BackgroundMicroglia—the resident immune cells of the brain—are activated after brain lesions, e.g., cerebral ischemia, and polarize towards a classic “M1” pro-inflammatory or an alternative “M2” anti-inflammatory phenotype following characteristic temporo-spatial patterns, contributing either to secondary tissue damage or to regenerative responses. They closely interact with endogenous neural stem cells (NSCs) residing in distinct niches of the adult brain. The current study aimed at elucidating the dynamics of microglia polarization and their differential effects on NSC function.ResultsPrimary rat microglia in vitro were polarized towards a M1 phenotype by LPS, or to a M2 phenotype by IL4, while simultaneous exposure to LPS plus IL4 resulted in a hybrid phenotype expressing both M1- and M2-characteristic markers. M2 microglia migrated less but exhibit higher phagocytic activity than M1 microglia. Defined mediators switched microglia from one polarization state to the other, a process more effective when transforming M2 microglia towards M1 than vice versa. Polarized microglia had differential effects on the differentiation potential of NSCs in vitro and in vivo, with M1 microglia promoting astrocytogenesis, while M2 microglia supported neurogenesis. Regardless of their polarization, microglia inhibited NSC proliferation, increased NSC migration, and accelerated NSC differentiation.ConclusionOverall, this study shed light on the complex conditions governing microglia polarization and the effects of differentially polarized microglia on critical functions of NSCs in vitro and in vivo. Refining the understanding of microglia activation and their modulatory effects on NSCs is likely to facilitate the development of innovative therapeutic concepts supporting the innate regenerative capacity of the brain.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1261-y) contains supplementary material, which is available to authorized users.

Humans can estimate the duration of intervals of time, and psychophysical experiments show that these estimations are subject to timing errors. According to standard theories of timing, these errors increase linearly with the interval to be estimated (Weber's law), and both at longer and shorter intervals, deviations from linearity are reported. This is not easily reconciled with the accumulation of neuronal noise, which would only lead to an increase with the square root of the interval. Here, we offer a neuronal model which explains the form of the error function as a result of a constrained optimization process. The model consists of a number of synfire chains with different transmission times, which project onto a set of readout neurons. We show that an increase in the transmission time corresponds to a superlinear increase of the timing errors. Under the assumption of a fixed chain length, the experimentally observed error function emerges from optimal selection of chains for each given interval. Furthermore, we show how this optimal selection could be implemented by competitive spike-timing dependent plasticity in the connections from the chains to the readout network, and discuss implications of our model on selective temporal learning and possible neural architectures of interval timing.

Responses to targets that appear at a noncued position within the same object (invalid-same) compared to a noncued position at an equidistant different object (invalid-different) tend to be faster and more accurate. These cueing effects have been taken as evidence that visual attention can be object based (Egly, Driver, & Rafal, Journal of Experimental Psychology: General, 123, 161-177, 1994). Recent findings, however, have shown that the object-based cueing effect is influenced by object orientation, suggesting that the cueing effect might be due to a more general facilitation of attentional shifts across the horizontal meridian (Al-Janabi & Greenberg, Attention, Perception, & Psychophysics, 1-17, 2016; Pilz, Roggeveen, Creighton, Bennet, & Sekuler, PLOS ONE, 7, e30693, 2012). The aim of this study was to investigate whether the object-based cueing effect is influenced by object similarity and orientation. According to the object-based attention account, objects that are less similar to each other should elicit stronger object-based cueing effects independent of object orientation, whereas the horizontal meridian theory would not predict any effect of object similarity. We manipulated object similarity by using a color (Exp. 1, Exp. 2A) or shape change (Exp. 2B) to distinguish two rectangles in a variation of the classic two-rectangle paradigm (Egly et al., 1994). We found that the object-based cueing effects were influenced by the orientation of the rectangles and strengthened by object dissimilarity. We suggest that object-based cueing effects are strongly affected by the facilitation of attention along the horizontal meridian, but that they also have an object-based attentional component, which is revealed when the dissimilarity between the presented objects is accentuated.