Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism.
Ontology highlight
ABSTRACT:
SUBMITTER: Cheadle L
PROVIDER: S-EPMC7666095 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The barrel cortex is within the primary somatosensory cortex of the rodent, and processes signals from the vibrissae. Much focus has been devoted to the function of neurons, more recently, the role of glial cells in the processing of sensory input has gained increasing interest. Microglia are the principal immune cells of the nervous system that survey and regulate the cellular constituents of the dynamic nervous system. We investigated the normal and disrupted development of microglia in barrel cortex by chronically depriving sensory signals via whisker trimming for the animals' first postnatal month. Using immunohistochemistry to label microglia, we performed morphological reconstructions as well as densitometry analyses as a function of developmental age and sensory experience. Findings suggest that both developmental age and sensory experience has profound impact on microglia morphology. Following chronic sensory deprivation, microglia undergo a morphological transition from a monitoring or resting state to an altered morphological state, by exhibiting expanded cell body size and retracted processes. Sensory restoration via whisker regrowth returns these morphological alterations back to age-matched control values. Our results indicate that microglia may be recruited to participate in the modulation of neuronal structural remodeling during developmental critical periods and in response to alteration in sensory input.
| S-EPMC6944757 | biostudies-literature
Project description:Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood.Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor Fc?RIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes.This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.
| S-EPMC2991294 | biostudies-literature
Project description:Neocortical circuitry can alter throughout life with experience. However, the contributions of changes in synaptic strength and modifications in neuronal wiring to experience-dependent plasticity in mature animals remain unclear. We trimmed whiskers of rats and made electrophysiological recordings after whisker cortical maps have developed. Measurements of miniature EPSPs suggested that synaptic inputs to layer 2/3 pyramidal neurons were altered at the junction of deprived and spared cortex in primary somatosensory cortex. Whole-cell recordings were made from pairs of synaptically connected pyramidal neurons to investigate possible changes in local excitatory connections between layer 2/3 pyramidal neurons. The neurons were filled with fluorescent dyes during recording and reconstructed in three dimensions using confocal microscopy and image deconvolution to identify putative synapses. We show that sensory deprivation induces a striking reduction in connectivity between layer 2/3 pyramidal neurons in deprived cortex without large-scale, compensatory increases in the strength of remaining local excitatory connections. A markedly different situation occurs in spared cortex. Connection strength is potentiated, but local excitatory connectivity and synapse number per connection are unchanged. Our data suggest that alterations in local excitatory circuitry enhance the expansion of spared representations into deprived cortex. Moreover, our findings offer one explanation for how the responses of spared and deprived cortex to sensory deprivation can be dissociated in developed animals.
| S-EPMC2043248 | biostudies-literature
Project description:Large-scale biophysical circuit models provide mechanistic insights into the micro-scale and macro-scale properties of brain organization that shape complex patterns of spontaneous brain activity. We developed a spatially heterogeneous large-scale dynamical circuit model that allowed for variation in local synaptic properties across the human cortex. Here we show that parameterizing local circuit properties with both anatomical and functional gradients generates more realistic static and dynamic resting-state functional connectivity (FC). Furthermore, empirical and simulated FC dynamics demonstrates remarkably similar sharp transitions in FC patterns, suggesting the existence of multiple attractors. Time-varying regional fMRI amplitude may track multi-stability in FC dynamics. Causal manipulation of the large-scale circuit model suggests that sensory-motor regions are a driver of FC dynamics. Finally, the spatial distribution of sensory-motor drivers matches the principal gradient of gene expression that encompasses certain interneuron classes, suggesting that heterogeneity in excitation-inhibition balance might shape multi-stability in FC dynamics.
| S-EPMC8568904 | biostudies-literature
Project description:In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a 4 week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first 1 to 4 days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade.
| S-EPMC4008496 | biostudies-literature
Project description:The brain constantly generates predictions about the environment to guide action. Unexpected events lead to surprise and can necessitate the modification of ongoing behavior. Surprise can occur for any sensory domain, but it is not clear how these separate surprise signals are integrated to affect motor output. By applying a trial-to-trial Bayesian surprise model to human electroencephalography data recorded during a cross-modal oddball task, we tested whether there are separate predictive models for different sensory modalities (visual, auditory), or whether expectations are integrated across modalities such that surprise in one modality decreases surprise for a subsequent unexpected event in the other modality. We found that while surprise was represented in a common frontal signature across sensory modalities (the fronto-central P3 event-related potential), the single-trial amplitudes of this signature more closely conformed to a model with separate surprise terms for each sensory domain. We then investigated whether surprise-related fronto-central P3 activity indexes the rapid inhibitory control of ongoing behavior after surprise, as suggested by recent theories. Confirming this prediction, the fronto-central P3 amplitude after both auditory and visual unexpected events was highly correlated with the fronto-central P3 found after stop-signals (measured in a separate stop-signal task). Moreover, surprise-related and stopping-related activity loaded onto the same component in a cross-task independent components analysis. Together, these findings suggest that medial frontal cortex maintains separate predictive models for different sensory domains, but engages a common mechanism for inhibitory control of behavior regardless of the source of surprise.
| S-EPMC6687204 | biostudies-literature
Project description:Neuronal activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized. However, the fundamental question of whether and how sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here, in vivo calcium imaging, optogenetics, and pharmacological approaches reveal that granule neuron activation in the anterior dorsal cerebellar vermis (ADCV) plays a crucial role in a novel delay tactile startle learning paradigm in mice. Strikingly, using large-scale transcriptome and chromatin profiling, we have discovered that activation of the motor learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator Cohesin in ADCV granule neurons in adult mice disrupts activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.
2019-05-09 | GSE127995 | GEO
Project description:Hypoxic pseudopalisades are a pathological hallmark of human glioblastoma, which is linked to tumour malignancy and aggressiveness. Yet, their function and role in the tumour development have scarcely been explored. It is thought that pseudopalisades are formed by malignant cells escaping from the hypoxic environment, although evidence of the immune component of pseudopalisades has been elusive. In the present work, we analyse the immunological constituent of hypoxic pseudopalisades using high-resolution three-dimensional confocal imaging in tissue blocks from excised tumours of glioblastoma patients and mimic the hypoxic gradient in microfluidic platforms in vitro to understand the cellular motility. We visualize that glioblastoma-associated microglia and macrophages abundantly populate pseudopalisades, displaying an elongated kinetic morphology across the pseudopalisades, and are oriented towards the necrotic focus. In vitro experiments demonstrate that under hypoxic gradient, microglia show a particular motile behaviour characterized by the increase of cellular persistence in contrast with glioma cells. Importantly, we show that glioblastoma-associated microglia and macrophages utilize fibres of glioma cells as a haptotactic cue to navigate along the anisotropic structure of the pseudopalisades and display a high phagocytic activity at the necrotic border of the pseudopalisades. In this study, we demonstrate that glioblastoma-associated microglia and macrophages are the main immune cells of pseudopalisades in glioblastoma, travelling to necrotic areas to clear the resulting components of the prothrombotic milieu, suggesting that the scavenging features of glioblastoma-associated microglia and macrophages at the pseudopalisades serve as an essential counterpart for glioma cell invasion.
| S-EPMC7491442 | biostudies-literature
Project description:Neuronal-activity-dependent transcription couples sensory experience to adaptive responses of the brain including learning and memory. Mechanisms of activity-dependent gene expression including alterations of the epigenome have been characterized1-8. However, the fundamental question of whether sensory experience remodels chromatin architecture in the adult brain in vivo to induce neural code transformations and learning and memory remains to be addressed. Here we use in vivo calcium imaging, optogenetics and pharmacological approaches to show that granule neuron activation in the anterior dorsal cerebellar vermis has a crucial role in a delay tactile startle learning paradigm in mice. Of note, using large-scale transcriptome and chromatin profiling, we show that activation of the motor-learning-linked granule neuron circuit reorganizes neuronal chromatin including through long-distance enhancer-promoter and transcriptionally active compartment interactions to orchestrate distinct granule neuron gene expression modules. Conditional CRISPR knockout of the chromatin architecture regulator cohesin in anterior dorsal cerebellar vermis granule neurons in adult mice disrupts enhancer-promoter interactions, activity-dependent transcription and motor learning. These findings define how sensory experience patterns chromatin architecture and neural circuit coding in the brain to drive motor learning.
| S-EPMC6542709 | biostudies-literature
Project description:Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of ?2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch. VIDEO ABSTRACT.
| S-EPMC6347413 | biostudies-literature