Impact of Adverse Life Events on Neuroplasticity

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 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，而氧化应激增加与脑源性神经营养因子 (BDNF) 和抗氧化酶等神经保护蛋白表达减少相关。 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 AD 模型中压力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。 一些具有丰富淀粉样蛋白和/或异常磷酸化 tau 蛋白的 AD 小鼠模型会出现记忆障碍。然而，注意力和执行控制等多个非记忆认知领域在 AD 个体的早期也受到损害。目前，尚不清楚 β-淀粉样蛋白前体蛋白 (APP) 和 tau 蛋白的突变是否足以在该疾病的小鼠模型中引起类似的 AD 样注意力缺陷。为了解决这个问题，我们在新开发的基于触摸屏的注意力和反应控制的 5 选择系列反应时间测试中测试了 3xTgAD 小鼠（表达 APPswe、PS1M146V 和 tauP301L 突变）和野生型对照小鼠。当任务的注意力需求较高时，3xTgAD 小鼠对短暂的、空间上不可预测的刺激的关注不太准确，并且还表现出比野生型小鼠做出更持久反应的普遍趋势。 3xTgAD小鼠的注意力损害在两个方面与AD患者相当：首先，尽管3xTgAD小鼠最初的反应与野生型小鼠一样准确，但它们随后无法在任务持续时间内维持注意力；其次，胆碱酯酶抑制剂多奈哌齐（Aricept）增强了维持注意力的能力。这些发现表明，家族性 AD 突变不仅影响记忆，还会导致注意力严重受损，注意力是由前额叶皮层及其传入神经支持的认知领域。由于注意力缺陷可能会影响记忆编码和其他认知能力，因此我们的研究结果对于评估 AD 动物模型的疾病机制和治疗方法具有重要意义。 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-突触核蛋白积累有关。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 患者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。 亨廷顿病 (HD) 与严重的自主神经功能障碍有关，包括心血管控制失调，通常先于认知或运动症状出现。 HD 患者和 HD 小鼠模型大脑中的脑源性神经营养因子 (BDNF) 水平降低，恢复 BDNF 水平可以防止 HD 小鼠的神经元损失并延长生存期。我们推断，HD 中心率的变化可能与脑干心血管控制核中 BDNF 信号的改变有关。在这里，我们发现 HD (N171-82Q) 小鼠在症状前和疾病早期阶段的心率升高，并且心率对约束应激的反应减弱。 HD 小鼠和人类 HD 患者中含有心血管核的脑干区域的 BDNF 水平显着降低。 BDNF 的中央管理使心率恢复到控制水平。我们的研究结果建立了 HD 小鼠脑干心血管核中 BDNF 表达减少与心率异常之间的联系，并提出了纠正 HD 心血管功能障碍的新治疗靶点。 在另一项研究中，我们发现铜蓝蛋白（Cp；一种铁调节蛋白）缺乏会导致旷场和高架十字迷宫测试中的焦虑样行为加剧。这种焦虑表型与血浆皮质酮水平升高有关。先前的研究提供的证据表明，焦虑症和长期压力与海马体中血清素（5HT）和脑源性神经营养因子（BDNF）水平的降低有关。我们发现 CpKO 小鼠海马中 5HT 和去甲肾上腺素 (NE) 的水平以及 BDNF 及其受体 trkB 的表达显着降低。因此，Cp 缺乏通过涉及海马中铁、5HT、NE 和 BDNF 水平降低的机制引起焦虑表型。

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. Several mouse models of AD with abundant amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. 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. Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD. In another study we found that ceruloplasmin (Cp; an iron-regulating protein) deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of 5HT and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, 5HT, NE, and BDNF in the hippocampus.