Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Neuroscience. 2013 Jun 3;239:228-40. doi: 10.1016/j.neuroscience.2012.10.014. Epub 2012 Oct 16.
During development of the nervous system, the formation of connections (synapses) between neurons is dependent upon electrical activity in those neurons, and neurotrophic factors produced by target cells play a pivotal role in such activity-dependent sculpting of the neural networks. A similar interplay between neurotransmitter and neurotrophic factor signaling pathways mediates adaptive responses of neural networks to environmental demands in adult mammals, with the excitatory neurotransmitter glutamate and brain-derived neurotrophic factor (BDNF) being particularly prominent regulators of synaptic plasticity throughout the central nervous system. Optimal brain health throughout the lifespan is promoted by intermittent challenges such as exercise, cognitive stimulation and dietary energy restriction, that subject neurons to activity-related metabolic stress. At the molecular level, such challenges to neurons result in the production of proteins involved in neurogenesis, learning and memory and neuronal survival; examples include proteins that regulate mitochondrial biogenesis, protein quality control, and resistance of cells to oxidative, metabolic and proteotoxic stress. BDNF signaling mediates up-regulation of several such proteins including the protein chaperone GRP-78, antioxidant enzymes, the cell survival protein Bcl-2, and the DNA repair enzyme APE1. Insufficient exposure to such challenges, genetic factors may conspire to impair BDNF production and/or signaling resulting in the vulnerability of the brain to injury and neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Further, BDNF signaling is negatively regulated by glucocorticoids. Glucocorticoids impair synaptic plasticity in the brain by negatively regulating spine density, neurogenesis and long-term potentiation, effects that are potentially linked to glucocorticoid regulation of BDNF. Findings suggest that BDNF signaling in specific brain regions mediates some of the beneficial effects of exercise and energy restriction on peripheral energy metabolism and the cardiovascular system. Collectively, the findings described in this article suggest the possibility of developing prescriptions for optimal brain health based on activity-dependent BDNF signaling.
在神经系统发育过程中，神经元之间连接（突触）的形成依赖于这些神经元中的电活动，而靶细胞产生的神经营养因子在这种活动依赖性的神经网络塑造中起着关键作用。在成年哺乳动物中，神经递质和神经营养因子信号通路之间的类似相互作用介导了神经网络对环境需求的适应性反应，兴奋性神经递质谷氨酸和脑源性神经营养因子（BDNF）是整个中枢神经系统中突触可塑性的特别重要调节因子。间歇性挑战，如运动、认知刺激和饮食能量限制，可以促进整个生命周期的大脑健康，使神经元受到与活动相关的代谢应激。在分子水平上，神经元受到的这些挑战会导致参与神经发生、学习和记忆以及神经元存活的蛋白质的产生；这些蛋白质的例子包括调节线粒体生物发生、蛋白质质量控制以及细胞对氧化、代谢和蛋白毒性应激的抗性的蛋白质。BDNF 信号转导介导了几种蛋白质的上调，包括蛋白伴侣 GRP-78、抗氧化酶、细胞存活蛋白 Bcl-2 和 DNA 修复酶 APE1。如果没有充分暴露于这些挑战中，遗传因素可能会协同作用，导致 BDNF 的产生和/或信号转导受损，从而使大脑容易受到损伤和神经退行性疾病的影响，包括阿尔茨海默病、帕金森病和亨廷顿病。此外，BDNF 信号转导受到糖皮质激素的负调控。糖皮质激素通过负调节棘突密度、神经发生和长时程增强来损害大脑中的突触可塑性，这些效应可能与糖皮质激素对 BDNF 的调节有关。研究结果表明，BDNF 信号转导在特定脑区介导了运动和能量限制对周围能量代谢和心血管系统的一些有益影响。总的来说，本文描述的研究结果表明，基于活动依赖性 BDNF 信号转导，有可能制定出最佳大脑健康的处方。
