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

Area of Science:

• Neuroscience
• Computational Biology
• Cognitive Science

Background:

• Normal aging causes myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), often linked to cognitive decline.
• The role of remyelination in compensating for myelin degradation, particularly in conjunction with ongoing degradation, remains computationally unexplored.

Approach:

• Developed a multicompartment pyramidal neuron model simulating myelinated axon segments (paranodes, juxtaparanodes, internodes, tight junctions) using dlPFC data.
• Quantified conduction velocity (CV) changes and action potential (AP) failures due to demyelination and remyelination.
• Utilized Lasso regression to identify parameters influencing axonal susceptibility to CV changes during demyelination and remyelination.
• Integrated single-neuron model results into a spiking neural network model of working memory.

Key Points:

• Complete remyelination largely restored axonal transmission and network function to baseline levels.
• Models predict that biologically plausible levels of myelin damage, without compensatory mechanisms, can explain significant age-related working memory deficits.
• Distinct parameter sets were identified that modulate an axon's susceptibility to CV changes following demyelination versus remyelination.

Conclusions:

• This computational study links empirical data from electron microscopy to behavioral outcomes in aging.
• Age-related myelin changes, particularly uncompensated myelin dystrophy, are computationally shown to be a significant cause of working memory impairment.
• Findings have implications for understanding demyelinating diseases like multiple sclerosis and schizophrenia.