Project description:People with spinal cord injury (SCI) are predisposed to pressure ulcers (PU). PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions. An agent-based model (ABM) of ischemia/reperfusion-induced inflammation and PU (the PUABM) was created, calibrated to serial images of post-SCI PU, and used to investigate potential treatments in silico. Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI. These morphological features, along with simulated cell counts and mediator concentrations, suggested that the influence of inflammatory dynamics caused simulations to be committed to "better" vs. "worse" outcomes by 4 days of simulated time and prior to ulcer formation. Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence. Using the PUABM, in silico trials of anti-inflammatory treatments such as corticosteroids and a neutralizing antibody targeted at Damage-Associated Molecular Pattern molecules (DAMPs) suggested that, at best, early application at a sufficiently high dose could attenuate local inflammation and reduce pressure-associated tissue damage, but could not reduce PU incidence. The PUABM thus shows promise as an adjunct for mechanistic understanding, diagnosis, and design of therapies in the setting of PU.
Project description:Place cells develop spatially-tuned receptive fields during the early stages of novel environment exploration. The generative mechanism underlying these spatially-selective responses remains largely elusive, but has been associated with theta rhythmicity. An important factor implicating the transformation of silent cells to place cells is a spatially-uniform depolarization that is mediated by a persistent sodium current. This neuronal current is modulated by extracellular calcium concentration, which, in turn, is actively controlled by astrocytes. However, there is no established relationship between the neuronal depolarization and astrocytic activity. To consider this link, we designed a bioplausible computational model of a neuronal-astrocytic network, where astrocytes induced the transient emergence of place fields in silent cells, and accelerated the plasticity-induced consolidation of place cells. Interestingly, theta oscillations emerged naturally at the network level, resulting from the astrocytic modulation of subcellular neuronal properties. Our results suggest that astrocytes participate in spatial mapping and exploration, and further highlight the computational roles of these cells in the brain.
Project description:Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.
Project description:The origins and functional significance of theta phase precession in the hippocampus remain obscure, in part, because of the difficulty of reproducing hippocampal place cell firing in experimental settings where the biophysical underpinnings can be examined in detail. The present study concerns a neurobiologically based computational model of the emergence of theta phase precession in which the responses of a single model CA3 pyramidal cell are examined in the context of stimulation by realistic afferent spike trains including those of place cells in entorhinal cortex, dentate gyrus, and other CA3 pyramidal cells. Spike-timing dependent plasticity in the model CA3 pyramidal cell leads to a spatially correlated associational synaptic drive that subsequently creates a spatially asymmetric expansion of the model cell's place field. Following an initial training period, theta phase precession can be seen in the firing patterns of the model CA3 pyramidal cell. Through selective manipulations of the model it is possible to decompose theta phase precession in CA3 into the separate contributing factors of inheritance from upstream afferents in the dentate gyrus and entorhinal cortex, the interaction of synaptically controlled increasing afferent drive with phasic inhibition, and the theta phase difference between dentate gyrus granule cell and CA3 pyramidal cell activity. In the context of a single CA3 pyramidal cell, the model shows that each of these factors plays a role in theta phase precession within CA3 and suggests that no one single factor offers a complete explanation of the phenomenon. The model also shows parallels between theta phase encoding and pattern completion within the CA3 autoassociative network.
Project description:Blebbing occurs when the cytoskeleton detaches from the cell membrane, resulting in the pressure-driven flow of cytosol towards the area of detachment and the local expansion of the cell membrane. Recent interest has focused on cells that use blebbing for migrating through 3D fibrous matrices. In particular, metastatic cancer cells have been shown to use blebs for motility. A dynamic computational model of the cell is presented that includes mechanics of and the interactions between the intracellular fluid, the actin cortex and the cell membrane. The computational model is used to explore the relative roles in bleb formation time of cytoplasmic viscosity and drag between the cortex and the cytosol. A regime of values for the drag coefficient and cytoplasmic viscosity values that match bleb formation timescales is presented. The model results are then used to predict the Darcy permeability and the volume fraction of the cortex.
Project description:Hippocampal place-cell sequences observed during awake immobility often represent previous experience, suggesting a role in memory processes. However, recent reports of goals being overrepresented in sequential activity suggest a role in short-term planning, although a detailed understanding of the origins of hippocampal sequential activity and of its functional role is still lacking. In particular, it is unknown which mechanism could support efficient planning by generating place-cell sequences biased toward known goal locations, in an adaptive and constructive fashion. To address these questions, we propose a model of spatial learning and sequence generation as interdependent processes, integrating cortical contextual coding, synaptic plasticity and neuromodulatory mechanisms into a map-based approach. Following goal learning, sequential activity emerges from continuous attractor network dynamics biased by goal memory inputs. We apply Bayesian decoding on the resulting spike trains, allowing a direct comparison with experimental data. Simulations show that this model (1) explains the generation of never-experienced sequence trajectories in familiar environments, without requiring virtual self-motion signals, (2) accounts for the bias in place-cell sequences toward goal locations, (3) highlights their utility in flexible route planning, and (4) provides specific testable predictions.
Project description:Calcium signaling plays a pivotal role in cardiomyocytes, coupling electrical excitation to mechanical contraction of the heart. Determining locations of active calcium release sites, and how their recruitment changes in response to stimuli and in disease states is therefore of central interest in cardiac physiology. Current algorithms for detecting release sites from live cell imaging data are however not easily validated against a known "ground truth," which makes interpretation of the output of such algorithms, in particular the degree of confidence in site detection, a challenging task. Computational models are capable of integrating findings from multiple sources into a consistent, predictive framework. In cellular physiology, such models have the potential to reveal structure and function beyond the temporal and spatial resolution limitations of individual experimental measurements. Here, we create a spatially detailed computational model of calcium release in an eight sarcomere section of a ventricular cardiomyocyte, using electron tomography reconstruction of cardiac ultrastructure and confocal imaging of protein localization. This provides a high-resolution model of calcium diffusion from intracellular stores, which can be used as a platform to simulate confocal fluorescence imaging in the context of known ground truth structures from the higher resolution model. We use this capability to evaluate the performance of a recently proposed method for detecting the functional response of calcium release sites in live cells. Model permutations reveal how calcium release site density and mitochondria acting as diffusion barriers impact the detection performance of the algorithm. We demonstrate that site density has the greatest impact on detection precision and recall, in particular affecting the effective detectable depth of sites in confocal data. Our findings provide guidance on how such detection algorithms may best be applied to experimental data and give insights into limitations when using two-dimensional microscopy images to analyse three-dimensional cellular structures.
Project description:While grid cells in the medial entorhinal cortex (MEC) of rodents have multiple, regularly arranged firing fields, place cells in the cornu ammonis (CA) regions of the hippocampus mostly have single spatial firing fields. Since there are extensive projections from MEC to the CA regions, many models have suggested that a feedforward network can transform grid cell firing into robust place cell firing. However, these models generate place fields that are consistently too small compared to those recorded in experiments. Here, we argue that it is implausible that grid cell activity alone can be transformed into place cells with robust place fields of realistic size in a feedforward network. We propose two solutions to this problem. Firstly, weakly spatially modulated cells, which are abundant throughout EC, provide input to downstream place cells along with grid cells. This simple model reproduces many place cell characteristics as well as results from lesion studies. Secondly, the recurrent connections between place cells in the CA3 network generate robust and realistic place fields. Both mechanisms could work in parallel in the hippocampal formation and this redundancy might account for the robustness of place cell responses to a range of disruptions of the hippocampal circuitry.
Project description:The epidermis and the stratum corneum (SC) as its outermost layer have evolved to protect the body from evaporative water loss to the environment. To morphologically represent the extremely flattened cells of the SC - and thereby the epidermal barrier - in a multicellular computational model, we developed a 3D biomechanical model (BM) based on ellipsoid cell shapes. We integrated the BM in the multicellular modelling and simulation platform EPISIM. We created a cell behavioural model (CBM) with EPISIM encompassing regulatory feedback loops between the epidermal barrier, water loss to the environment, and water and calcium flow within the tissue. This CBM allows a small number of stem cells to initiate self-organizing epidermal stratification, yielding the spontaneous emergence of water and calcium gradients comparable to experimental data. We find that the 3D in silico epidermis attains homeostasis most quickly at high ambient humidity, and once in homeostasis the epidermal barrier robustly buffers changes in humidity. Our model yields an in silico epidermis with a previously unattained realistic morphology, whose cell neighbour topology is validated with experimental data obtained from in vivo images. This work paves the way to computationally investigate how an impaired SC barrier precipitates disease.
Project description:The morphogenetic process of cardiac looping transforms the straight heart tube into a curved tube that resembles the shape of the future four-chambered heart. Although great progress has been made in identifying the molecular and genetic factors involved in looping, the physical mechanisms that drive this process have remained poorly understood. Recent work, however, has shed new light on this complicated problem. After briefly reviewing the current state of knowledge, we propose a relatively comprehensive hypothesis for the mechanics of the first phase of looping, termed c-looping, as the straight heart tube deforms into a c-shaped tube. According to this hypothesis, differential hypertrophic growth in the myocardium supplies the main forces that cause the heart tube to bend ventrally, while regional growth and cytoskeletal contraction in the omphalomesenteric veins (primitive atria) and compressive loads exerted by the splanchnopleuric membrane drive rightward torsion. A computational model based on realistic embryonic heart geometry is used to test the physical plausibility of this hypothesis. The behavior of the model is in reasonable agreement with available experimental data from control and perturbed embryos, offering support for our hypothesis. The results also suggest, however, that several other mechanisms contribute secondarily to normal looping, and we speculate that these mechanisms play backup roles when looping is perturbed. Finally, some outstanding questions are discussed for future study.