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 - 尘科交流与长期联系起来 神经回路功能和行为的变化 星形胶质细胞通常被称为被动支持单元，实际上与大量的数量紧密相关 神经元突触并感知其活动，使其成为理想的蜂窝探测器和集成剂 突触传输。此外，星形胶质细胞重塑突触电路和功能通过指示突触 形成和可塑性。但是，星形胶质细胞是否以及如何发挥作用来调节 复杂的行为仍然未知。 在此协作项目中要检验的总体假设是星形胶质细胞是临时的 集成剂，该集成剂检测和整合局部突触活动和长期测试 传输。在这个主题项目（项目3）中，要测试的具体假设是信号 个体或星形胶质细胞的综合属性的集成特性使它们能够成为 在获取目标指导行为期间，经验驱动的合成活动。这些被夹住的星形胶质细胞 通过对星形胶质细胞染色质的表观遗传重塑来“参与”学习的行为，导致 星形细胞基因表达，结构和功能的长期变化（AIM1）。这种参与 允许星形胶质细胞通过两种方式重新连接局部突触电路。 1）通过更改数字 其域内的兴奋性和/或抑制性突触，因此调节局部兴奋/抑制作用 平衡，以及2）改变其突触关联和神经胶体的渗透，从而控制 神经递质的细胞外浓度。初步发现表明星形胶质细胞 介导的突触重塑不是学习的必要条件，而是为了适应 学习的行为。这些发现指出了这些提出的行为参与的特定作用 星形胶质细胞重新布线底层电路，为将来的活动准备这些电路， 学习的行为不再有效-e.g。实现预期结果的努力超出了 奖励的价值（AIM2）。这些行为参与的星形胶质细胞与它们的合奏形成 神经元的反部位，两者都可以立即通过早期基因表达来识别。在 行为的表现，这些星形胶质细胞 - 神经合奏被启发出来，以感知动作的变化/ 结果的偶然性使他们可以指示停止学习的行为（AIM3）。 这些假设将与其他团队合作，将以三个目标进行测试，并进行机械蓝图 对于醒着的行为小鼠大脑中的星形胶质细胞 - 神经元通信。所以， 这些提出的研究被毒死，以揭示星形胶质细胞如何响应，整合和调节 长期尺度的神经元连通性。此外，与其他团队一起，这些发现 将指导新的遗传编码指标和病毒工具的开发，以询问神经元 Glia电路在体内（项目2和4），并为神经元提供信息，测试和完善预测 星形胶质细胞信号传导机制是感觉运动处理（项目1）。