Myelin Dystrophy in Aging Prefrontal Cortex Impairs Signal Transmission and Working Memory

Core Concepts

Myelin degradation and incomplete remyelination in the aging prefrontal cortex can account for substantial working memory impairment.

Abstract

This computational study investigates how age-related myelin changes in the prefrontal cortex affect action potential (AP) propagation in individual neurons and working memory performance in spiking neural networks. The key findings are: Demyelination in the single neuron model leads to slower conduction velocities and eventually AP failures, with the degree of impairment depending on the extent of myelin loss. Remyelination of previously demyelinated segments can partially recover conduction velocities and reduce AP failures, but incomplete remyelination leaves some segments bare and impairs signal transmission. In the spiking neural network model of working memory, AP failures corresponding to demyelination conditions progressively impair memory duration and precision, whereas conduction delays alone have little effect. Combining neurons with intact and perturbed myelin sheaths, to mimic the heterogeneity observed in aging brains, shows that fewer normal myelin sheaths and a higher proportion of new, shorter myelin segments are associated with decreased working memory performance. The results suggest that myelin dystrophy alone can account for substantial working memory decline with aging, and point to myelin changes as a key factor in age-related cognitive impairment. The computational framework provides a mechanistic link between empirical observations of myelin alterations and their functional consequences for neural circuit function.

Stats

Removing 75% of myelin lamellae from 25% of myelinated segments led to a 70% reduction in conduction velocity and 35% of action potentials failing. Remyelinating all previously demyelinated segments with 75% of the original myelin lamellae restored 98% of the conduction velocity delay and reduced action potential failures to 1.8%.

Quotes

"Myelin degradation begins as oligodendrocytes degenerate due to oxidative stress, and that axons accumulate dense inclusions in spaces between the lamellae of their associated myelin sheaths." "Aged subjects also had a significant proportion of abnormally short and thin myelin sheaths."

Key Insights Distilled From

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

by Ibanez,S., S... at www.biorxiv.org 09-01-2023

https://www.biorxiv.org/content/10.1101/2023.08.30.555476v2

Deeper Inquiries

How do the effects of myelin changes on working memory differ across brain regions or cognitive domains

The effects of myelin changes on working memory can vary across different brain regions and cognitive domains. Myelin alterations in the prefrontal cortex, for example, can lead to impaired signal transmission and working memory decline, as seen in the context provided. This region is crucial for executive functions, including working memory. In contrast, myelin changes in sensory or motor regions may impact sensory processing or motor coordination, respectively. The impact of myelin changes on working memory may also differ based on the specific cognitive domain being assessed. For instance, myelin alterations in the hippocampus, a region important for memory formation, could have a more pronounced effect on long-term memory compared to short-term working memory tasks. Therefore, the effects of myelin changes on working memory can be region-specific and domain-specific, highlighting the complex relationship between myelin integrity and cognitive function.

What other cellular or network-level mechanisms could compensate for the detrimental effects of myelin dystrophy on working memory

Several cellular and network-level mechanisms could potentially compensate for the detrimental effects of myelin dystrophy on working memory. One possible compensatory mechanism is synaptic plasticity, where changes in synaptic strength and connectivity could help maintain neural communication despite myelin alterations. For example, an increase in synaptic efficacy or the formation of new synapses could enhance signal transmission in the presence of compromised myelin. Additionally, neural network reorganization or recruitment of alternative pathways could help bypass areas with myelin damage, allowing for information processing to continue through alternative routes. Furthermore, changes in neurotransmitter levels or receptor sensitivity could modulate neural activity to mitigate the impact of myelin dystrophy on working memory. Overall, the brain has the capacity for plasticity and adaptation, which may enable it to compensate for myelin-related deficits and maintain cognitive function to some extent.

Could targeted remyelination therapies or other interventions to restore normal myelin structure improve cognitive function in aging or neurological conditions

Targeted remyelination therapies or interventions aimed at restoring normal myelin structure could potentially improve cognitive function in aging or neurological conditions characterized by myelin dystrophy. By promoting the repair and regeneration of damaged myelin sheaths, these therapies could enhance signal transmission efficiency, reduce AP failures, and improve neural communication within the brain. Remyelination treatments could lead to faster conduction velocities, more reliable action potential propagation, and overall better neural network function, which are essential for optimal cognitive performance. Additionally, interventions that support oligodendrocyte health and function, such as promoting oligodendrocyte survival or enhancing myelin repair mechanisms, could also contribute to cognitive improvement. Overall, restoring normal myelin structure through targeted interventions holds promise for enhancing cognitive function in individuals affected by myelin-related cognitive impairments.