@article{7033, abstract = {Removal of the Bax gene from mice completely protects the somas of retinal ganglion cells (RGCs) from apoptosis following optic nerve injury. This makes BAX a promising therapeutic target to prevent neurodegeneration. In this study, Bax+/− mice were used to test the hypothesis that lowering the quantity of BAX in RGCs would delay apoptosis following optic nerve injury. RGCs were damaged by performing optic nerve crush (ONC) and then immunostaining for phospho-cJUN, and quantitative PCR were used to monitor the status of the BAX activation mechanism in the months following injury. The apoptotic susceptibility of injured cells was directly tested by virally introducing GFP-BAX into Bax−/− RGCs after injury. The competency of quiescent RGCs to reactivate their BAX activation mechanism was tested by intravitreal injection of the JNK pathway agonist, anisomycin. Twenty-four weeks after ONC, Bax+/− mice had significantly less cell loss in their RGC layer than Bax+/+ mice 3 weeks after ONC. Bax+/− and Bax+/+ RGCs exhibited similar patterns of nuclear phospho-cJUN accumulation immediately after ONC, which persisted in Bax+/− RGCs for up to 7 weeks before abating. The transcriptional activation of BAX-activating genes was similar in Bax+/− and Bax+/+ RGCs following ONC. Intriguingly, cells deactivated their BAX activation mechanism between 7 and 12 weeks after crush. Introduction of GFP-BAX into Bax−/− cells at 4 weeks after ONC showed that these cells had a nearly normal capacity to activate this protein, but this capacity was lost 8 weeks after crush. Collectively, these data suggest that 8–12 weeks after crush, damaged cells no longer displayed increased susceptibility to BAX activation relative to their naïve counterparts. In this same timeframe, retinal glial activation and the signaling of the pro-apoptotic JNK pathway also abated. Quiescent RGCs did not show a timely reactivation of their JNK pathway following intravitreal injection with anisomycin. These findings demonstrate that lowering the quantity of BAX in RGCs is neuroprotective after acute injury. Damaged RGCs enter a quiescent state months after injury and are no longer responsive to an apoptotic stimulus. Quiescent RGCs will require rejuvenation to reacquire functionality.}, author = {Donahue, RJ and Maes, Margaret E and Grosser, JA and Nickells, RW}, issn = {1559-1182}, journal = {Molecular Neurobiology}, number = {2}, pages = {1070–1084}, publisher = {Springer Nature}, title = {{BAX-depleted retinal ganglion cells survive and become quiescent following optic nerve damage}}, doi = {10.1007/s12035-019-01783-7}, volume = {57}, year = {2020}, } @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{7095, abstract = {BAX, a member of the BCL2 gene family, controls the committed step of the intrinsic apoptotic program. Mitochondrial fragmentation is a commonly observed feature of apoptosis, which occurs through the process of mitochondrial fission. BAX has consistently been associated with mitochondrial fission, yet how BAX participates in the process of mitochondrial fragmentation during apoptosis remains to be tested. Time-lapse imaging of BAX recruitment and mitochondrial fragmentation demonstrates that rapid mitochondrial fragmentation during apoptosis occurs after the complete recruitment of BAX to the mitochondrial outer membrane (MOM). The requirement of a fully functioning BAX protein for the fission process was demonstrated further in BAX/BAK-deficient HCT116 cells expressing a P168A mutant of BAX. The mutant performed fusion to restore the mitochondrial network. but was not demonstrably recruited to the MOM after apoptosis induction. Under these conditions, mitochondrial fragmentation was blocked. Additionally, we show that loss of the fission protein, dynamin-like protein 1 (DRP1), does not temporally affect the initiation time or rate of BAX recruitment, but does reduce the final level of BAX recruited to the MOM during the late phase of BAX recruitment. These correlative observations suggest a model where late-stage BAX oligomers play a functional part of the mitochondrial fragmentation machinery in apoptotic cells.}, author = {Maes, Margaret E and Grosser, J. A. and Fehrman, R. L. and Schlamp, C. L. and Nickells, R. W.}, issn = {2045-2322}, journal = {Scientific Reports}, publisher = {Springer Nature}, title = {{Completion of BAX recruitment correlates with mitochondrial fission during apoptosis}}, doi = {10.1038/s41598-019-53049-w}, volume = {9}, year = {2019}, } @article{6412, abstract = {Polycomb group (PcG) proteins play critical roles in the epigenetic inheritance of cell fate. The Polycomb Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to enforce gene silencing, but how transcriptional repression is propagated through mitotic cell divisions remains a key unresolved question. Using reversible tethering of PcG proteins to ectopic sites in mouse embryonic stem cells, here we show that PRC1 can trigger transcriptional repression and Polycomb-dependent chromatin modifications. We find that canonical PRC1 (cPRC1), but not variant PRC1, maintains gene silencing through cell division upon reversal of tethering. Propagation of gene repression is sustained by cis-acting histone modifications, PRC2-mediated H3K27me3 and cPRC1-mediated H2AK119ub1, promoting a sequence-independent feedback mechanism for PcG protein recruitment. Thus, the distinct PRC1 complexes present in vertebrates can differentially regulate epigenetic maintenance of gene silencing, potentially enabling dynamic heritable responses to complex stimuli. Our findings reveal how PcG repression is potentially inherited in vertebrates.}, author = {Moussa, Hagar F. and Bsteh, Daniel and Yelagandula, Ramesh and Pribitzer, Carina and Stecher, Karin and Bartalska, Katarina and Michetti, Luca and Wang, Jingkui and Zepeda-Martinez, Jorge A. and Elling, Ulrich and Stuckey, Jacob I. and James, Lindsey I. and Frye, Stephen V. and Bell, Oliver}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Springer Nature}, title = {{Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing}}, doi = {10.1038/s41467-019-09628-6}, volume = {10}, year = {2019}, } @article{6521, abstract = {Microglia have emerged as a critical component of neurodegenerative diseases. Genetic manipulation of microglia can elucidate their functional impact in disease. In neuroscience, recombinant viruses such as lentiviruses and adeno-associated viruses (AAVs) have been successfully used to target various cell types in the brain, although effective transduction of microglia is rare. In this review, we provide a short background of lentiviruses and AAVs, and strategies for designing recombinant viral vectors. Then, we will summarize recent literature on successful microglial transductions in vitro and in vivo, and discuss the current challenges. Finally, we provide guidelines for reporting the efficiency and specificity of viral targeting in microglia, which will enable the microglial research community to assess and improve methodologies for future studies.}, author = {Maes, Margaret E and Colombo, Gloria and Schulz, Rouven and Siegert, Sandra}, issn = {0304-3940}, journal = {Neuroscience Letters}, publisher = {Elsevier}, title = {{Targeting microglia with lentivirus and AAV: Recent advances and remaining challenges}}, doi = {10.1016/j.neulet.2019.134310}, volume = {707}, year = {2019}, } @article{32, abstract = {The functional role of AMPA receptor (AMPAR)-mediated synaptic signaling between neurons and oligodendrocyte precursor cells (OPCs) remains enigmatic. We modified the properties of AMPARs at axon-OPC synapses in the mouse corpus callosum in vivo during the peak of myelination by targeting the GluA2 subunit. Expression of the unedited (Ca2+ permeable) or the pore-dead GluA2 subunit of AMPARs triggered proliferation of OPCs and reduced their differentiation into oligodendrocytes. Expression of the cytoplasmic C-terminal (GluA2(813-862)) of the GluA2 subunit (C-tail), a modification designed to affect the interaction between GluA2 and AMPAR-binding proteins and to perturb trafficking of GluA2-containing AMPARs, decreased the differentiation of OPCs without affecting their proliferation. These findings suggest that ionotropic and non-ionotropic properties of AMPARs in OPCs, as well as specific aspects of AMPAR-mediated signaling at axon-OPC synapses in the mouse corpus callosum, are important for balancing the response of OPCs to proliferation and differentiation cues. In the brain, oligodendrocyte precursor cells (OPCs) receive glutamatergic AMPA-receptor-mediated synaptic input from neurons. Chen et al. show that modifying AMPA-receptor properties at axon-OPC synapses alters proliferation and differentiation of OPCs. This expands the traditional view of synaptic transmission by suggesting neurons also use synapses to modulate behavior of glia.}, author = {Chen, Ting and Kula, Bartosz and Nagy, Balint and Barzan, Ruxandra and Gall, Andrea and Ehrlich, Ingrid and Kukley, Maria}, journal = {Cell Reports}, number = {4}, pages = {852 -- 861.e7}, publisher = {Elsevier}, title = {{In Vivo regulation of Oligodendrocyte processor cell proliferation and differentiation by the AMPA-receptor Subunit GluA2}}, doi = {10.1016/j.celrep.2018.09.066}, volume = {25}, year = {2018}, } @article{708, abstract = {In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells.}, author = {Nagy, Balint and Hovhannisyan, Anahit and Barzan, Ruxandra and Chen, Ting and Kukley, Maria}, issn = {15449173}, journal = {PLoS Biology}, number = {8}, publisher = {Public Library of Science}, title = {{Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum}}, doi = {10.1371/journal.pbio.2001993}, volume = {15}, year = {2017}, } @article{557, abstract = {PURPOSE. Gene therapy of retinal ganglion cells (RGCs) has promise as a powerful therapeutic for the rescue and regeneration of these cells after optic nerve damage. However, early after damage, RGCs undergo atrophic changes, including gene silencing. It is not known if these changes will deleteriously affect transduction and transgene expression, or if the therapeutic protein can influence reactivation of the endogenous genome. METHODS. Double-transgenic mice carrying a Rosa26-(LoxP)-tdTomato reporter, and a mutant allele for the proapoptotic Bax gene were reared. The Bax mutant blocks apoptosis, but RGCs still exhibit nuclear atrophy and gene silencing. At times ranging from 1 hour to 4 weeks after optic nerve crush (ONC), eyes received an intravitreal injection of AAV2 virus carrying the Cre recombinase. Successful transduction was monitored by expression of the tdTomato reporter. Immunostaining was used to localize tdTomato expression in select cell types. RESULTS. Successful transduction of RGCs was achieved at all time points after ONC using AAV2 expressing Cre from the phosphoglycerate kinase (Pgk) promoter, but not the CMV promoter. ONC promoted an increase in the transduction of cell types in the inner nuclear layer, including Müller cells and rod bipolar neurons. There was minimal evidence of transduction of amacrine cells and astrocytes in the inner retina or optic nerve. CONCLUSIONS. Damaged RGCs can be transduced and at least some endogenous genes can be subsequently activated. Optic nerve damage may change retinal architecture to allow greater penetration of an AAV2 virus to transduce several additional cell types in the inner nuclear layer.}, author = {Nickells, Robert and Schmitt, Heather and Maes, Margaret E and Schlamp, Cassandra}, issn = {01460404}, journal = {Investigative Ophthalmology and Visual Science}, number = {14}, pages = {6091 -- 6104}, publisher = {Association for Research in Vision and Ophthalmology}, title = {{AAV2 mediated transduction of the mouse retina after optic nerve injury}}, doi = {10.1167/iovs.17-22634}, volume = {58}, year = {2017}, } @article{1253, abstract = {This article provides an introduction to the role of microRNAs in the nervous system and outlines their potential involvement in the pathophysiology of schizophrenia, which is hypothesized to arise owing to environmental factors and genetic predisposition.}, author = {Tsai, Lihuei and Siegert, Sandra}, issn = {2168-622X}, journal = {JAMA Psychiatry}, number = {4}, pages = {409 -- 410}, publisher = {American Medical Association}, title = {{How MicroRNAs Are involved in splitting the mind}}, doi = {10.1001/jamapsychiatry.2015.3144}, volume = {73}, year = {2016}, }