Persistent Memory Deficits and Histone Modification after a Systemic Inflammatory Event

Abstract

Inflammatory events, including myocardial infarction (MI), illness, or major surgery, commonly lead to cognitive deficits that persist for months or years, far beyond the duration of inflammation. The cognitive deficits correlate with poorer outcomes as well as increased morbidity and mortality. These clinical observations are paralleled in animal models of MI and inflammation. However, the mechanisms mediating such persistent effects remain unknown. Epigenetic modifications induced by cytokine signaling are one potential mechanism. In particular, dysregulation of histone acetylation can be triggered by inflammation and also induce memory deficits. We hypothesized that, although the initial cytokine signaling would be resolved within 8 weeks after MI, changes in histone modifications would persist and mediate lasting cognitive impairments.MethodsWe used a surgical model of MI in male and female mice, with sham‐operated (sham) and non‐operated (non‐op) control groups. Eight weeks after the MI group's surgery, memory was assessed using context fear conditioning (3 min exposure to context followed by a single 0.8mA, 2sec foot shock). In separate animals, hippocampus and blood serum were collected 8 weeks after MI. We used multiplex cytokine analysis to determine levels in the hippocampus. In addition, we conducted western blotting to determine persistent alterations in histone acetylation, phospho‐acetylation and methylation. Finally, we analyzed hearts from MI and sham animals to determine infarct size.Results and DiscussionEight weeks after MI surgery, both male and female mice exhibited impairments in fear conditioning compared with non‐op control animals. In addition, female ‐ but not male ‐ sham mice exhibited deficits in context fear conditioning. This suggests that female mice are more susceptible to persistent memory deficits even after a lower level inflammatory event. There were no differences in peripheral or hippocampal cytokine levels 8 wks post‐MI; therefore, the cognitive deficits were not due to ongoing inflammatory signaling. Future work will determine a causal role for dysregulated histone acetylation in the persistent memory deficits following an inflammatory event. Identifying the mechanisms underlying this process will provide novel targets for prevention and treatment of persistent cognitive deficits after MI, illness or major surgery.Support or Funding InformationThis research was supported by a National Institutes of Health grant (R00 MH093459, NCT)