Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain

TY - JOUR

T1 - Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain

AU - Broad, Kevin D

AU - Kawano, Go

AU - Fierens, Igor

AU - Rocha-Ferreira, Eridan

AU - Hristova, Mariya

AU - Ezzati, Mojgan

AU - Rostami, Jamshid

AU - Alonso-Alconada, Daniel

AU - Chaban, Badr

AU - Hassell, Jane

AU - Fleiss, Bobbi

AU - Gressens, Pierre

AU - Sanders, Robert D

AU - Robertson, Nicola J

PY - 2017/3/29

Y1 - 2017/3/29

N2 - In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia.

AB - In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia.

KW - Aldosterone

KW - Anesthesia, General

KW - Anesthetics, Inhalation

KW - Animals

KW - Animals, Newborn

KW - B-Lymphocytes

KW - Cell Death

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Developmental

KW - Gyrus Cinguli

KW - Hernia, Inguinal

KW - Herniorrhaphy

KW - Isoflurane

KW - Male

KW - Mitogen-Activated Protein Kinase 7

KW - Nerve Net

KW - Nitric Oxide Synthase Type III

KW - Receptors, GABA-A

KW - Sequence Analysis, RNA

KW - Signal Transduction

KW - Swine

KW - Thrombin

KW - Journal Article

U2 - 10.1371/journal.pone.0173413

DO - 10.1371/journal.pone.0173413

M3 - Article

C2 - 28355229

SN - 1932-6203

VL - 12

JO - PLoS ONE

JF - PLoS ONE

IS - 3

M1 - e0173413

ER -