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

Abstract

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.

Age-related myelin deficits in the auditory brain stem contribute to cocktail-party deficits

“…Alterations in myelination within the auditory brainstem affect the speed of electrical propagation and, consequently, the timing of auditory brainstem activity 18,20,[23][24][25] . Evidence from various studies indicates that myelination deficiencies contribute to the aging brain phenotype 26,27 , begging the question whether age-related myelination deficits might contribute to a decline in timing within the sound localization pathway, which in turn might contribute to presbycusis. Binaural hearing is known to mediate not only sound localization abilities per se but also help a listener in acoustically busy environments such as crowded restaurants where multiple sound sources are active simultaneously while a listener typically wants to focus on a single sound source such as the voice of a conversation partner.…”