title: Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain.
abstract: 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.
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Go
authors.initials: G
authors.lastname: Kawano
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Igor
authors.initials: I
authors.lastname: Fierens
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Ezzati
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Rostami
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alonso-Alconada
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Badr
authors.initials: B
authors.lastname: Chaban
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Hassell
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas Campus, London, United Kingdom.|Inserm, U1141, Paris, France.|University Paris Diderot, Sorbonne Paris Cite, UMRS 1141, Paris, France.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: Centre for the Developing Brain, Kings College, St Thomas Campus, London, United Kingdom.|Inserm, U1141, Paris, France.|University Paris Diderot, Sorbonne Paris Cite, UMRS 1141, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.affiliation: Institute for Women's Health, University College London, London, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000450:Aldosterone / Q000235:genetics / Q000378:metabolism; D000768:Anesthesia, General / Q000009:adverse effects*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006552:Hernia, Inguinal / Q000150:complications* / Q000601:surgery; D059685:Herniorrhaphy / Q000009:adverse effects*; D007530:Isoflurane / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013552:Swine; D013917:Thrombin / Q000235:genetics / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D011963:Receptors, GABA-A; D000450:Aldosterone; D007530:Isoflurane; D052250:Nitric Oxide Synthase Type III; D048054:Mitogen-Activated Protein Kinase 7; D013917:Thrombin