Myelin dystrophy in the aging prefrontal cortex leads to impaired signal transmission and working memory decline: a multiscale computational study.

Normal aging leads to myelin alternations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are often correlated with cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First we built a multicompartment pyramidal neuron model fit to monkey dlPFC data, with axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions, to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination in a population of neurons. Lasso regression identified distinctive parameter sets likely to modulate an axon's susceptibility to CV changes following demyelination versus remyelination. Next we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from electron microscopy up to behavior on aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.

Spontaneous synaptic drive in detrusor smooth muscle: computational investigation and implications for urinary bladder function.

The detrusor, a key component of the urinary bladder wall, is a densely innervated syncytial smooth muscle tissue. Random spontaneous release of neurotransmitter at neuromuscular junctions (NMJs) in the detrusor gives rise to spontaneous excitatory junction potentials (SEJPs). These sub-threshold passive signals not only offer insights into the syncytial nature of the tissue, their spatio-temporal integration is critical to the generation of spontaneous neurogenic action potentials which lead to focal contractions during the filling phase of the bladder. Given the structural complexity and the contractile nature of the tissue, electrophysiological investigations on spatio-temporal integration of SEJPs in the detrusor are technically challenging. Here we report a biophysically constrained computational model of a detrusor syncytium overlaid with spatially distributed innervation, using which we explored salient features of the integration of SEJPs in the tissue and the key factors that contribute to this integration. We validated our model against experimental data, ascertaining that observations were congruent with theoretical predictions. With the help of comparative studies, we propose that the amplitude of the spatio-temporally integrated SEJP is most sensitive to the inter-cellular coupling strength in the detrusor, while frequency of observed events depends more strongly on innervation density. An experimentally testable prediction arising from our study is that spontaneous release frequency of neurotransmitter may be implicated in the generation of detrusor overactivity. Set against histological observations, we also conjecture possible changes in the electrical activity of the detrusor during pathology involving patchy denervation. Our model thus provides a physiologically realistic, heuristic framework to investigate the spread and integration of passive potentials in an innervated syncytial tissue under normal conditions and in pathophysiology.

Cellular Environment in a Bundle Modulates SEJP Characteristics in Detrusor Smooth Muscle.

Smooth muscle that ensheathes the urinary bladder wall is known as the detrusor. The detrusor has a bundled syncytial architecture where groups of electrically coupled cells form discrete bundles. Electrical activity recorded from detrusor cells is varied. Among the electrical signals recorded from the detrusor, spontaneous excitatory junction potentials (SEJPs) are events that are sub-threshold for spike generation. SEJPs are caused by spontaneous random release of neurotransmitter molecules from varicosities of innervating nerves. SEJPs recorded from different cells of the detrusor vary in amplitude and/or kinetics, and the reasons for variability are obscure. Our hypothesis was that variety in SEJP characteristics may be attributed to the biophysical micro-environment of a cell (in a bundle), where it arises. With the help of computational models, we show how cellular environment factor, such as size of a bundle significantly alters the amplitude as well as kinetics of SEJPs. These findings are congruent with experimental observations. Our results also suggest that characteristically different SEJPs may be observed in identical detrusor cells, with the difference arising from their neighbourhood rather than the inherent nature of the cells. Consequently, SEJP characteristics might be indicative of the cellular environment of electrophysiological recording.

Spatiotemporal dynamics of synaptic drive in urinary bladder syncytium: A computational investigation.

The urinary bladder wall is composed of the detrusor smooth muscle (DSM) in which adjacent cells are electrically coupled to form a three dimensional syncytium. The structural complexity of the tissue is further enhanced by a distributed innervation pattern. Experimental techniques employed in order to analyze detrusor excitability have been unable as yet to provide a satisfactory understanding of either the normal electrical functioning of the tissue, or of the changes that come about in pathological conditions. Our work aims at exploring the interplay between factors that determines the spread of junction potentials in the tissue which is critical for generation of action potential and subsequent contraction of the bladder wall. Results from our model suggest that in the detrusor syncytium, the mean interval between subsequent spontaneous neurotransmitter releases at a single varicosity is about 91.5 seconds such that in the normally functioning tissue, spontaneous transient depolarizations (STDs) occur with a mean interval of 2-7 seconds. Increase in neurotransmitter release frequency might result in higher excitability of the tissue, leading to bladder instability. Results also indicate that increase in intercellular coupling is another probable cause for such a pathophysiological scenario.