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Impact of Adverse Life Events on Neuroplasticity

不良生活事件对神经可塑性的影响

基本信息

批准号：
8931512
负责人：
Mark Mattson
金额：
$ 48.59万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8931512
关键词：
Acute Adrenal Glands Adverse effects Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Animal Model Antioxidants Anxiety Attention deficit hyperactivity disorder Attenuated Autonomic nervous system Autopsy Behavior Behavioral Biochemical Biological Markers Bipolar Disorder Blood Glucose Brain Brain Stem Brain-Derived Neurotrophic Factor Cardiovascular system Cellular Stress Response Chronic Chronic stress Cognitive deficits Communities Congenital neurologic anomalies Corticosterone Cues Data Development Diabetes Mellitus Diet Disease Emotional Endogenous depression Enzymes Epidemiology Evaluation Event Exercise Exhibits Experimental Models Functional disorder Glucocorticoids Goals Heart Heart Rate Hippocampus (Brain)Home environment Human Hyperphagia Immunoblotting Impaired cognition Impairment Impulsivity Individual Insulin Lead Learning Life Measures Mediating Memory Memory impairment Mental disorders MicroRNAs Modeling Molecular Motor Mus Nerve Degeneration Neuronal Dysfunction Neuronal Plasticity Neurons Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Novelty-Seeking Behaviors Outcome Overweight Oxidative Stress Parkinson Disease Pathology Pathway interactions Patients Personality inventories Physiological Plasma Potential Energy Predisposition Process Proteins Psychosocial Stress Regulation Reporting Research Rest Risk Factors Role Sampling Signal Transduction Sleep Sleep Deprivation Spouses Staging Stress Structure Substantia nigra structure Symptoms Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Intervention Transgenic Mice Transgenic Organisms Up-Regulation Uric Acid Variant Wild Type Mouse Work biological adaptation to stress clinically relevant cognitive function conditioned fear dopaminergic neuron experience human data inhibitor/antagonist male memory recognition morris water maze mouse model mutant neurogenesis neurotrophic factor normal aging novel strategies object recognition peptide A psychosocial response social stress stressor synuclein tau Proteins tau-1 trait

项目摘要

Chronic stresses such as loss of a spouse or sleep deprivation, may cause memory impairments and increase susceptibility to AD. Experimental models of stress demonstrate impairments in spatial memory, contextual memory and object recognition in response to psychosocial or environmental stress. Yet, it remains to be determined if and how environmental stress modifies the cellular and molecular alterations that result in cognitive deficits in normal aging and in AD. We are employing mouse models to test the hypothesis that chronic psychosocial stress and sleep deprivation will accelerate the development of cognitive impairment in normal aging and in AD. Using the triple-transgenic AD mouse model (3xTgAD mice) we are determining the effects of chronic stress on amyloidogenes, tau pathology, synaptic dysfunction and learning and memory impairment. We are testing the hypothesis that aging and AD compromise adaptive cellular stress response pathways resulting in increased oxidative stress associated with reduced expression of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and antioxidant enzymes. In related studies we have found that, in a model of type 2 diabetes, overeating results in hyperactivation of the neuroendocrine stress system, and that elevated levels of adrenal glucocorticoids impair hippocampal synaptic plasticity and neurogenesis, and that these stress-related alterations are associated with a deficit in cognitive function. Interestingly, regular exercise and dietary energy restriction can counteract the adverse effects of diabetes on hippocampal plasticity by a mechanism involving up-regulation of the expression of the neurotrophic factor BDNF. Chronic stress may be a risk factor for developing Alzheimer's disease (AD), but most studies of the effects of stress in models of AD utilize acute adverse stressors of questionable clinical relevance. We therefore undertook a study to determine how chronic psychosocial stress affects behavioral and pathological outcomes in an animal model of AD, and to elucidate underlying mechanisms. A triple-transgenic mouse model of AD (3xTgAD mice) and nontransgenic control mice were used to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety, and hippocampal amyloid, phosphorylated tau (ptau), and brain-derived neurotrophic factor (BDNF) levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6-week stress period 3xTgAD mice displayed increased anxiety, elevated levels of amyloid; oligomers and intraneuronal amyloid;, and decreased brain-derived neurotrophic factor levels, whereas control mice did not. Our findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates amyloid; accumulation and impairs neurotrophic signaling. Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of -synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of -synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of -synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals. Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid β-peptide (Aβ) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aβ and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aβ and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD. The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention. Studying the progressive change in miRNAs modulation during aging of 3xTgAD mice, we identified miRNAs that were regulated in earlier stages of AD, suggesting them as potential AD biomarkers. We characterized AD- and EE-related effects in the mouse hippocampus on tomosyn, an inhibitor of the synaptic transmission machinery. While EE reduced tomosyn levels, tomosyn levels were increased in old mice.

失去配偶或睡眠不足等慢性压力可能会导致记忆障碍并增加患 AD 的易感性。压力的实验模型表明，在应对心理社会或环境压力时，空间记忆、情境记忆和物体识别都会受到损害。然而，环境压力是否以及如何改变导致正常衰老和 AD 认知缺陷的细胞和分子变化仍有待确定。我们正在使用小鼠模型来检验以下假设：慢性社会心理压力和睡眠不足会加速正常衰老和 AD 中认知障碍的发展。使用三重转基因 AD 小鼠模型（3xTgAD 小鼠），我们正在确定慢性应激对淀粉样蛋白生成、tau 病理学、突触功能障碍以及学习和记忆障碍的影响。我们正在测试这样的假设：衰老和 AD 会损害适应性细胞应激反应途径，导致氧化应激增加，而氧化应激增加与神经保护蛋白（如脑源性神经营养因子 (BDNF) 和抗氧化酶）表达减少相关。在相关研究中，我们发现，在2型糖尿病模型中，暴饮暴食会导致神经内分泌应激系统过度激活，肾上腺糖皮质激素水平升高会损害海马突触可塑性和神经发生，而这些与应激相关的改变与认知功能缺陷有关。有趣的是，定期运动和饮食能量限制可以通过上调神经营养因子 BDNF 表达的机制来抵消糖尿病对海马可塑性的不利影响。慢性压力可能是发生阿尔茨海默病 (AD) 的一个危险因素，但大多数关于压力对 AD 模型影响的研究都利用了临床相关性值得怀疑的急性不良压力源。因此，我们进行了一项研究，以确定慢性心理社会压力如何影响 AD 动物模型的行为和病理结果，并阐明潜在机制。使用 AD 三重转基因小鼠模型（3xTgAD 小鼠）和非转基因对照小鼠来测试慢性轻度社会压力对血糖、血浆糖皮质激素、血浆胰岛素、焦虑以及海马淀粉样蛋白、磷酸化 tau (ptau) 和脑源性神经营养因子 (BDNF) 水平的影响。尽管对照组和 3xTgAD 小鼠在轻度社会压力期间皮质酮水平均升高，但在 6 周压力期结束时，3xTgAD 小鼠表现出焦虑增加、淀粉样蛋白水平升高；寡聚物和神经元内淀粉样蛋白；并降低脑源性神经营养因子水平，而对照小鼠则没有。我们的研究结果表明，3xTgAD 小鼠比对照小鼠更容易受到慢性社会心理压力的影响，并且这种慢性压力会加剧淀粉样蛋白的产生；积累并损害神经营养信号。帕金森病 (PD) 患者经常表现出自主神经系统 (ANS) 对心率的调节受损，在许多情况下，这可能先于运动症状出现。尸检研究结果表明，脑干病理学（包括 β-突触核蛋白的积累）先于 PD 黑质中的多巴胺能神经元受损。然而，导致脑干自主神经元早期功能障碍的分子和细胞机制尚不清楚。在这里，我们报道表达导致家族性 PD 的 β-突触核蛋白突变体的小鼠表现出异常的心脏自主控制，其特征是静息心率升高和心血管应激反应受损，与副交感神经活动减少和脑干中 β-突触核蛋白积聚有关。这些 ANS 异常发生在疾病过程的早期。高能量饮食会加剧β-突触核蛋白对心率控制的不利影响，而间歇性能量限制会改善这种不利影响。我们的研究结果建立了 PD 中心血管系统脑干控制早期失调的小鼠模型，并进一步表明能量限制有可能减轻 ANS 功能障碍，特别是在超重个体中。阿尔茨海默病 (AD) 可能会加剧与年龄相关的睡眠失调。 AD 和睡眠限制都会损害认知，但尚不清楚轻微的慢性睡眠限制是否会改变 AD 所涉及的蛋白质病理过程。这项工作的目的是在 AD 小鼠模型中检验睡眠限制会加重记忆障碍以及淀粉样蛋白 β 肽 (Aβ) 和 pTau 在大脑中积聚的假设，重点是循环糖皮质激素 (GC) 的作用。使用改良的多平台技术，对雄性 3xTgAD 小鼠进行每天 6 小时的睡眠限制 (SR)，持续 6 周，并将行为（莫里斯水迷宫、恐惧条件反射、开放场）和生化（免疫印迹）结果与每天进行笼子转移的小鼠（大笼对照；LCC）以及留在其家笼中的对照小鼠（对照；CTL）进行比较。一周后，与 CTL 相比，LCC 和 SR 小鼠的血浆皮质酮均显着升高（p<0.002）。四周时，SR 小鼠的循环皮质酮水平比 CTL 增加两倍。行为数据表明 SR 小鼠存在情境记忆和线索记忆缺陷，而 LCC 或 CTL 则不存在这种缺陷（p<0.04）。与 CTL 和 LCC 相比，SR 小鼠皮质中的 Aβ 和 pTau 水平均有所增加；然而，海马体中没有注意到这些变化。皮质 Aβ 和 pTau 水平与循环皮质酮之间的显着正相关表明 GC 在调节 AD 小鼠模型睡眠限制后观察到的行为和生化变化中具有潜在作用。控制冲动的能力差异很大，难以控制冲动可能会产生严重的后果；在极端情况下，它是许多精神疾病的决定性特征。来自不同研究方向的证据表明，在以高度冲动为特征的精神疾病中，尿酸会升高，例如注意力缺陷/多动障碍和双相情感障碍。目前的研究测试了人类和小鼠的冲动与高尿酸相关的假设。我们使用两个纵向非临床社区样本（总计 n = 6883），测试了尿酸与使用修订版 NEO 人格量表测量的特质冲动的正常变异之间是否存在关联。我们还通过比较自然尿酸水平较低的野生型小鼠和经过基因改造积累高水平尿酸的小鼠，研究了尿酸对行为的影响。在这两个人类样本中，冲动特质的情绪方面，特别是冲动和寻求刺激，同时与较高水平的尿酸相关，并且在 3 至 5 年后测量尿酸。与人类数据一致，转基因小鼠比野生型小鼠表现出明显更多的探索和寻求新奇的行为。较高的尿酸与人类和小鼠的冲动有关。冲动的生物标志物的识别可能有助于更好地理解冲动所涉及的生理机制，并可能提出治疗干预的潜在目标。通过研究 3xTgAD 小鼠衰老过程中 miRNA 调节的渐进变化，我们鉴定了在 AD 早期阶段受到调节的 miRNA，表明它们是潜在的 AD 生物标志物。我们表征了小鼠海马体对突触传递机制抑制剂 tomosyn 的 AD 和 EE 相关影响。虽然 EE 降低了断层同步水平，但老年小鼠的断层同步水平却增加了。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).

DOI：
10.1523/jneurosci.5242-10.2011
发表时间：
2011-03-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Romberg C;Mattson MP;Mughal MR;Bussey TJ;Saksida LM
通讯作者：
Saksida LM

Molecular control of the amount, subcellular location, and activity state of translation elongation factor 2 in neurons experiencing stress.

在经历压力的神经元中，对量的数量，亚细胞位置和活性状态的分子控制。

DOI：
10.1016/j.freeradbiomed.2013.03.016
发表时间：
2013-08
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Argueelles, Sandro;Camandola, Simonetta;Hutchison, Emmette R.;Cutler, Roy G.;Ayala, Antonio;Mattson, Mark P.
通讯作者：
Mattson, Mark P.

Age and energy intake interact to modify cell stress pathways and stroke outcome.

DOI：
10.1002/ana.21798
发表时间：
2010-01
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Arumugam, Thiruma V.;Phillips, Terry M.;Cheng, Aiwu;Morrell, Christopher H.;Mattson, Mark P.;Wan, Ruiqian
通讯作者：
Wan, Ruiqian

Activity-dependent, stress-responsive BDNF signaling and the quest for optimal brain health and resilience throughout the lifespan.