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  • Mid-Term Report Summary - ASTROMNESIS (The language of astrocytes: multilevel analysis to understand astrocyte communication and its role in memory-related brain operations and in cognitive behavior)

astromnesis Report Summary

Project ID: 340368
Funded under: FP7-IDEAS-ERC
Country: Switzerland

Mid-Term Report Summary - ASTROMNESIS (The language of astrocytes: multilevel analysis to understand astrocyte communication and its role in memory-related brain operations and in cognitive behavior)

The “astromnesis” project studies the role of astrocytes in learning and memory processes. Analysis is performed at four different and connected levels: sub-cellular, cellular, circuital, and behavioral. It is a relatively recent acquisition that astrocytes are capable of communication and interact with synapses and circuits underlying cognitive behavior. However, it is still unclear which role signal exchanges between neurons and astrocytes have in cognitive processes, as it is unclear exactly how neurons and astrocytes communicate. Our project aims at bringing light on these aspects via the development of new experimental technologies. In this direction, we have worked to better understand the structural-functional relations of neurons and astrocytes in brain tissue. To start, we have defined a number of astrocytic proteins that participate in the communication with neurons and studied their sub-cellular distribution using light microscopy, including STED super-resolution. Next, we have moved analysis to the ultrastructural level. Because the methods currently in use are not good for preserving the astrocyte ultrastructure, we have tested new ones with promising results, which let us hope to obtain soon the first reliable description of the organization of internal organelles and communication-related proteins in these cells. At the cellular level, we have succeeded in visualizing in 3D the interconnected activity (in terms of Ca2+ dynamics) of astrocytes and synapses. This is an important technical and scientific advance, overcoming all the previous studies that used 2D imaging. Indeed, 2D imaging reports activity from only 4% of the astrocyte volume, whereas our new 3D approach reports activity from the whole individual astrocyte. The findings are surprising, as the cell shows activity everywhere, mostly local and asynchronous, suggesting that astrocytes and synapses communicate mainly at local level. Interestingly, most previous studies interpreted the synaptic roles of astrocytes based on the spatio-temporal features of the large Ca2+ signals observed in the cell soma. However, our 3D approach suggests revision of such interpretations, as it shows that somatic events are very infrequent compared to the local activities observed in the cell peripheries, where high is the intermingling with synapses. Moreover, contrary to the dominating idea that astrocytes are activated only by intense neuronal firing, we show that they respond even to minimal neuronal activity, but in very tiny regions. We could track such regions thanks to our 3D approach and the use of algorithms capable of extracting the signals correlated in space and time to the axonal activity from the whole monitored volume. Another important development was the generation of several new lines of transgenic mice with modifications in specific components of the astrocyte signaling. These mice are precious tools in order to define the contribution of astrocyte signaling at integrated level, in particular in the circuits active during cognitive performance. To this end, we have set up a battery of behavioral tests that evaluate various aspects of learning and memory, and have already discovered that one of our lines, in which only astrocytes can transduce the action of the pro-inflammatory cytokine TNFalpha, displays a specific cognitive defect in a murine model of a human pathology. This proves that astrocyte signaling is critically involved in the functioning of cognitive circuits, at least during a pathological process. This study was published in the prestigious journal, Cell. It remains to be established if astrocyte signaling contributes to memory also under physiological conditions. This is the goal of the studies in the next phase of the project together with the attempt of linking circuital and behavioral information via the monitoring of astrocyte/neuronal activity in a cognitive area while animals perform a cognitive task involving that area.

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