Loss of Recurrent Excitation Disrupts Sleep Slow Oscillations in the Aging Brain

Abstract

AbstractSleep-dependent memory consolidation relies on slow oscillations (SOs) that coordinate thalamocortical-hippocampal dynamics during slow-wave sleep (SWS). Aging disrupts SO properties, reducing SO amplitude, density, and slope, yet the circuit-level mechanisms linking structural brain changes to these disruptions remain poorly understood. Here we present a multi-scale, whole-brain thalamocortical network model incorporating biologically grounded human connectivity derived from diffusion MRI tractography, comprising over 10,000 cortical columns per hemisphere with spiking pyramidal and inhibitory neurons and an anatomically differentiated thalamic network. Simulating progressive synaptic loss, we find that selective degradation of recurrent excitatory connectivity, but not excitatory-inhibitory projections, reproduces empirically observed age-related SO changes. Increased SO duration was driven primarily by prolonged Down states, while Up state duration and spike density were reduced, suggesting a possible mechanism for impaired memory consolidation. These results suggest that aging selectively disrupts the temporal structure of SWS critical for interference-free memory consolidation, providing mechanistic insight into cognitive decline in the aging brain. Supported by: NIH (grants 1R01MH125557, 1RF1NS132913, 1R01AG099626 to MB)