Astrocytic Contributions to Long Term Memory & Synaptic Plasticity

星形胶质细胞对长期记忆的贡献

• 批准号: 8267253
• 负责人: Sarah Stern
• 金额: $ 3.42万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-16 至 2014-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267253
• 关键词: AIDS Dementia Complex; Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Affect; Alzheimer' s Disease; Arousal; Astrocytes; Behavioral; Binding Proteins; Brain; Brain Diseases; Cell Culture Techniques; Cells; Complement; Coupling; D-arabitol; Data; Dendrites; Development; Disease; Engineering; Frequencies; Glial Fibrillary Acidic Protein; Glycogen; Glycogen Phosphorylase; Hippocampus (Brain); Injection of therapeutic agent; Intermediate Filament Proteins; Laboratories; Lactate Transporter; Lateral; Learning; Literature; Long-Term Potentiation; Maintenance; Measures; Mediating; Memory; Memory impairment; Metabolic; Molecular Target; Neurodegenerative Disorders; Neuroglia; Neurons; Norepinephrine; Pathway interactions; Peptide Elongation Factor 1; Phase; Play; Preparation; Process; Propranolol; Protein Biosynthesis; Proteins; Rattus; Reporting; Research Design; Resistance; Role; Small Interfering RNA; Specificity; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Time; Training; Western Blotting; Work; adrenergic; analog; base; behavior test; cognitive function; conditioned fear; emotional experience; experience; expression vector; glycogenolysis; in vivo; inhibitor/antagonist; knock-down; locus ceruleus structure; long term memory; noradrenergic; public health relevance; tool

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.

描述（由适用提供）：内存整合是在标签状态下存在的新学习的信息变成持久的内存，对破坏具有抵抗力2,3,4。长期记忆巩固需要从头蛋白质的合成，并且很可能树突状蛋白合成也参与了该过程5。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相关性8。像记忆巩固一样，LTP（L-LTP）的后期形式也需要蛋白质合成，并且已被证明需要特异性的树突状蛋白质合成以及体细胞蛋白质合成9。情感经历的记忆，例如基于恐惧条件的抑制性避免（IA）范式在各种恐怖中受到调节35。在唤醒期间，去甲肾上腺素是从凝固层中释放出来的，并通过 - 肾上腺素受体增强记忆41。关于LTP也是如此，这同样由去甲肾上腺素10,50调节。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和记忆和LTP中起着比以前想象的更大的作用。通过通过糖原分解并通过单羧酸盐转运蛋白转移神经元的乳酸，星形胶质细胞对于记忆巩固和LTP维持至关重要（请参阅初步数据）。有趣的是，星形胶质细胞存在 - 肾上腺素的接收器，当刺激15,16,37,37,38,39,40时，星形胶质细胞也具有代谢作用。该项目将测试星形胶质细胞对长期记忆和LTP的贡献。具体而言，它将检验以下假设，即星形胶质细胞通过通过鞋底提供星形胶质细胞 - 神经元偶联来促成记忆形成，从而支持与树突状蛋白质合成相关的高能量需求。此外，它将检验以下假设：在星形细胞 - 神经元偶联中介导去甲肾上腺素能的记忆调节。 公共卫生相关性：星形胶质细胞对脑部疾病的贡献是广泛的，但仍然非常不受欢迎，但是已经在几种神经退行性疾病中报道了星形胶质细胞和小胶质细胞激活，包括艾滋病痴呆症复合物，阿尔茨海默氏病和阿尔茨海默氏病和疗养营养性的侧面硬化症66。这种过渡可以通过功能性放松管制，甚至是星形胶质细胞的变性来实现，因此通常在这些细胞和神经元之间发生的串扰造成破坏。这是不正确的神经元相互作用可能与神经元的进化有关，并有助于疾病的发展，并阐明了认知功能中星形胶质细胞 - 神经元偶联的机制，包括学习和记忆，包括学习和记忆力，使我们能够更好地了解正常的脑功能，并识别出一些治疗性介入的潜在分子靶标。