Astrocytes are not merely passive members of the circuit, but that they may also be directly involved with neuronal computation. Indeed, astrocytes are well suited to a potential widespread role in the circuit: they tile the CNS with near- complet coverage, are connected into an extensive syncytium via gap junctions, and processes from a single astrocyte can contact up to tens of thousands of synapses. In fact, we have recently shown how even the stimulation of single astrocyte can control circuit-wide neuronal synchronizations in the cortex. Tools to study astrocytes are significantly less developed than those available to investigate neuronal function and, consequently, most research on astrocytic information processing has been limited and incomplete. Astrocyte researchers need methods to selectively measure and manipulate the function of astrocytes in vivo. Two-photon excitation, which penetrates living tissue while affording single-cell resolution, combined with compatible optochemical or optogenetic probes, could be an ideal technical platform for future astrocyte research. We propose to develop novel two-photon and computational tools to provide subcellular and circuit-level analysis of astrocytic function in neural circuits in vivo, using a nvel astrocyte-specific Brainbow mouse line. These tools include two- photon optogenetic and caged compounds, methods to image groups of astrocytes in 3D, and computational algorithms to reveal interactions of astrocytes with neurons in the circuit. With this award, we will provide the astroglia community with a wide range of optical and computational tools that can be readily adapted for use in vivo. This work will enable the investigation of the roles of astrocytes in shaping neuronal activity in the cortical microcircuit and beyond, and thus could have a fundamental impact on how we view neuro-glia processing, as well as on solidifying the role of an overlooked circuit constituent-the astrocyte-in cortical synchrony and computation. Finally, this work could introduce a novel potential means to assay or control neuronal function for potential therapeutic purposes: through specific activation of astrocytes.
Two-photon optical control of astrocytic function Astrocytes are glial cells whose role in the function of neural circuits has likely been underestimated, partl due to the lack of techniques to selectively study and manipulate them in living tissue. Two-photon microscopy offers an optical method to both image and optically manipulate the activity of astrocytes in the brain in vivo. We propose to develop a set of genetic, optochemical, optogenetic, hardware and computational tools to enable a full-fledged investigation of the functional roles of astrocytes in awake animals, and to be used as potential assays or therapeutic approaches for mental diseases where astrocytes impact their pathophysiology.
| Liou, Jyun-You; Ma, Hongtao; Wenzel, Michael et al. (2018) Role of inhibitory control in modulating focal seizure spread. Brain 141:2083-2097 |
| Yang, Weijian; Carrillo-Reid, Luis; Bando, Yuki et al. (2018) Simultaneous two-photon imaging and two-photon optogenetics of cortical circuits in three dimensions. Elife 7: |
| Agetsuma, Masakazu; Hamm, Jordan P; Tao, Kentaro et al. (2018) Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex. Cereb Cortex 28:1831-1845 |
| Cartailler, Jerome; Kwon, Taekyung; Yuste, Rafael et al. (2018) Deconvolution of Voltage Sensor Time Series and Electro-diffusion Modeling Reveal the Role of Spine Geometry in Controlling Synaptic Strength. Neuron 97:1126-1136.e10 |
| Izquierdo-Serra, Mercè; Hirtz, Jan J; Shababo, Ben et al. (2018) Two-Photon Optogenetic Mapping of Excitatory Synaptic Connectivity and Strength. iScience 8:15-28 |
| Yang, Weijian; Yuste, Rafael (2018) Holographic imaging and photostimulation of neural activity. Curr Opin Neurobiol 50:211-221 |
| Migliori, Bianca; Datta, Malika S; Dupre, Christophe et al. (2018) Light sheet theta microscopy for rapid high-resolution imaging of large biological samples. BMC Biol 16:57 |
| Wei, Lu; Chen, Zhixing; Shi, Lixue et al. (2017) Super-multiplex vibrational imaging. Nature 544:465-470 |
| Hamm, Jordan P; Peterka, Darcy S; Gogos, Joseph A et al. (2017) Altered Cortical Ensembles in Mouse Models of Schizophrenia. Neuron 94:153-167.e8 |
| Carrillo-Reid, Luis; Yang, Weijian; Kang Miller, Jae-Eun et al. (2017) Imaging and Optically Manipulating Neuronal Ensembles. Annu Rev Biophys 46:271-293 |
Showing the most recent 10 out of 33 publications
