Astrocytic Contributions to Long Term Memory & Synaptic Plasticity

描述（由申请人提供）：记忆巩固是指新学习到的信息在不稳定状态下成为持久记忆的过程。长期记忆的巩固需要从头合成蛋白质，而树突蛋白的合成很可能也参与了这一过程。长期增强（LTP）是突触强度的持续增加，被认为是长期记忆的细胞关联8。与记忆巩固一样，LTP的晚期形式（L-LTP）也需要蛋白质合成，并且已被证明特别需要树突蛋白合成和体细胞蛋白合成9。情绪体验的记忆，如在基于恐惧条件的抑制性回避（IA）范式中产生的记忆，受到各种激素的调节35。在觉醒过程中，去甲肾上腺素从蓝斑释放，并通过肾上腺素能受体增强记忆。LTP也是如此，它同样由去甲肾上腺素调节10,50。最近来自我们实验室和其他人的证据表明，星形胶质细胞在学习、记忆和LTP中发挥的作用比以前认为的要大。星形胶质细胞通过糖原分解和单羧酸转运体向神经元提供乳酸，对记忆巩固和LTP维持至关重要（见初步数据）。有趣的是，-肾上腺素能受体存在于星形胶质细胞上，并且在星形胶质细胞受到刺激时也具有代谢作用15,16,37,38,39,40。本项目将测试星形胶质细胞对长期记忆和LTP的贡献。具体来说，它将验证星形胶质细胞通过乳酸支持树突蛋白合成激活相关的高能需求，从而提供星形胶质细胞-神经元耦合，从而对记忆形成起关键作用的假设。此外，它将验证记忆的去甲肾上腺素能依赖性调节是由星形细胞-神经元偶联介导的假设。

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.