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

项目摘要：项目 3 - 将神经元-星形胶质细胞通讯与长期联系起来 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细胞，实际上与大量细胞密切相关。 神经元突触并感知它们的活动，使它们成为理想的细胞探测器和整合器 突触传递。此外，星形胶质细胞通过指示突触来重塑突触回路和功能 形成和可塑性。然而，星形胶质细胞是否以及如何在介导中发挥指导作用 复杂的行为仍然未知。 在这个合作项目中要测试的总体假设是星形胶质细胞充当时间 整合器，检测并整合局部突触活动和长投射神经调节 传输。在这个子项目（项目3）中，要测试的具体假设是信号 星形胶质细胞个体或合胞体的整合特性使它们能够被夹带 在获得目标导向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 通过星形细胞染色质的表观遗传重塑而“参与”习得的行为，从而导致 星形胶质细胞基因表达、结构和功能的长期变化（目标1）。这次订婚 允许星形胶质细胞以两种方式重新连接局部突触电路； 1）通过改变数量 其域内的兴奋性和/或抑制性突触，从而调节局部兴奋/抑制 平衡，2）通过改变突触关联和神经纤维浸润，从而控制 神经递质的细胞外浓度。初步研究结果表明星形胶质细胞 介导的突触重塑对于学习来说不是必需的，而是对于适应能力来说是必需的 习得的行为。这些发现指出了这些拟议的行为参与的具体作用 星形胶质细胞对底层电路进行重新布线，为这些电路为未来的可能发生的情况做好准备， 学到的行为不再有效 - 例如为达到预期结果而付出的努力超过了 奖励的价值（目标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，两者都可以通过立即早期基因表达来识别。期间 行为的表现，这些星形胶质细胞-神经元群已准备好感知行为/行为的变化 意外结果，以便他们可以指示停止习得的行为（目标 3）。 与其他团队合作，这些假设将在三个目标和机械蓝图上进行测试 在清醒行为的小鼠大脑中将产生星形胶质细胞-神经元通讯。因此， 这些拟议的研究旨在揭示星形胶质细胞如何响应、整合和调节 长时间尺度的神经元连接。此外，与其他团队一起，这些发现 将指导新型基因编码指标和病毒工具的开发来询问神经元 体内神经胶质细胞回路（项目 2 和 4）并为神经元提供信息、测试和完善预测 感觉运动处理背后的星形胶质细胞信号传导机制（项目 1）。

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).