Sepsis-Induced Changes in Spectral Segregation and Kinetics of Hippocampal Oscillatory States in Rats

Abstract

Sepsis-associated encephalopathy (SAE) is a frequent severe complication of sepsis and the systemic inflammatory response syndrome, associated with high mortality and long-term neurological consequences in surviving patients. One of the main clinical signs of SAE are discontinuous sleep periods that are fragmented by frequent awakenings. Even though this brain state fragmentation strongly impacts the functionality of the nervous- and other systems, its underlying network mechanisms are still poorly understood. In this work, we therefore aim to characterize the properties and dynamics of brain oscillatory states in response to SAE in an acute rat model of sepsis induced by high dose LPS (10 mg/kg). To focus on intrinsically generated brain state dynamics, we used a urethane model that spares oscillatory activity in REM- and NREM-like sleep states. Intraperitoneal LPS injection led to a robust instability of both oscillatory states resulting in several folds more state transitions. We identified opposing shifts in low frequency oscillations (1-9 Hz) in REM and NREM-like states under influence of LPS. This resulted in increased similarity between both states. Moreover, the state-space jitter in both states increased as well, pointing to higher within-state instability. The reduction of inter-state spectral distances in 2-D state space, combined with increased within-state jitter might represent a key factor in changing the energy landscape of brain oscillatory state attractors, and hence lead to altered sleep architecture. Their emergence during sepsis might point to a mechanism underlying severe sleep fragmentation as described both in sepsis patients and SAE animal models.Significance statementSepsis-associated encephalopathy is a severe complication of sepsis that leads to sleep and cognitive issues in sepsis survivors. Electrophysiological changes in brain activity may serve as early biomarkers of SAE, but also affect subsequent outcomes. Here, we investigated hippocampal oscillatory activity in an LPS-mediated rat model of sepsis under urethane anaesthesia, with a focus on state transition dynamics. We observed increased similarity between REM-like and NREM-like states and reduced within-state stability, as a possible cause of sepsis-related sleep fragmentation. Inability to maintain stable vigilance states not only disrupts sleep and its restorative functions, but may also directly affect cognitive functions.