Biophysical mechanisms of default mode network function and dysfunction.

Area of Science:

• Neuroscience
• Computational Neuroscience
• Systems Neuroscience

Background:

• The default mode network (DMN) is crucial for internal cognition but its suppression by external stimuli is poorly understood at the cellular level.
• Disruptions in the DMN are linked to various brain disorders, often associated with imbalances in neuronal excitation and inhibition.

Purpose of the Study:

• To elucidate the cellular mechanisms underlying DMN suppression by salient stimuli.
• To investigate how disruptions in neuronal excitatory-inhibitory balance affect DMN function and robustness.
• To model the link between cellular-level alterations and large-scale network dynamics in the brain.

Main Methods:

• Whole-brain computational modeling incorporating neuronal biophysics.
• Integration of retrograde tracer-derived directional mouse brain connectomics.
• Systematic brain-wide analysis and parameter space exploration of network dynamics.

Main Results:

• Insula stimulation effectively suppresses DMN activity, while cingulate cortex stimulation shows antagonistic effects.
• DMN integrity is robust across a wide range of excitatory-inhibitory balance and cholinergic modulation.
• Distinct failure modes of DMN function were identified, including loss of responsiveness and network fragmentation, with specific brain hubs showing differential vulnerability.

Conclusions:

• The study provides a mechanistic framework linking cellular excitatory-inhibitory balance to DMN robustness and vulnerability.
• The findings highlight the insula's critical role in DMN suppression and identify specific regulatory hubs like the retrosplenial cortex as vulnerable points.
• The model offers insights into the heterogeneous patterns of DMN dysfunction observed in brain disorders and suggests potential therapeutic targets.