems; Pathology; Pathway interactions; Phenotype; Physiological Adaptation; Plasma; Postpartum Period; Pregnancy; Protocols documentation; Psychosocial Stress; Publishing; Quality of life; Receptor Signaling; Regulation; Research; Risk; Risk Factors; Rodent; Role; Senile Plaques; Social Behavior; Social Interaction; Social isolation; Stress; Stressful Event; Symptoms; Synapses; Synaptic plasticity; Techniques; Testing; Woman; base; behavioral outcome; cingulate cortex; cognitive function; critical period; density; early life stress; experience; healing; high risk; hypothalamic-pituitary-adrenal axis; in vivo; male; men; mouse model; neural circuit; neuropathology; novel; object recognition; optogenetics; prevent; psychologic; social; social cognition; stressor

PROJECT SUMMARY/ABSTRACT The primary goal of our NIMH R01 project (R01MH116869) is to elucidate the role of adolescent stress on social cognition in the postpartum period. We have discovered that adolescent psychosocial stress, in conjunction with the stressful events of pregnancy/delivery, leads to long-lasting deficits in social behaviors in the postpartum period. We have also demonstrated that the social behavioral deficits in stressed dams are caused by glucocorticoid receptor (GR)-mediated functional alteration of anterior insula (AI)-prelimbic cortex (PrL) projections. These results show the causal role of enhanced GR signaling in the AI-PrL pathway underlying adolescent stress-induced social behavioral deficits in the postpartum period. Recent studies demonstrate that females have a significantly greater risk for the development of Alzheimer’s disease (AD) than males. Early life stress drives the progression of AD and exacerbates symptoms. Pathology in AI and dorsal anterior cingulate cortex [dACC, homologous to the PrL in rodents] have been implicated in AD. However, the mechanisms underlying the deficits at the circuit level remain unclear. By modifying the protocol of our ongoing R01 project, we may be able to explore the relationship between the dysfunction of this circuit and the acceleration of the AD-related phenotypes in females. In this proposed supplemental study, we will test the hypothesis that adolescent social isolation, in conjunction with the stressful events of pregnancy/delivery, accelerates the onset of AD-related deficits in social behaviors via AI-PrL functional alterations. To address our hypothesis, we will pursue the following specific two Aims: In Aim 1, we will examine whether adolescent social isolation accelerates the onset of AD-related deficits in social behaviors in 5xFAD dams. Plasma corticosterone levels, plaques of Aβ and amyloid, and synaptic density will be measured to examine the effects of adolescent stress on regulation of the HPA axis and AD-related neuropathology in 5xFAD dams. In Aim 2, we will investigate how mediation of the AI-PrL projections, a novel cortico-cortical pathway, alters social behaviors in 5xFAD dams exposed to adolescent social isolation. This supplemental study will generate critical data to understand the influence of adolescent psychosocial stress on neuronal function and behavior in the context of AD. The finding will also stimulate research to manipulate a specific circuit at a critical period in order to intervene in AD-related pathology and symptoms.

项目概要/摘要 我们的 NIMH R01 项目 (R01MH116869) 的主要目标是阐明青少年压力对社交的影响。 我们发现，青少年心理社会压力与产后认知有关。 怀孕/分娩的压力事件会导致产后社会行为的长期缺陷 我们还证明了受压水坝的社会行为缺陷是由以下因素引起的。 糖皮质激素受体（GR）介导的前岛叶（AI）-前边缘皮质（PrL）功能改变 这些结果显示了增强的 GR 信号在 AI-PrL 通路中的因果作用。 最近的研究表明，青少年压力引起的产后社会行为缺陷。 女性早期患阿尔茨海默氏病 (AD) 的风险显着高于男性。 压力会导致 AD 的进展，并使 AI 和背侧前扣带回的病理症状恶化。 皮层 [dACC，与啮齿类动物的 PrL 同源] 与 AD 相关，但其机制尚未明确。 通过修改我们正在进行的 R01 项目的协议，电路层面的缺陷仍然不清楚。 我们也许能够探索该电路的功能障碍与加速之间的关系 在这项拟议的补充研究中，我们将检验以下假设： 青少年的社会孤立，加上怀孕/分娩的压力事件，加速了发病 通过 AI-PrL 功能改变来研究 AD 相关的社会行为缺陷 为了验证我们的假设，我们将 追求以下两个具体目标：在目标 1 中，我们将研究青少年是否存在社会孤立 加速 5xFAD 母鼠血浆皮质酮水平中与 AD 相关的社会行为缺陷的发生， 将测量 Aβ 和淀粉样蛋白斑块以及突触密度，以检查青少年压力的影响 在目标 2 中，我们将研究如何调节 5xFAD 水坝中的 HPA 轴和 AD 相关神经病理学。 AI-PrL 投射（一种新的皮质-皮质通路）的调节改变了 5xFAD 水坝的社会行为 这项补充研究将产生关键数据来了解青少年的社会隔离。 AD 背景下青少年心理社会压力对神经功能和行为的影响。 还将刺激在关键时期操纵特定电路以干预 AD 相关疾病的研究 病理和症状。