Myelin dystrophy impairs signal transmission and working memory in a multiscale model of the aging prefrontal cortex
Ibañez, Sara (Universitat Autònoma de Barcelona. Departament de Matemàtiques)
Sengupta, Nilapratim (Boston University Chobanian & Avedisian School of Medicine)
Luebke, Jennifer I (Boston University Chobanian & Avedisian School of Medicine)
Wimmer, Klaus (Universitat Autònoma de Barcelona. Departament de Matemàtiques)
Weaver, Christina M (Franklin and Marshall College)

Date:	2024
Abstract:	Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of 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 empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent 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 ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.
Grants:	Agencia Estatal de Investigación PCI2020-112035 Agencia Estatal de Investigación CEX2020-001084-M European Commission 800858
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Multicompartment model ; Bump attractor ; Myelin dystrophy ; Working memory ; Aging ; Rhesus monkey ; None
Published in:	eLife, Vol. 12 (July 2024) , art. RP90964, ISSN 2050-084X

DOI: 10.7554/eLife.90964
PMID: 39028036

29 p, 4.8 MB

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