Astrocytes actively support long-range molecular clock synchronization of segregated neuronal populations.
In mammals, the suprachiasmatic nucleus of the hypothalamus is the master circadian pacemaker that synchronizes the clocks in the central nervous system and periphery, thus orchestrating rhythms throughout the body. However, little is known about how so many cellular clocks within and across brain circuits can be effectively synchronized. In this work, we investigated the implication of two possible pathways: (i) astrocytes-mediated synchronization and (ii) neuronal paracrine factors-mediated synchronization. By taking advantage of a lab-on-a-chip microfluidic device developed in our laboratory, here we report that both pathways are involved. We found the paracrine factors-mediated synchronization of molecular clocks is diffusion-limited and, in our device, effective only in case of a short distance between neuronal populations. Interestingly, interconnecting astrocytes define an active signaling channel that can synchronize molecular clocks of neuronal populations also at longer distances. At mechanism level, we found that astrocytes-mediated synchronization involves both GABA and glutamate, while neuronal paracrine factors-mediated synchronization occurs through GABA signaling. These findings identify a previously unknown role of astrocytes as active cells that might distribute long-range signals to synchronize the brain clocks, thus further strengthening the importance of reciprocal interactions between glial and neuronal cells in the context of circadian circuitry.
Acknowledgements: The authors would like to thank Marina Nanni and IIT clean-room staff for their technical support in primary cultures preparations and microfabrication, respectively, and the IIT-Neurofacility technical staff for their excellent support. We also thank Alberto Perna for his helping with the Supporting Video, and the Animal Facility staff of IIT central research labs in Genoa for their assistance in animal experiments. This work was supported by intramural funds of Fondazione Istituto Italiano di Tecnologia (IIT) to D.D.P.T. and L.B.; O.B.M. was partly supported by the European Research Executive Agency (REA) through the FP7-PEOPLE-2014-IEF ‘ASTROCLOCK’ (629867); Fondazione CARIPLO research grant (2015-0590) and “Ramon y Cajal” contract (RYC2018-026293-I).