Astrocytic Contributions to Long Term Memory & Synaptic Plasticity

描述(申请人提供)：记忆巩固是一个过程，通过这个过程，新学到的信息以一种不稳定的状态存在，变成一个长期的记忆，对干扰2，3，4。长期的记忆巩固需要从头开始的蛋白质合成，很可能树突状蛋白质的合成也参与了这个过程5。长时程增强(LTP)是突触强度的持续增加，被认为是与长期记忆相关的细胞8。像记忆巩固一样，晚期LTP(L-LTP)也需要蛋白质合成，并且已经被证明特别需要树突状蛋白质合成和体细胞蛋白质合成9。对情绪体验的记忆，例如那些在基于恐惧条件作用的抑制性回避(IA)范式中产生的记忆，受到各种激素的调节。在觉醒过程中，去甲肾上腺素从蓝斑释放出来，并通过肾上腺素能受体41增强记忆。LTP也是如此，它同样受去甲肾上腺素10，50的调节。来自我们实验室和其他实验室的最新证据表明，星形胶质细胞在学习、记忆和LTP方面发挥的作用比之前认为的更大。星形胶质细胞通过糖原分解将乳酸贡献给神经元，并通过单羧酸转运体进行转移，因此对记忆巩固和长时程增强至关重要(见初步数据)。有趣的是，β-肾上腺素能受体存在于星形胶质细胞上，当刺激15、16、37、38、39、40时，也对星形胶质细胞产生代谢作用。这个项目将测试星形胶质细胞对长期记忆和长时程增强的贡献。具体地说，它将测试这一假说，即星形胶质细胞通过乳酸提供星形胶质细胞-神经元耦合，从而支持与激活树突状蛋白合成相关的高能需求，从而对记忆形成做出关键贡献。此外，它还将检验去甲肾上腺素依赖的记忆调制是由星形胶质细胞-神经元耦合介导的假设。 公共卫生相关性：星形胶质细胞对脑部疾病的贡献是巨大的，但仍未得到充分的研究，但已有报道在几种神经退行性疾病中激活星形胶质细胞和小胶质细胞，包括艾滋病痴呆复合体、阿尔茨海默病和肌萎缩侧索硬化症66。这种转变可能伴随着星形胶质细胞的功能失调，甚至退化，从而导致这些细胞和神经元之间通常发生的串扰中断67。因此，不正确的神经元-星形胶质细胞相互作用可能参与神经元的紊乱并促进疾病的发展，阐明星形胶质细胞-神经元耦合在包括学习和记忆在内的认知功能中的机制将使我们能够更好地了解正常的大脑功能，并确定潜在的分子靶点，用于治疗几种疾病。

DESCRIPTION (provided by applicant): Memory consolidation is the process by which the newly learned information, which exists in a labile state, becomes a long-lasting memory that is resistant to disruption2,3,4. Long-term memory consolidation requires de novo protein synthesis, and it is very likely that dendritic protein synthesis is also involved in this process5. Long-term potentiation (LTP) is a persistent increase in synaptic strength, and is considered a cellular correlate for long-term memory8. Like memory consolidation, late forms of LTP (L-LTP) also require protein synthesis, and have been shown to specifically require dendritic protein synthesis as well as somatic protein synthesis9. Memories of emotional experiences such as those produced in the fear conditioning-based inhibitory avoidance (IA) paradigm, are subject to modulation by various hormones35. Noradrenaline is released from the locus coeruleus during arousal and enhances memory via ¿-adrenergic receptors41. The same is true in regards to LTP, which is likewise modulated by noradrenaline10,50. Recent evidence from our laboratory and others suggest that astrocytes play a larger role in both learning and memory and LTP than previously thought. By contributing lactate to neurons through glycogenolysis and transfer via monocarboxylate transporters, astrocytes are critical to memory consolidation and LTP maintenance (see preliminary data). Interestingly, ¿-adrenergic receptors are present on astrocytes and have also metabolic effects in astrocytes when stimulated15,16,37,38,39,40. This project will test the contribution of astrocytes to long-term memory and LTP. Specifically, it will test the hypothesis that astrocytes critically contribute to memory formation by providing astrocytic-neuronal coupling through lactate that supports the high-energy demands associated with activation of dendritic protein synthesis. Furthermore, it will test the hypothesis that the noradrenergic-dependent modulation of memory is mediated by the astrocytic-neuronal coupling. PUBLIC HEALTH RELEVANCE: The contribution of astrocytes to brain diseases is vast and still very underexplored, but astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis66. This transition may be accompanied by functional deregulation and even degeneration of the astrocytes with the consequent disruption of the crosstalk normally occurring between these cells and neurons67. Thus, incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development, and elucidating the mechanisms that underlie the astrocyte-neuronal coupling in cognitive functions including learning and memory should enable us to better understand normal brain function and identify potential molecular targets for therapeutic intervention in several disorders.