Impact of Adverse Life Events on Neuroplasticity

长期的压力，如丧偶或睡眠不足，可能导致记忆障碍，增加对阿尔茨海默病的易感性。压力的实验模型表明，在社会心理或环境压力下，空间记忆、情境记忆和物体识别受损。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改变仍有待确定。我们正在使用小鼠模型来验证慢性社会心理压力和睡眠剥夺会加速正常衰老和AD患者认知障碍的发展这一假设。利用三重转基因AD小鼠模型（3xTgAD小鼠），我们正在确定慢性应激对淀粉样蛋白形成、tau病理、突触功能障碍和学习记忆障碍的影响。我们正在测试衰老和AD损害适应性细胞应激反应途径的假设，导致氧化应激增加，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，暴饮暴食导致神经内分泌应激系统的过度激活，肾上腺糖皮质激素水平升高损害海马突触可塑性和神经发生，这些与压力相关的改变与认知功能缺陷有关。有趣的是，有规律的运动和饮食能量限制可以通过上调神经营养因子BDNF的表达来抵消糖尿病对海马可塑性的不利影响。

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.