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: 10294805
• 负责人: Cagla Eroglu
• 金额: $ 43.4万
• 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/10294805
• 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; Instruction; Learning; Link; Measures; Mediating; Memory; Modality; Molecular; Morphology; Mus; Neuroglia; Neurons; Neuropil; Neurotransmitters; New Acceptors; Outcome; Pathway interactions; Performance; Play; Prefrontal Cortex; Property; Proteomics; Reporter Genes; Rewards; Role; Sensory; Signal Pathway; Signal Transduction; Structure; Sum; Supporting Cell; Synapses; Synaptic Transmission; Testing; Time; Training; Transgenic Mice; Viral; awake; base; behavior change; cholinergic; detector; epigenome; experience; extracellular; histone modification; in vivo; learned behavior; molecular modeling; multiphoton imaging; neural circuit; neuronal circuitry; neuroregulation; 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).

项目概要：项目3-将神经元-星形胶质细胞通信与长期 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细胞，实际上与大量细胞密切相关 神经元突触和感觉他们的活动，使他们成为理想的细胞探测器和集成商， 突触传递此外，星形胶质细胞重塑突触回路，并通过指示突触 形成和可塑性。然而，星形胶质细胞是否以及如何在介导 复杂的行为仍然未知。 在这个合作项目中要测试的首要假设是，星形胶质细胞作为时间 整合子，其检测并整合局部突触活动和长投射神经调节 传动.在这个子项目（项目3）中，要检验的具体假设是， 星形胶质细胞个体或合胞体的整合特性允许它们被 在获得目标导向的行为过程中经验驱动的突触活动。这些夹带的星形胶质细胞 通过星形胶质细胞染色质的表观遗传重塑与学习行为“接合”，导致 星形胶质细胞基因表达、结构和功能的长期变化（Aim 1）。这种接合 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 兴奋性和/或抑制性突触，从而调节局部兴奋/抑制 平衡，和2）通过改变它们的突触关联和神经元浸润，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所必需的，而是为了适应性。 学习行为。这些发现指出了这些拟议的行为参与的具体作用， 星形胶质细胞在重新布线的基础电路，以准备这些电路为未来的可能性， 学习的行为不再有效-例如，实现预期结果的努力超过了 奖励的价值（Aim 2）。这些行为参与的星形胶质细胞与它们的 神经元对应部分，这两者都可以通过立即早期基因表达来鉴定。期间 行为的表现，这些星形胶质细胞-神经元集合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学习的行为（目标3）。 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进行测试。 用于清醒行为小鼠大脑中星形胶质细胞-神经元通信的信号将被产生。因此，我们认为， 这些拟议的研究准备揭示星形胶质细胞如何响应，整合和调节 神经元的连接性。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， 神经胶质细胞回路在体内（项目2和4）和通知，测试，并完善预测神经元- 星形胶质细胞信号转导机制的感觉运动处理（项目1）。