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

点击翻译按钮获取中文摘要

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).