Disturbance of Neuronal Homeostasis and Disruption of Neuronal Network Dynamics Caused by Tau Proteinopathy

Background and Research Objectives

Homeostatic mechanisms play a crucial role in maintaining the stability of brain functions. Under normal circumstances, neuronal activity set-points, such as firing rates, are dynamically adjusted through homeostatic mechanisms to accommodate disruptions caused by processes like learning and development. However, neurodegenerative diseases (NDDs) may disrupt these set-points, leading to declines in cognitive and behavioral functions. Tau proteinopathy, a major neurodegenerative disease, forms abnormal Tau protein aggregates in the brain, resulting in loss of neuronal function. The main manifestations of Tau proteinopathy include the phosphorylation accumulation of Tau proteins and degradation of neuronal network structure. Studies suggest that the disruption of neuronal network levels in Tau proteinopathy might be the root cause of cognitive function decline.

This study, led by James N. McGregor and others from Washington University in St. Louis and published in the journal Neuron, aims to systematically investigate the impact of Tau proteinopathy on neuronal homeostatic set-points, particularly changes in network level dynamics, such as criticality. Researchers tracked the hippocampal neuronal activity of a Tau proteinopathy mouse model to determine how Tau proteinopathy disrupts network dynamics, thereby revealing the dynamic mechanism of cognitive decline caused by Tau proteinopathy.

Research Methods

Study Design

This study used a P301S/E4 (TE4) mouse model, which overexpresses the human Tau protein gene with a P301S mutation in the hippocampus. By recording hippocampal neuronal unit activity continuously over a long period (over 500 days), the research team conducted a multi-angle evaluation of different homeostatic set-points in neuronal activity, focusing on firing rates, pairwise correlations among neurons, and network-level criticality.

During the study, the team conducted various experiments on the mice, including analyses of neuronal activity in different sleep-wake states, tracking changes in homeostatic set-points across different cell types, and dynamic analyses of neuron interactions associated with Tau proteinopathy. Additionally, researchers used the Extreme Gradient Boosting (XGBoost) model to classify and analyze data to identify whether various dynamic characteristics could distinguish the genotype of the mice, revealing differences in neuronal activity patterns induced by neurodegenerative diseases.

Major Experimental Steps

1. Analysis of Homeostatic Set-points of Single Neuron Firing Rates: Recorded and analyzed the firing rates of single neurons to investigate whether Tau proteinopathy affects the firing set-point of individual neurons.

2. Pairwise Correlation Analysis: Calculated pairwise correlations within short time windows (30 minutes) to explore the influence of Tau proteinopathy on the strength of local network interactions.

3. Network Criticality Analysis: The research team assessed network criticality by observing neuronal avalanche behavior and size-duration power-law distributions of neuronal activities. By quantifying deviations from the criticality coefficient (Deviation from Criticality Coefficient, DCC), the study explored changes in the homeostatic set-points at the network level.

Statistical Analysis

To validate the reliability of the results, the research team employed statistical methods such as hierarchical bootstrap tests and mixed-effects models. Through these analyses, researchers gained deeper insights into how Tau proteinopathy affects the stability of neuronal activity and the dynamic characteristics of neural networks.

Research Results

Results at the Single Neuron Level

The study did not detect significant effects of Tau proteinopathy on single-neuron firing rates and spike-time variance. Even in the late stages of the disease, the impact of Tau proteinopathy on firing rates and spike timing remained minimal, indicating strong robustness of the homeostatic set-points of neuronal activity at the single-neuron level.

Dynamic Disruption at the Network Level

In contrast to single-neuron activity, the impact of Tau proteinopathy at the network level was particularly significant. The study found that as Tau proteinopathy progressed, the network’s criticality deviated significantly from the ideal state. Especially during the late stages of the disease, TE4 mice exhibited severe disruptions in criticality, with network activities gradually deviating from the critical point. This deviation not only manifested differences in behavioral states (such as sleep or wakefulness) but also showed significant correlations with anatomical and pathological characteristics of the disease, such as hippocampal atrophy and Tau protein deposition.

Correlation of Behavioral State and Dynamic Characteristics

The research team further explored the impact of Tau proteinopathy on neuronal activity during different sleep-wake states. The experiments showed that in the awake state, the deviation in criticality was more pronounced in TE4 mice, while the influence of Tau proteinopathy was relatively minor during sleep. This result suggests that sleep may have a restorative effect on network activities, but in the late stages of Tau proteinopathy, this restorative effect may not be sufficient to fully counteract the destructive impact of the disease.

Significance and Conclusion

This study reveals the dynamic disruption of neuronal network levels caused by Tau proteinopathy, especially the deviation of criticality set-points. Despite the strong stability of single-neuron activity, homeostatic set-points at the network level exhibit significant dynamic disturbances in Tau proteinopathy. The study suggests that criticality might be a major affected node in neurodegenerative diseases and provides potential support for using criticality as a biomarker.

Moreover, the dynamic changes of Tau proteinopathy in different behavioral states offer new perspectives for understanding the role of sleep in neurodegenerative diseases. The results suggest that sleep may have a positive effect on maintaining network criticality, thus exploring specific mechanisms through which sleep sustains criticality could aid in developing potential therapeutic interventions.

Highlights of the Study

• Consistency of Criticality Disruption with Tau Proteinopathy Progression: The study systematically demonstrates the disruption of network level criticality by Tau proteinopathy for the first time, indicating that deviation of criticality may be an early dynamic feature of neurodegenerative diseases.
• Robustness of Single-Neuron Activity: Although the homeostatic set-points at the network level deviate significantly, the set-points at the single-neuron level remain stable during the progression of Tau proteinopathy.
• Protective Role of Sleep: The results indicate that the sleep state may play a significant role in restoring network criticality, although this effect diminishes in the late stages of the disease, providing new ideas for future exploration of sleep interventions.

Summary

By revealing the effects of Tau proteinopathy on neuronal network homeostatic set-points, this study expands our understanding of the mechanisms underlying neurodegenerative diseases. The findings demonstrate that while Tau proteinopathy has little impact on single-neuron activity, its disruption of network dynamics, particularly criticality, is highly significant. Deviation in criticality serves as a marker of disease progression, offering a potential tool for early detection and diagnosis. Meanwhile, the potential significance of sleep in maintaining network homeostasis highlights a new direction for exploring treatments for neurodegenerative diseases.