This study extends the known roles

This study extends the known roles of glial cells to include aspecific computation (temporal integration of a behaviorallyrelevant mismatch signal), resulting in a direct, fast effect onbrain and behavioral state (induction of passivity within seconds).The traditional view of astrocytes as supporting cellsfor neurons is known to be incomplete (Araque et al., 2014;Kjaerby et al., 2017), as they actively influence neuronal activity.In the hippocampus, astrocytes can be intermediates betweencholinergic input and interneurons (Pabst et al., 2016). Glialcells in zebrafish are activated before and during generalizedseizures (Verdugo et al., 2019). These and other studies (Adamskyet al., 2018; Ding et al., 2013; Paukert et al., 2014; Poskanzerand Yuste, 2016; Srinivasan et al., 2015) point to anintegrated role for astrocytes in information processing in braincircuits.Our study establishes radial astrocytes as essential computationalelements in a circuit that mediates an adaptive behavioralresponse. The algorithm implemented by the radial astrocyteshere is surprisingly analogous to that observed in mouse hippocampal slices (Deemyad et al., 2018). There, astrocytesintegrate neural signals over many seconds and then suddenlyswitch into a mode where they drive strong inhibition. This ‘‘integrateand suppress’’ functional motif may therefore generalizeacross neural systems and species. Interestingly, a role for astrocytesin regulating active and passive states of circuits, albeit in amechanistically different form and on a longer timescale, wasconjectured a century ago (Ramon y Cajal, 1895).How do radial astrocytes drive activity in GABAergic edgecells? Astrocytes can influence synaptic transmission andneuronal firing in multiple ways (Bazargani and Attwell, 2016),but it is unclear which mechanisms are most relevant in vivo(Fiacco and McCarthy, 2018; Savtchouk and Volterra, 2018). InDrosophila, astrocytes inhibit downstream neurons likelythrough ATP secretion to influence chemotaxis and startlebehavior (Ma et al., 2016). Astrocytes can release GABA (Anguloet al., 2008; Lee et al., 2010; Christensen et al., 2018). They canalso influence neuronal firing by modulating extracellular ioniccomposition. On slow timescales, astrocytes affect neuronalfiring via changes in the density of inward-rectifying K+ membranechannels during depression in rodents (Cui et al., 2018).On faster timescales, glia-like support cells in the developing cochleatrigger neural activity in adjacent hair cells by modulatingextracellular K+ through a calcium-activated chloride channel(Wang et al., 2015). Our study shows that radial astrocytesmodulate neurons and influence behavior over seconds (likelytriggered by intracellular Ca2+ signaling, but possibly via othersecond messenger systems). The molecular mechanisms werenot identified, but may include active control of extracellularion concentrations near the GABAergic neurons. Radial astrocytesmay affect behavior through more pathways than onlythe GABAergic L-MO cells. Other routes may exist betweenthe glial cells and other neuron types, potentially including directsuppressive effects (Christensen et al., 2018; Wang et al., 2012)on premotor neurons.