Muscle Injury Induces Postoperative Cognitive Dysfunction

Lorna Guéniot,Victoria Lepere,Patricia Flamant,Pierre L Goossens,Fabrice Chrétien,Marine Le Dudal,Olivier Langeron,Gabriela Ferreira De Medeiros,Anne Danckaert,Grégory Jouvion

doi:10.1038/s41598-020-59639-3

Abstract

Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encountered in a wide range of surgeries, has not been explored in POCD occurrence. We propose a physical model of muscle injury in CX3CR1GFP/+ mice (displaying green fluorescent microglial cells) to study POCD, with morphological, behavioral and molecular approaches. We highlighted: alteration of short- and long-term memory after muscle regeneration, wide microglial reactivity in the brain, including hippocampus area, 24 hours after muscle injury, and an alteration of central brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) balance, 28 days after muscle injury. Our results suggest for the first time that muscle injury can have early as well as late impacts on the brain. Our CX3CR1GFP/+ model can also facilitate microglial investigation, more specifically their pivotal role in neuroinflammation and synaptic plasticity, in the pathophysiology of POCD.

Highlights

Postoperative cognitive dysfunction (POCD) is a well-recognized phenomenon affecting patients of any age undergoing surgical procedures[1,2]
A wide variety of surgeries may lead to POCD, but the type of surgery and anesthesia does not appear to influence its incidence in non-cardiac surgeries[10]
Translational research is trying to decipher the underlying mechanisms leading to cognitive dysfunction after surgery (POCD), progressively incriminating tissue destruction as a triggering factor

Summary

Introduction

Postoperative cognitive dysfunction (POCD) is a well-recognized phenomenon affecting patients of any age undergoing surgical procedures[1,2]. Murine tibial fracture is one of the most widely used animal model to mimic POCD15,21,22 It combines sufficient tissue destruction and chronic pain to allow neurologic impairments even www.nature.com/scientificreports in young adult mice, while other models of surgery-induced cognitive decline - such as splenectomy[23] and laparotomy24,25 - need to be executed in more susceptible mice (older or females). Our aim was to propose a less traumatic murine model of POCD with a faster recovery period after surgical procedure It allowed observation of cognitive impairment while histological and functional recovery of limb was complete, even in young adult male mice. Early morphological reactivity of microglia, late cognitive function and brain neurotrophic levels were precisely assessed after muscle surgery

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