Linking Neuron-Astrocyte Communication to Long-Term Changes in Neural Circuit Function and Behavior

将神经元-星形胶质细胞通讯与神经回路功能和行为的长期变化联系起来

• 批准号: 10693174
• 负责人: Cagla Eroglu
• 金额: $ 43.73万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693174
• 关键词: Affect; Astrocytes; Behavior; Behavioral; Brain; CRISPR/Cas technology; Cell Adhesion; Chemosensitization; Chromatin; Collaborations; Communication; Complement; Complex; Cues; Data; Development; ERG gene; Epigenetic Process; Equilibrium; Excitatory Synapse; Future; Gene Expression; Genetic; Giant Cells; Goals; Image; Immediate-Early Genes; Impairment; Individual; Infiltration; Inhibitory Synapse; Instinct; Learning; Link; Measures; Mediating; Memory; Modality; Molecular; Morphology; Mus; Neuroglia; Neurons; Neuropil; Neurotransmitters; Outcome; Pathway interactions; Performance; Play; Prefrontal Cortex; Property; Proteomics; Reporter Genes; Rewards; Role; Searching Behavior; Sensory; Signal Pathway; Signal Transduction; Structure; Supporting Cell; Synapses; Synaptic Transmission; Testing; Time; Training; Transgenic Mice; Viral; awake; behavior change; cholinergic; detector; epigenome; experience; extracellular; histone modification; in vivo; learned behavior; molecular modeling; multiphoton imaging; neural circuit; neuronal circuitry; neuroregulation; neurotransmission; noradrenergic; novel; synaptic function; synaptogenesis; tool; transmission process

Project Summary: Project 3- Linking Neuron-Astrocyte Communication to Long-Term Changes in Neural Circuit Function and Behavior Astrocytes, which are often dubbed as the passive support cells, in fact closely associate with a vast number of neuronal synapses and sense their activity, making them ideal cellular detectors and integrators of synaptic transmission. Moreover, astrocytes remodel synaptic circuitry and function by instructing synapse formation and plasticity. However, whether and how astrocytes play an instructive role to mediate complex behaviors remains unknown. The overarching hypothesis to be tested in this collaborative project is that astrocytes act as temporal integrators, which detect and integrate local synaptic activity and long-projecting neuromodulatory transmissions. In this subproject (Project 3), the specific hypothesis to be tested is that signal integration property of individual or syncytia of astrocytes allows them to become entrained by experience-driven synaptic activity during acquisition of goal-directed behaviors. These entrained astrocytes become “engaged” with the learned behavior by epigenetic remodeling of astrocytic chromatin, leading to long-term changes in astrocytic gene expression, structure and function (Aim1). This engagement allows the astrocytes to rewire the local synaptic circuitry in two ways; 1) by changing the numbers of excitatory and/or inhibitory synapses within their domains, thus modulate the local excitation/inhibition balance, and 2) by altering their synapse association and neuropil infiltration, thus controlling extracellular concentrations of neurotransmitters. Preliminary findings suggest that astrocyte- mediated synaptic remodeling is not necessary for learning, but rather for the adaptability of the learned behaviors. These findings point out a specific role for these proposed behaviorally-engaged astrocytes in rewiring of the underlying circuits to prepare these circuits for a future eventuality, in which the learned behavior is no longer effective -e.g. the effort to achieve the desired outcome exceeds the value of the reward (Aim2). These behaviorally-engaged astrocytes form ensembles with their neuronal counter parts, both of which can be identified by immediate early gene expression. During the performance of behaviors, these astrocyte-neuron ensembles are primed to sense the changes in action/ outcome contingency so that they can instruct to stop the learned behaviors (Aim3). Working in concert with other teams, these hypotheses will be tested in three aims, and a mechanistic blueprint for astrocyte-neuron communication in the awake behaving mouse brain will be generated. Therefore, these proposed studies are poised to reveal how astrocytes respond to, integrate, and modulate neuronal connectivity in long-time scales. Furthermore, in conjunction with other teams, these findings will guide the development of novel genetically encoded indicators and viral tools to interrogate neuron- glia circuits in vivo (Projects 2 and 4) and inform, test, and refine predictions for neuron- astrocyte signaling mechanisms underlying sensorimotor processing (Project 1).

项目摘要：项目3-将神经元-星形胶质细胞的沟通联系到长期 神经回路功能和行为的改变 星形胶质细胞，通常被称为被动支持细胞，实际上与大量的 神经突触和感觉它们的活动，使它们成为理想的细胞检测器和集成器 突触传递。此外，星形胶质细胞通过指示突触来重塑突触电路和功能 形成和可塑性。然而，星形胶质细胞是否以及如何发挥指导作用来调节 复杂的行为仍然未知。 在这个合作项目中要测试的最重要的假设是星形胶质细胞作为时间 检测和整合局部突触活动和长投射神经调制的积分器 变速箱。在这个子项目(项目3)中，要检验的具体假设是该信号 星形胶质细胞个体或合胞体的整合特性使它们能够被 目标导向行为习得过程中经验驱动的突触活动。这些携带的星形胶质细胞 通过星形细胞染色质的表观遗传重塑而与习得的行为“接触”，导致 星形胶质细胞基因表达、结构和功能的长期变化(Aim1)。这份合约 允许星形胶质细胞以两种方式重新连接局部突触电路；1)通过改变 在其区域内的兴奋性和/或抑制性突触，从而调节局部的兴奋/抑制 平衡，以及2)通过改变它们的突触联系和神经纤维的渗透，从而控制 神经递质的胞外浓度。初步研究表明，星形胶质细胞- 介导性突触重塑不是学习所必需的，而是学习所必需的 习得的行为。这些发现指出了这些被提议的行为参与的特定作用 星形胶质细胞在基础电路的重新布线中，为未来的可能情况做好准备，在 习得的行为不再有效--例如实现预期结果的努力超过了 奖励的价值(AIM2)。这些行为参与的星形胶质细胞与它们的 神经元的对应物，两者都可以通过即刻早期基因表达来识别。在.期间 行为的表现，这些星形胶质细胞-神经元群体被准备好感知行为的变化/ 结果偶然性，以便他们可以指示停止习得的行为(Aim3)。 与其他团队合作，这些假设将在三个目标和一个机械蓝图中得到验证 对于清醒行为的小鼠大脑中的星形胶质细胞和神经元的交流将会产生。因此， 这些拟议的研究将揭示星形胶质细胞如何响应、整合和调节 长时间尺度上的神经元连接。此外，与其他团队合作，这些发现 将指导开发新的遗传编码指示器和病毒工具来审问神经元- 活体中的神经胶质细胞电路(项目2和4)，并提供信息，测试和完善神经元预测- 星形胶质细胞感觉运动处理的信号机制(项目1)。