@article{11478, abstract = {Cerebral organoids differentiated from human-induced pluripotent stem cells (hiPSC) provide a unique opportunity to investigate brain development. However, organoids usually lack microglia, brain-resident immune cells, which are present in the early embryonic brain and participate in neuronal circuit development. Here, we find IBA1+ microglia-like cells alongside retinal cups between week 3 and 4 in 2.5D culture with an unguided retinal organoid differentiation protocol. Microglia do not infiltrate the neuroectoderm and instead enrich within non-pigmented, 3D-cystic compartments that develop in parallel to the 3D-retinal organoids. When we guide the retinal organoid differentiation with low-dosed BMP4, we prevent cup development and enhance microglia and 3D-cysts formation. Mass spectrometry identifies these 3D-cysts to express mesenchymal and epithelial markers. We confirmed this microglia-preferred environment also within the unguided protocol, providing insight into microglial behavior and migration and offer a model to study how they enter and distribute within the human brain.}, author = {Bartalska, Katarina and Hübschmann, Verena and Korkut, Medina and Cubero, Ryan J and Venturino, Alessandro and Rössler, Karl and Czech, Thomas and Siegert, Sandra}, issn = {2589-0042}, journal = {iScience}, number = {7}, publisher = {Elsevier}, title = {{A systematic characterization of microglia-like cell occurrence during retinal organoid differentiation}}, doi = {10.1016/j.isci.2022.104580}, volume = {25}, year = {2022}, } @article{12244, abstract = {Environmental cues influence the highly dynamic morphology of microglia. Strategies to characterize these changes usually involve user-selected morphometric features, which preclude the identification of a spectrum of context-dependent morphological phenotypes. Here we develop MorphOMICs, a topological data analysis approach, which enables semiautomatic mapping of microglial morphology into an atlas of cue-dependent phenotypes and overcomes feature-selection biases and biological variability. We extract spatially heterogeneous and sexually dimorphic morphological phenotypes for seven adult mouse brain regions. This sex-specific phenotype declines with maturation but increases over the disease trajectories in two neurodegeneration mouse models, with females showing a faster morphological shift in affected brain regions. Remarkably, microglia morphologies reflect an adaptation upon repeated exposure to ketamine anesthesia and do not recover to control morphologies. Finally, we demonstrate that both long primary processes and short terminal processes provide distinct insights to morphological phenotypes. MorphOMICs opens a new perspective to characterize microglial morphology.}, author = {Colombo, Gloria and Cubero, Ryan J and Kanari, Lida and Venturino, Alessandro and Schulz, Rouven and Scolamiero, Martina and Agerberg, Jens and Mathys, Hansruedi and Tsai, Li-Huei and Chachólski, Wojciech and Hess, Kathryn and Siegert, Sandra}, issn = {1546-1726}, journal = {Nature Neuroscience}, keywords = {General Neuroscience}, number = {10}, pages = {1379--1393}, publisher = {Springer Nature}, title = {{A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes}}, doi = {10.1038/s41593-022-01167-6}, volume = {25}, year = {2022}, } @article{9642, abstract = {Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.}, author = {Venturino, Alessandro and Schulz, Rouven and De Jesús-Cortés, Héctor and Maes, Margaret E and Nagy, Balint and Reilly-Andújar, Francis and Colombo, Gloria and Cubero, Ryan J and Schoot Uiterkamp, Florianne E and Bear, Mark F. and Siegert, Sandra}, issn = {22111247}, journal = {Cell Reports}, number = {1}, publisher = {Elsevier}, title = {{Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain}}, doi = {10.1016/j.celrep.2021.109313}, volume = {36}, year = {2021}, } @article{9874, abstract = {Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.}, author = {Raso, Andrea and Dirkx, Ellen and Sampaio-Pinto, Vasco and el Azzouzi, Hamid and Cubero, Ryan J and Sorensen, Daniel W. and Ottaviani, Lara and Olieslagers, Servé and Huibers, Manon M. and de Weger, Roel and Siddiqi, Sailay and Moimas, Silvia and Torrini, Consuelo and Zentillin, Lorena and Braga, Luca and Nascimento, Diana S. and da Costa Martins, Paula A. and van Berlo, Jop H. and Zacchigna, Serena and Giacca, Mauro and De Windt, Leon J.}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration}}, doi = {10.1038/s41467-021-25211-4}, volume = {12}, year = {2021}, } @article{7369, abstract = {Neuronal responses to complex stimuli and tasks can encompass a wide range of time scales. Understanding these responses requires measures that characterize how the information on these response patterns are represented across multiple temporal resolutions. In this paper we propose a metric – which we call multiscale relevance (MSR) – to capture the dynamical variability of the activity of single neurons across different time scales. The MSR is a non-parametric, fully featureless indicator in that it uses only the time stamps of the firing activity without resorting to any a priori covariate or invoking any specific structure in the tuning curve for neural activity. When applied to neural data from the mEC and from the ADn and PoS regions of freely-behaving rodents, we found that neurons having low MSR tend to have low mutual information and low firing sparsity across the correlates that are believed to be encoded by the region of the brain where the recordings were made. In addition, neurons with high MSR contain significant information on spatial navigation and allow to decode spatial position or head direction as efficiently as those neurons whose firing activity has high mutual information with the covariate to be decoded and significantly better than the set of neurons with high local variations in their interspike intervals. Given these results, we propose that the MSR can be used as a measure to rank and select neurons for their information content without the need to appeal to any a priori covariate.}, author = {Cubero, Ryan J and Marsili, Matteo and Roudi, Yasser}, issn = {1573-6873}, journal = {Journal of Computational Neuroscience}, keywords = {Time series analysis, Multiple time scale analysis, Spike train data, Information theory, Bayesian decoding}, pages = {85--102}, publisher = {Springer Nature}, title = {{Multiscale relevance and informative encoding in neuronal spike trains}}, doi = {10.1007/s10827-020-00740-x}, volume = {48}, year = {2020}, } @article{7632, abstract = {The posterior parietal cortex (PPC) and frontal motor areas comprise a cortical network supporting goal-directed behaviour, with functions including sensorimotor transformations and decision making. In primates, this network links performed and observed actions via mirror neurons, which fire both when individuals perform an action and when they observe the same action performed by a conspecific. Mirror neurons are believed to be important for social learning, but it is not known whether mirror-like neurons occur in similar networks in other social species, such as rodents, or if they can be measured in such models using paradigms where observers passively view a demonstrator. Therefore, we imaged Ca2+ responses in PPC and secondary motor cortex (M2) while mice performed and observed pellet-reaching and wheel-running tasks, and found that cell populations in both areas robustly encoded several naturalistic behaviours. However, neural responses to the same set of observed actions were absent, although we verified that observer mice were attentive to performers and that PPC neurons responded reliably to visual cues. Statistical modelling also indicated that executed actions outperformed observed actions in predicting neural responses. These results raise the possibility that sensorimotor action recognition in rodents could take place outside of the parieto-frontal circuit, and underscore that detecting socially-driven neural coding depends critically on the species and behavioural paradigm used.}, author = {Tombaz, Tuce and Dunn, Benjamin A. and Hovde, Karoline and Cubero, Ryan J and Mimica, Bartul and Mamidanna, Pranav and Roudi, Yasser and Whitlock, Jonathan R.}, issn = {20452322}, journal = {Scientific reports}, number = {1}, publisher = {Springer Nature}, title = {{Action representation in the mouse parieto-frontal network}}, doi = {10.1038/s41598-020-62089-6}, volume = {10}, year = {2020}, } @article{7128, abstract = {Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.}, author = {Torrini, Consuelo and Cubero, Ryan J and Dirkx, Ellen and Braga, Luca and Ali, Hashim and Prosdocimo, Giulia and Gutierrez, Maria Ines and Collesi, Chiara and Licastro, Danilo and Zentilin, Lorena and Mano, Miguel and Zacchigna, Serena and Vendruscolo, Michele and Marsili, Matteo and Samal, Areejit and Giacca, Mauro}, issn = {2211-1247}, journal = {Cell Reports}, keywords = {cardiomyocyte, cell cycle, Cofilin2, cytoskeleton, Hippo, microRNA, regeneration, YAP}, number = {9}, pages = {2759--2771.e5}, publisher = {Elsevier}, title = {{Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation}}, doi = {10.1016/j.celrep.2019.05.005}, volume = {27}, year = {2019}, } @article{7130, abstract = {We show that statistical criticality, i.e. the occurrence of power law frequency distributions, arises in samples that are maximally informative about the underlying generating process. In order to reach this conclusion, we first identify the frequency with which different outcomes occur in a sample, as the variable carrying useful information on the generative process. The entropy of the frequency, that we call relevance, provides an upper bound to the number of informative bits. This differs from the entropy of the data, that we take as a measure of resolution. Samples that maximise relevance at a given resolution—that we call maximally informative samples—exhibit statistical criticality. In particular, Zipf's law arises at the optimal trade-off between resolution (i.e. compression) and relevance. As a byproduct, we derive a bound of the maximal number of parameters that can be estimated from a dataset, in the absence of prior knowledge on the generative model. Furthermore, we relate criticality to the statistical properties of the representation of the data generating process. We show that, as a consequence of the concentration property of the asymptotic equipartition property, representations that are maximally informative about the data generating process are characterised by an exponential distribution of energy levels. This arises from a principle of minimal entropy, that is conjugate of the maximum entropy principle in statistical mechanics. This explains why statistical criticality requires no parameter fine tuning in maximally informative samples.}, author = {Cubero, Ryan J and Jo, Junghyo and Marsili, Matteo and Roudi, Yasser and Song, Juyong}, issn = {1742-5468}, journal = {Journal of Statistical Mechanics: Theory and Experiment}, keywords = {optimization under uncertainty, source coding, large deviation}, number = {6}, publisher = {IOP Publishing}, title = {{Statistical criticality arises in most informative representations}}, doi = {10.1088/1742-5468/ab16c8}, volume = {2019}, year = {2019}, } @article{7126, abstract = {In the Minimum Description Length (MDL) principle, learning from the data is equivalent to an optimal coding problem. We show that the codes that achieve optimal compression in MDL are critical in a very precise sense. First, when they are taken as generative models of samples, they generate samples with broad empirical distributions and with a high value of the relevance, defined as the entropy of the empirical frequencies. These results are derived for different statistical models (Dirichlet model, independent and pairwise dependent spin models, and restricted Boltzmann machines). Second, MDL codes sit precisely at a second order phase transition point where the symmetry between the sampled outcomes is spontaneously broken. The order parameter controlling the phase transition is the coding cost of the samples. The phase transition is a manifestation of the optimality of MDL codes, and it arises because codes that achieve a higher compression do not exist. These results suggest a clear interpretation of the widespread occurrence of statistical criticality as a characterization of samples which are maximally informative on the underlying generative process.}, author = {Cubero, Ryan J and Marsili, Matteo and Roudi, Yasser}, issn = {1099-4300}, journal = {Entropy}, keywords = {Minimum Description Length, normalized maximum likelihood, statistical criticality, phase transitions, large deviations}, number = {10}, publisher = {MDPI}, title = {{Minimum description length codes are critical}}, doi = {10.3390/e20100755}, volume = {20}, year = {2018}, }