@phdthesis{19456,
abstract = {Making decisions requires flexibly adapting to changing environments, a process that
depends on accurately interpreting current contingencies and integrating them with
past experience. Two brain regions are particularly critical for this process, the medial
prefrontal cortex (mPFC) and the hippocampus. Using contextual information from the
hippocampus, the mPFC selects relevant cognitive frameworks and suppresses
irrelevant ones to guide appropriate actions. Several studies have shown that some
mPFC pyramidal neurons become spatially tuned when spatial information is required
to guide goal-directed behavior. However, the role of prefrontal spatial representations
in learning and decision making is not well understood. This work aims to characterize
the role of mPFC spatial tuning in supporting a contextual association task. Rats were
trained to learn two cue–location associations on a radial arm maze over multiple days,
while we simultaneously recorded from dorsal CA1 of the hippocampus and the
prelimbic area of the mPFC. We describe a subset of spatially tuned hippocampal and
prefrontal pyramidal neurons that “flicker” between multiple spatial representations on
different trials, suggesting dynamic, context-dependent coding. This flickering may
provide a substrate for how the network reorganizes in response to task demands,
likely by enabling the flexible evaluation of competing representations. },
author = {Cumpelik, Andrea D},
isbn = {978-3-99078-056-5},
issn = {2663-337X},
keywords = {neuroscience, decision making, learning, cognitive flexibility, medial prefrontal cortex, hippocampus, electrophysiology},
pages = {96},
publisher = {Institute of Science and Technology Austria},
title = {{The role of prefrontal spatial coding in supporting a contextual association task}},
doi = {10.15479/AT-ISTA-19456},
year = {2025},
}
@article{15257,
abstract = {Root gravitropic bending represents a fundamental aspect of terrestrial plant physiology. Gravity is perceived by sedimentation of starch-rich plastids (statoliths) to the bottom of the central root cap cells. Following gravity perception, intercellular auxin transport is redirected downwards leading to an asymmetric auxin accumulation at the lower root side causing inhibition of cell expansion, ultimately resulting in downwards bending. How gravity-induced statoliths repositioning is translated into asymmetric auxin distribution remains unclear despite PIN auxin efflux carriers and the Negative Gravitropic Response of roots (NGR) proteins polarize along statolith sedimentation, thus providing a plausible mechanism for auxin flow redirection. In this study, using a functional NGR1-GFP construct, we visualized the NGR1 localization on the statolith surface and plasma membrane (PM) domains in close proximity to the statoliths, correlating with their movements. We determined that NGR1 binding to these PM domains is indispensable for NGR1 functionality and relies on cysteine acylation and adjacent polybasic regions as well as on lipid and sterol PM composition. Detailed timing of the early events following graviperception suggested that both NGR1 repolarization and initial auxin asymmetry precede the visible PIN3 polarization. This discrepancy motivated us to unveil a rapid, NGR-dependent translocation of PIN-activating AGCVIII kinase D6PK towards lower PMs of gravity-perceiving cells, thus providing an attractive model for rapid redirection of auxin fluxes following gravistimulation.},
author = {Kulich, Ivan and Schmid, Julia and Teplova, Anastasiia and Qi, Linlin and Friml, Jiří},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Rapid translocation of NGR proteins driving polarization of PIN-activating D6 protein kinase during root gravitropism}},
doi = {10.7554/elife.91523},
volume = {12},
year = {2024},
}
@article{14683,
abstract = {Mosaic analysis with double markers (MADM) technology enables the generation of genetic mosaic tissue in mice and high-resolution phenotyping at the individual cell level. Here, we present a protocol for isolating MADM-labeled cells with high yield for downstream molecular analyses using fluorescence-activated cell sorting (FACS). We describe steps for generating MADM-labeled mice, perfusion, single-cell suspension, and debris removal. We then detail procedures for cell sorting by FACS and downstream analysis. This protocol is suitable for embryonic to adult mice.
For complete details on the use and execution of this protocol, please refer to Contreras et al. (2021).1},
author = {Amberg, Nicole and Cheung, Giselle T and Hippenmeyer, Simon},
issn = {2666-1667},
journal = {STAR Protocols},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},
number = {1},
publisher = {Elsevier},
title = {{Protocol for sorting cells from mouse brains labeled with mosaic analysis with double markers by flow cytometry}},
doi = {10.1016/j.xpro.2023.102771},
volume = {5},
year = {2024},
}
@article{15033,
abstract = {The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM.},
author = {Adamowski, Maciek and Matijevic, Ivana and Friml, Jiří},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Developmental patterning function of GNOM ARF-GEF mediated from the cell periphery}},
doi = {10.7554/elife.68993},
volume = {13},
year = {2024},
}
@article{12562,
abstract = {Presynaptic inputs determine the pattern of activation of postsynaptic neurons in a neural circuit. Molecular and genetic pathways that regulate the selective formation of subsets of presynaptic inputs are largely unknown, despite significant understanding of the general process of synaptogenesis. In this study, we have begun to identify such factors using the spinal monosynaptic stretch reflex circuit as a model system. In this neuronal circuit, Ia proprioceptive afferents establish monosynaptic connections with spinal motor neurons that project to the same muscle (termed homonymous connections) or muscles with related or synergistic function. However, monosynaptic connections are not formed with motor neurons innervating muscles with antagonistic functions. The ETS transcription factor ER81 (also known as ETV1) is expressed by all proprioceptive afferents, but only a small set of motor neuron pools in the lumbar spinal cord of the mouse. Here we use conditional mouse genetic techniques to eliminate Er81 expression selectively from motor neurons. We find that ablation of Er81 in motor neurons reduces synaptic inputs from proprioceptive afferents conveying information from homonymous and synergistic muscles, with no change observed in the connectivity pattern from antagonistic proprioceptive afferents. In summary, these findings suggest a role for ER81 in defined motor neuron pools to control the assembly of specific presynaptic inputs and thereby influence the profile of activation of these motor neurons.},
author = {Ladle, David R. and Hippenmeyer, Simon},
issn = {1522-1598},
journal = {Journal of Neurophysiology},
keywords = {Physiology, General Neuroscience},
number = {3},
pages = {501--512},
publisher = {American Physiological Society},
title = {{Loss of ETV1/ER81 in motor neurons leads to reduced monosynaptic inputs from proprioceptive sensory neurons}},
doi = {10.1152/jn.00172.2022},
volume = {129},
year = {2023},
}
@article{12679,
abstract = {How to generate a brain of correct size and with appropriate cell-type diversity during development is a major question in Neuroscience. In the developing neocortex, radial glial progenitor (RGP) cells are the main neural stem cells that produce cortical excitatory projection neurons, glial cells, and establish the prospective postnatal stem cell niche in the lateral ventricles. RGPs follow a tightly orchestrated developmental program that when disrupted can result in severe cortical malformations such as microcephaly and megalencephaly. The precise cellular and molecular mechanisms instructing faithful RGP lineage progression are however not well understood. This review will summarize recent conceptual advances that contribute to our understanding of the general principles of RGP lineage progression.},
author = {Hippenmeyer, Simon},
issn = {0959-4388},
journal = {Current Opinion in Neurobiology},
keywords = {General Neuroscience},
number = {4},
publisher = {Elsevier},
title = {{Principles of neural stem cell lineage progression: Insights from developing cerebral cortex}},
doi = {10.1016/j.conb.2023.102695},
volume = {79},
year = {2023},
}
@article{11460,
abstract = {Background: Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which can vary in extent from focal to global. Furthermore, NMDs show a substantial comorbidity with other neurodevelopmental disorders, notably autism spectrum disorders (ASDs). Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene WDFY3. However, the cellular origins of these defects in Wdfy3 mutant mice remain elusive and uncovering it will provide critical insight into WDFY3-dependent disease pathology.
Methods: Here, in an effort to untangle the origins of NMDs in Wdfy3lacZ mice, we employed mosaic analysis with double markers (MADM). MADM technology enabled us to genetically distinctly track and phenotypically analyze mutant and wild-type cells concomitantly in vivo using immunofluorescent techniques.
Results: We revealed a cell autonomous requirement of WDFY3 for accurate laminar positioning of cortical projection neurons and elimination of mispositioned cells during early postnatal life. In addition, we identified significant deviations in dendritic arborization, as well as synaptic density and morphology between wild type, heterozygous, and homozygous Wdfy3 mutant neurons in Wdfy3-MADM reporter mice at postnatal stages.
Limitations: While Wdfy3 mutant mice have provided valuable insight into prenatal aspects of ASD pathology that remain inaccessible to investigation in humans, like most animal models, they do not a perfectly replicate all aspects of human ASD biology. The lack of human data makes it indeterminate whether morphological deviations described here apply to ASD patients or some of the other neurodevelopmental conditions associated with WDFY3 mutation.
Conclusions: Our genetic approach revealed several cell autonomous requirements of WDFY3 in neuronal development that could underlie the pathogenic mechanisms of WDFY3-related neurodevelopmental conditions. The results are also consistent with findings in other ASD animal models and patients and suggest an important role for WDFY3 in regulating neuronal function and interconnectivity in postnatal life.},
author = {Schaaf, Zachary A. and Tat, Lyvin and Cannizzaro, Noemi and Green, Ralph and Rülicke, Thomas and Hippenmeyer, Simon and Zarbalis, Konstantinos S.},
issn = {2040-2392},
journal = {Molecular Autism},
keywords = {Psychiatry and Mental health, Developmental Biology, Developmental Neuroscience, Molecular Biology},
publisher = {Springer Nature},
title = {{WDFY3 mutation alters laminar position and morphology of cortical neurons}},
doi = {10.1186/s13229-022-00508-3},
volume = {13},
year = {2022},
}
@article{12117,
abstract = {To understand how potential gene manipulations affect in vitro microglia, we provide a set of short protocols to evaluate microglia identity and function. We detail steps for immunostaining to determine microglia identity. We describe three functional assays for microglia: phagocytosis, calcium response following ATP stimulation, and cytokine expression upon inflammatory stimuli. We apply these protocols to human induced-pluripotent-stem-cell (hiPSC)-derived microglia, but they can be also applied to other in vitro microglial models including primary mouse microglia.
For complete details on the use and execution of this protocol, please refer to Bartalska et al. (2022).1},
author = {Hübschmann, Verena and Korkut, Medina and Siegert, Sandra},
issn = {2666-1667},
journal = {STAR Protocols},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},
number = {4},
publisher = {Elsevier},
title = {{Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay}},
doi = {10.1016/j.xpro.2022.101866},
volume = {3},
year = {2022},
}
@article{12140,
abstract = {Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.},
author = {Basilico, Bernadette and Ferrucci, Laura and Khan, Azka and Di Angelantonio, Silvia and Ragozzino, Davide and Reverte, Ingrid},
issn = {1662-5102},
journal = {Frontiers in Cellular Neuroscience},
keywords = {Cellular and Molecular Neuroscience},
publisher = {Frontiers Media},
title = {{What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior}},
doi = {10.3389/fncel.2022.1022431},
volume = {16},
year = {2022},
}
@article{12149,
abstract = {Editorial on the Research Topic},
author = {Gambino, Giuditta and Bhik-Ghanie, Rebecca and Giglia, Giuseppe and Puig, M. Victoria and Ramirez Villegas, Juan F and Zaldivar, Daniel},
issn = {1662-5110},
journal = {Frontiers in Neural Circuits},
keywords = {Cellular and Molecular Neuroscience, Cognitive Neuroscience, Sensory Systems, Neuroscience (miscellaneous)},
publisher = {Frontiers Media},
title = {{Editorial: Neuromodulatory ascending systems: Their influence at the microscopic and macroscopic levels}},
doi = {10.3389/fncir.2022.1028154},
volume = {16},
year = {2022},
}
@article{12152,
abstract = {ESCRT-III filaments are composite cytoskeletal polymers that can constrict and cut cell membranes from the inside of the membrane neck. Membrane-bound ESCRT-III filaments undergo a series of dramatic composition and geometry changes in the presence of an ATP-consuming Vps4 enzyme, which causes stepwise changes in the membrane morphology. We set out to understand the physical mechanisms involved in translating the changes in ESCRT-III polymer composition into membrane deformation. We have built a coarse-grained model in which ESCRT-III polymers of different geometries and mechanical properties are allowed to copolymerise and bind to a deformable membrane. By modelling ATP-driven stepwise depolymerisation of specific polymers, we identify mechanical regimes in which changes in filament composition trigger the associated membrane transition from a flat to a buckled state, and then to a tubule state that eventually undergoes scission to release a small cargo-loaded vesicle. We then characterise how the location and kinetics of polymer loss affects the extent of membrane deformation and the efficiency of membrane neck scission. Our results identify the near-minimal mechanical conditions for the operation of shape-shifting composite polymers that sever membrane necks.},
author = {Jiang, Xiuyun and Harker-Kirschneck, Lena and Vanhille-Campos, Christian Eduardo and Pfitzner, Anna-Katharina and Lominadze, Elene and Roux, Aurélien and Baum, Buzz and Šarić, Anđela},
issn = {1553-7358},
journal = {PLOS Computational Biology},
keywords = {Computational Theory and Mathematics, Cellular and Molecular Neuroscience, Genetics, Molecular Biology, Ecology, Modeling and Simulation, Ecology, Evolution, Behavior and Systematics},
number = {10},
publisher = {Public Library of Science},
title = {{Modelling membrane reshaping by staged polymerization of ESCRT-III filaments}},
doi = {10.1371/journal.pcbi.1010586},
volume = {18},
year = {2022},
}
@article{12157,
abstract = {Polygenic adaptation is thought to be ubiquitous, yet remains poorly understood. Here, we model this process analytically, in the plausible setting of a highly polygenic, quantitative trait that experiences a sudden shift in the fitness optimum. We show how the mean phenotype changes over time, depending on the effect sizes of loci that contribute to variance in the trait, and characterize the allele dynamics at these loci. Notably, we describe the two phases of the allele dynamics: The first is a rapid phase, in which directional selection introduces small frequency differences between alleles whose effects are aligned with or opposed to the shift, ultimately leading to small differences in their probability of fixation during a second, longer phase, governed by stabilizing selection. As we discuss, key results should hold in more general settings and have important implications for efforts to identify the genetic basis of adaptation in humans and other species.},
author = {Hayward, Laura and Sella, Guy},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Polygenic adaptation after a sudden change in environment}},
doi = {10.7554/elife.66697},
volume = {11},
year = {2022},
}
@article{12212,
abstract = {Alzheimer’s disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-β (Aβ) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model.},
author = {Martín-Belmonte, Alejandro and Aguado, Carolina and Alfaro-Ruiz, Rocío and Moreno-Martínez, Ana Esther and de la Ossa, Luis and Aso, Ester and Gómez-Acero, Laura and Shigemoto, Ryuichi and Fukazawa, Yugo and Ciruela, Francisco and Luján, Rafael},
issn = {1758-9193},
journal = {Alzheimer's Research & Therapy},
keywords = {Cognitive Neuroscience, Neurology (clinical), Neurology},
publisher = {Springer Nature},
title = {{Nanoscale alterations in GABAB receptors and GIRK channel organization on the hippocampus of APP/PS1 mice}},
doi = {10.1186/s13195-022-01078-5},
volume = {14},
year = {2022},
}
@article{12251,
abstract = {Amyloid formation is linked to devastating neurodegenerative diseases, motivating detailed studies of the mechanisms of amyloid formation. For Aβ, the peptide associated with Alzheimer’s disease, the mechanism and rate of aggregation have been established for a range of variants and conditions in vitro and in bodily fluids. A key outstanding question is how the relative stabilities of monomers, fibrils and intermediates affect each step in the fibril formation process. By monitoring the kinetics of aggregation of Aβ42, in the presence of urea or guanidinium hydrochloride (GuHCl), we here determine the rates of the underlying microscopic steps and establish the importance of changes in relative stability induced by the presence of denaturant for each individual step. Denaturants shift the equilibrium towards the unfolded state of each species. We find that a non-ionic denaturant, urea, reduces the overall aggregation rate, and that the effect on nucleation is stronger than the effect on elongation. Urea reduces the rate of secondary nucleation by decreasing the coverage of fibril surfaces and the rate of nucleus formation. It also reduces the rate of primary nucleation, increasing its reaction order. The ionic denaturant, GuHCl, accelerates the aggregation at low denaturant concentrations and decelerates the aggregation at high denaturant concentrations. Below approximately 0.25 M GuHCl, the screening of repulsive electrostatic interactions between peptides by the charged denaturant dominates, leading to an increased aggregation rate. At higher GuHCl concentrations, the electrostatic repulsion is completely screened, and the denaturing effect dominates. The results illustrate how the differential effects of denaturants on stability of monomer, oligomer and fibril translate to differential effects on microscopic steps, with the rate of nucleation being most strongly reduced.},
author = {Weiffert, Tanja and Meisl, Georg and Curk, Samo and Cukalevski, Risto and Šarić, Anđela and Knowles, Tuomas P. J. and Linse, Sara},
issn = {1662-453X},
journal = {Frontiers in Neuroscience},
keywords = {General Neuroscience},
publisher = {Frontiers Media},
title = {{Influence of denaturants on amyloid β42 aggregation kinetics}},
doi = {10.3389/fnins.2022.943355},
volume = {16},
year = {2022},
}
@article{12280,
abstract = {In repeated interactions, players can use strategies that respond to the outcome of previous rounds. Much of the existing literature on direct reciprocity assumes that all competing individuals use the same strategy space. Here, we study both learning and evolutionary dynamics of players that differ in the strategy space they explore. We focus on the infinitely repeated donation game and compare three natural strategy spaces: memory-1 strategies, which consider the last moves of both players, reactive strategies, which respond to the last move of the co-player, and unconditional strategies. These three strategy spaces differ in the memory capacity that is needed. We compute the long term average payoff that is achieved in a pairwise learning process. We find that smaller strategy spaces can dominate larger ones. For weak selection, unconditional players dominate both reactive and memory-1 players. For intermediate selection, reactive players dominate memory-1 players. Only for strong selection and low cost-to-benefit ratio, memory-1 players dominate the others. We observe that the supergame between strategy spaces can be a social dilemma: maximum payoff is achieved if both players explore a larger strategy space, but smaller strategy spaces dominate.},
author = {Schmid, Laura and Hilbe, Christian and Chatterjee, Krishnendu and Nowak, Martin},
issn = {1553-7358},
journal = {PLOS Computational Biology},
keywords = {Computational Theory and Mathematics, Cellular and Molecular Neuroscience, Genetics, Molecular Biology, Ecology, Modeling and Simulation, Ecology, Evolution, Behavior and Systematics},
number = {6},
publisher = {Public Library of Science},
title = {{Direct reciprocity between individuals that use different strategy spaces}},
doi = {10.1371/journal.pcbi.1010149},
volume = {18},
year = {2022},
}
@article{12288,
abstract = {To understand the function of neuronal circuits, it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low throughput, low selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotropic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of ‘starter’ AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the mouse hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.},
author = {Sumser, Anton L and Jösch, Maximilian A and Jonas, Peter M and Ben Simon, Yoav},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling}},
doi = {10.7554/elife.79848},
volume = {11},
year = {2022},
}
@article{10818,
abstract = {Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.},
author = {Basilico, Bernadette and Ferrucci, Laura and Ratano, Patrizia and Golia, Maria T. and Grimaldi, Alfonso and Rosito, Maria and Ferretti, Valentina and Reverte, Ingrid and Sanchini, Caterina and Marrone, Maria C. and Giubettini, Maria and De Turris, Valeria and Salerno, Debora and Garofalo, Stefano and St‐Pierre, Marie‐Kim and Carrier, Micael and Renzi, Massimiliano and Pagani, Francesca and Modi, Brijesh and Raspa, Marcello and Scavizzi, Ferdinando and Gross, Cornelius T. and Marinelli, Silvia and Tremblay, Marie‐Ève and Caprioli, Daniele and Maggi, Laura and Limatola, Cristina and Di Angelantonio, Silvia and Ragozzino, Davide},
issn = {1098-1136},
journal = {Glia},
keywords = {Cellular and Molecular Neuroscience, Neurology},
number = {1},
pages = {173--195},
publisher = {Wiley},
title = {{Microglia control glutamatergic synapses in the adult mouse hippocampus}},
doi = {10.1002/glia.24101},
volume = {70},
year = {2022},
}
@article{11448,
abstract = {Studies of protein fitness landscapes reveal biophysical constraints guiding protein evolution and empower prediction of functional proteins. However, generalisation of these findings is limited due to scarceness of systematic data on fitness landscapes of proteins with a defined evolutionary relationship. We characterized the fitness peaks of four orthologous fluorescent proteins with a broad range of sequence divergence. While two of the four studied fitness peaks were sharp, the other two were considerably flatter, being almost entirely free of epistatic interactions. Mutationally robust proteins, characterized by a flat fitness peak, were not optimal templates for machine-learning-driven protein design – instead, predictions were more accurate for fragile proteins with epistatic landscapes. Our work paves insights for practical application of fitness landscape heterogeneity in protein engineering.},
author = {Gonzalez Somermeyer, Louisa and Fleiss, Aubin and Mishin, Alexander S and Bozhanova, Nina G and Igolkina, Anna A and Meiler, Jens and Alaball Pujol, Maria-Elisenda and Putintseva, Ekaterina V and Sarkisyan, Karen S and Kondrashov, Fyodor},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Heterogeneity of the GFP fitness landscape and data-driven protein design}},
doi = {10.7554/elife.75842},
volume = {11},
year = {2022},
}
@article{11447,
abstract = {Empirical essays of fitness landscapes suggest that they may be rugged, that is having multiple fitness peaks. Such fitness landscapes, those that have multiple peaks, necessarily have special local structures, called reciprocal sign epistasis (Poelwijk et al. in J Theor Biol 272:141–144, 2011). Here, we investigate the quantitative relationship between the number of fitness peaks and the number of reciprocal sign epistatic interactions. Previously, it has been shown (Poelwijk et al. in J Theor Biol 272:141–144, 2011) that pairwise reciprocal sign epistasis is a necessary but not sufficient condition for the existence of multiple peaks. Applying discrete Morse theory, which to our knowledge has never been used in this context, we extend this result by giving the minimal number of reciprocal sign epistatic interactions required to create a given number of peaks.},
author = {Saona Urmeneta, Raimundo J and Kondrashov, Fyodor and Khudiakova, Kseniia},
issn = {1522-9602},
journal = {Bulletin of Mathematical Biology},
keywords = {Computational Theory and Mathematics, General Agricultural and Biological Sciences, Pharmacology, General Environmental Science, General Biochemistry, Genetics and Molecular Biology, General Mathematics, Immunology, General Neuroscience},
number = {8},
publisher = {Springer Nature},
title = {{Relation between the number of peaks and the number of reciprocal sign epistatic interactions}},
doi = {10.1007/s11538-022-01029-z},
volume = {84},
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},
}