(851) Molecular Mechanisms of Thalamic Injury in Pediatric Cardiac Arrest

Introduction: The Thalamic Reticular Nucleus (TRN) contains inhibitory neurons which regulate arousal, attention, sensorimotor integration and sleep. TRN neurons selectively degenerate after cardiac arrest and resuscitation in humans and in animal models. Since TRN plays a key role in arousal and cognition, TRN injury may contribute to severe neurologic deficits onserved in cardiac arrest survivors. The molecular mechanisms underlying selective vulnerability of TRN neurons, however, are unknown. In this study, we use spatial transcriptomics in a rat model of pediatric asphyxial cardiac arrest and resuscitation to characterize molecular pathways involved in TRN injury.

Methods: Rats underwent either 11-min of cardiac arrest followed by resuscitation or a sham intervention. Brains were collected 5 hours after resuscitation. Spatial transcriptomics was performed using 10x Genomics Visium platform. TRN neurons were classified as a distinct cluster using principal component analysis. Differentially expressed gene (DEG) identification, Gene Ontology, and pathway networks in TRN were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the Gene Ontology Consortium database.

Results: Spatial gene expression profiling clearly identified TRN neurons as a distinct cluster among thalamic and hippocampal neurons. Out of 7,038 genes with measured expression in the TRN, 303 were differrentially expressed between sham and resuscitated rats. There were 29 pathways significantly affected by cardiac arrest and resuscitation in TRN neurons. We also identified 96 gene upstream regulators and 289 potential chemical upstream regulators as significantly enriched among TRN neurons. Pathway network analysis identified potential targets in lipid and atherosclerosis, cytokine-cytokine receptor interaction, MAPK signaling and gap junction pathways.

Conclusions: We identified the key genes and pathways regulated in TRN neurons after pediatric asphyxial cardiac arrest and resuscitation. These data will help guide development of mechanism-based interventions to protect TRN neurons from injury after resuscitation in order to improve arousal and attention in cardiac arrest survivors.