Quantifying the effect of uncertainty in input parameters in a simplified bidomain model of partial thickness ischaemia

Reduced blood flow in the coronary arteries can lead to damaged heart tissue (myocardial ischaemia). Although one method for detecting myocardial ischaemia involves changes in the ST segment of the electrocardiogram, the relationship between these changes and subendocardial ischaemia is not fully understood. In this study, we modelled ST-segment epicardial potentials in a slab model of cardiac ventricular tissue, with a central ischaemic region, using the bidomain model, which considers conduction longitudinal, transverse and normal to the cardiac fibres. We systematically quantified the effect of uncertainty on the input parameters, fibre rotation angle, ischaemic depth, blood conductivity and six bidomain conductivities, on outputs that characterise the epicardial potential distribution. We found that three typical types of epicardial potential distributions (one minimum over the central ischaemic region, a tripole of minima, and two minima flanking a central maximum) could all occur for a wide range of ischaemic depths. In addition, the positions of the minima were affected by both the fibre rotation angle and the ischaemic depth, but not by changes in the conductivity values. We also showed that the magnitude of ST depression is affected only by changes in the longitudinal and normal conductivities, but not by the transverse conductivities

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodeling. Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious. Here we report a new role for astrocytes in actively engulfing CNS synapses. This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses. Lastly, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify Megf10 and Mertk as critical players in the synapse remodeling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes

Heterogeneity of fractional anisotropy and mean diffusivity measurements by in vivo diffusion tensor imaging in normal human hearts

Background: Cardiac diffusion tensor imaging (cDTI) by cardiovascular magnetic resonance has the potential to assess microstructural changes through measures of fractional anisotropy (FA) and mean diffusivity (MD). However, normal variation in regional and transmural FA and MD is not well described. Methods: Twenty normal subjects were scanned using an optimised cDTI sequence at 3T in systole. FA and MD were quantified in 3 transmural layers and 4 regional myocardial walls. Results: FA was higher in the mesocardium (0.46 ±0.04) than the endocardium (0.40 ±0.04, p≤0.001) and epicardium (0.39 ±0.04, p≤0.001). On regional analysis, the FA in the septum was greater than the lateral wall (0.44 ±0.03 vs 0.40 ±0.05 p = 0.04). There was a transmural gradient in MD increasing towards the endocardium (epicardium 0.87 ±0.07 vs endocardium 0.91 ±0.08×10-3 mm2/s, p = 0.04). With the lateral wall (0.87 ± 0.08×10-3 mm2/s) as the reference, the MD was higher in the anterior wall (0.92 ±0.08×10-3 mm2/s, p = 0.016) and septum (0.92 ±0.07×10-3 mm2/s, p = 0.028). Transmurally the signal to noise ratio (SNR) was greatest in the mesocardium (14.5 ±2.5 vs endocardium 13.1 ±2.2, p<0.001; vs epicardium 12.0 ± 2.4, p<0.001) and regionally in the septum (16.0 ±3.4 vs lateral wall 11.5 ± 1.5, p<0.001). Transmural analysis suggested a relative reduction in the rate of change in helical angle (HA) within the mesocardium. Conclusions: In vivo FA and MD measurements in normal human heart are heterogeneous, varying significantly transmurally and regionally. Contributors to this heterogeneity are many, complex and interactive, but include SNR, variations in cardiac microstructure, partial volume effects and strain. These data indicate that the potential clinical use of FA and MD would require measurement standardisation by myocardial region and layer, unless pathological changes substantially exceed the normal variation identified

Rearrangement of Retinogeniculate Projection Patterns after Eye-Specific Segregation in Mice

It has been of interest whether and when the rearrangement of neuronal circuits can be induced after projection patterns are formed during development. Earlier studies using cats reported that the rearrangement of retinogeniculate projections could be induced even after eye-specific segregation has occurred, but detailed and quantitative characterization of this rearrangement has been lacking. Here we delineate the structural changes of retinogeniculate projections in the C57BL/6 mouse in response to monocular enucleation (ME) after eye-specific segregation. When ME was performed after eye-specific segregation, rearrangement of retinogeniculate axons in the dorsal lateral geniculate nucleus (dLGN) was observed within 5 days. Although this rearrangement was observed both along the dorsomedial-ventrolateral and outer-inner axes in the dLGN, it occurred more rapidly along the outer-inner axis. We also examined the critical period for this rearrangement and found that the rearrangement became almost absent by the beginning of the critical period for ocular dominance plasticity in the primary visual cortex. Taken together, our findings serve as a framework for the assessment of phenotypes of genetically altered mouse strains as well as provide insights into the mechanisms underlying the rearrangement of retinogeniculate projections

Burst-Time-Dependent Plasticity Robustly Guides ON/OFF Segregation in the Lateral Geniculate Nucleus

Spontaneous retinal activity (known as “waves”) remodels synaptic connectivity to the lateral geniculate nucleus (LGN) during development. Analysis of retinal waves recorded with multielectrode arrays in mouse suggested that a cue for the segregation of functionally distinct (ON and OFF) retinal ganglion cells (RGCs) in the LGN may be a desynchronization in their firing, where ON cells precede OFF cells by one second. Using the recorded retinal waves as input, with two different modeling approaches we explore timing-based plasticity rules for the evolution of synaptic weights to identify key features underlying ON/OFF segregation. First, we analytically derive a linear model for the evolution of ON and OFF weights, to understand how synaptic plasticity rules extract input firing properties to guide segregation. Second, we simulate postsynaptic activity with a nonlinear integrate-and-fire model to compare findings with the linear model. We find that spike-time-dependent plasticity, which modifies synaptic weights based on millisecond-long timing and order of pre- and postsynaptic spikes, fails to segregate ON and OFF retinal inputs in the absence of normalization. Implementing homeostatic mechanisms results in segregation, but only with carefully-tuned parameters. Furthermore, extending spike integration timescales to match the second-long input correlation timescales always leads to ON segregation because ON cells fire before OFF cells. We show that burst-time-dependent plasticity can robustly guide ON/OFF segregation in the LGN without normalization, by integrating pre- and postsynaptic bursts irrespective of their firing order and over second-long timescales. We predict that an LGN neuron will become ON- or OFF-responsive based on a local competition of the firing patterns of neighboring RGCs connecting to it. Finally, we demonstrate consistency with ON/OFF segregation in ferret, despite differences in the firing properties of retinal waves. Our model suggests that diverse input statistics of retinal waves can be robustly interpreted by a burst-based rule, which underlies retinogeniculate plasticity across different species

Millisecond-Timescale Local Network Coding in the Rat Primary Somatosensory Cortex

Correlation among neocortical neurons is thought to play an indispensable role in mediating sensory processing of external stimuli. The role of temporal precision in this correlation has been hypothesized to enhance information flow along sensory pathways. Its role in mediating the integration of information at the output of these pathways, however, remains poorly understood. Here, we examined spike timing correlation between simultaneously recorded layer V neurons within and across columns of the primary somatosensory cortex of anesthetized rats during unilateral whisker stimulation. We used Bayesian statistics and information theory to quantify the causal influence between the recorded cells with millisecond precision. For each stimulated whisker, we inferred stable, whisker-specific, dynamic Bayesian networks over many repeated trials, with network similarity of 83.3±6% within whisker, compared to only 50.3±18% across whiskers. These networks further provided information about whisker identity that was approximately 6 times higher than what was provided by the latency to first spike and 13 times higher than what was provided by the spike count of individual neurons examined separately. Furthermore, prediction of individual neurons' precise firing conditioned on knowledge of putative pre-synaptic cell firing was 3 times higher than predictions conditioned on stimulus onset alone. Taken together, these results suggest the presence of a temporally precise network coding mechanism that integrates information across neighboring columns within layer V about vibrissa position and whisking kinetics to mediate whisker movement by motor areas innervated by layer V