Several animal and emerging human studies suggest an association between an early exposure to general anesthesia (GA) and long-lasting problems with complex social and emotional behaviors such as inattentiveness, impulsivity, anxiogenic tendencies, as well as difficulties engaging in proper social intercourse, with significant increase in attention deficit and hyperactivity-type behaviors. To further investigate these behaviors, and to examine the potential of presently available rodent behavioral models to guide future assessments of long-term socio-emotional impairments in humans, we examined the long-term effects of GA on anxiety/fear and social behaviors. We exposed male and female Sprague-Dawley infant rats at the peak of their synaptogenesis to either GA containing midazolam (9 mg/kg, i.p.), 70% nitrous oxide (N2O) and 0.75% isoflurane (Iso) administered in 29–30% oxygen (experimental), or air (with 30% oxygen) plus the vehicle, 0.1% dimethyl sulfoxide (Sham) for 6 h. Behavioral experiments were conducted at adolescence (the open-field test) and young adulthood (the open-field test, the elevated plus-maze and the social novelty test). We report that an early exposure to GA during critical stages of brain development results in long-lasting increase in risk-taking tendencies and significant changes in the anxiety-related behaviors when tested in young adult rats. In addition, we noted novelty-seeking tendencies/less guarded behavior with changes in social discrimination. We conclude that early exposure to anesthesia may have lasting influences on emotional and social development. Importantly, our results show that currently used rodent behavioral models could be a good correlate to assess long-term socio-emotional GA-induced impairments observed in humans.
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Jevtovic-todorovic V, Hartman RE, Izumi Y et al (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882
Loepke AW, Istaphanous GK, McAuliffe JJ et al (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104. https://doi.org/10.1213/ane.0b013e31818cdb29
Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA et al (2011) Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 33:220–230. https://doi.org/10.1016/j.ntt.2011.01.001
Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR et al (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110:796–804. https://doi.org/10.1097/01.anes.0000344728.34332.5d
Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL et al (2011) Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128:e1053–e1061. https://doi.org/10.1542/peds.2011-0351
Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJJ et al (2012) Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 130:e476–e485. https://doi.org/10.1542/peds.2011-3822
Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M, Imaki J (2009) Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 110:628–637. https://doi.org/10.1097/ALN.0b013e3181974fa2
Raper J, Alvarado MC, Murphy KL, Baxter MG (2015) Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthesiology 123:1084–1092. https://doi.org/10.1097/ALN.0000000000000851
DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G (2009) A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol 21:286–291. https://doi.org/10.1097/ANA.0b013e3181a71f11
Chemaly M, El-Rajab MA, Ziade FM, Naja ZM (2014) Effect of one anesthetic exposure on long-term behavioral changes in children. J Clin Anesth 26:551–556. https://doi.org/10.1016/j.jclinane.2014.03.013
Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanić K, Welch TL, Olson MD et al (2012) Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 87:120–129. https://doi.org/10.1016/j.mayocp.2011.11.008
Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci 16:33–36
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328. https://doi.org/10.1038/nprot.2007.44
van der Kooij MA, Sandi C (2012) Social memories in rodents: Methods, mechanisms and modulation by stress. Neurosci Biobehav Rev 36:1763–1772. https://doi.org/10.1016/J.NEUBIOREV.2011.10.006
Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, Piven J, Crawley JN (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3:287–302. https://doi.org/10.1111/j.1601-1848.2004.00076.x
Cavigelli SA, Michael KC, West SG, Klein LC (2011) Behavioral responses to physical vs. social novelty in male and female laboratory rats. Behav Process 88:56–59. https://doi.org/10.1016/j.beproc.2011.06.006
Bakri M, Ismail E, Ali M, Elsedfy GO, Sayed TA, Ibrahim A (2015) Behavioral and emotional effects of repeated general anesthesia in young children. Saudi J Anaesth 9:161–166. https://doi.org/10.4103/1658-354X.152843
Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504
Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. https://doi.org/10.1016/S0014-2999(03)01272-X
Blizard DA, Lippman HR, Chen JJ (1975) Sex differences in open-field behavior in the rat: the inductive and activational role of gonadal hormones. Physiol Behav 14:601–608
Johnston AL, File SE (1991) Sex differences in animal tests of anxiety. Physiol Behav 49:245-250
Hyde JF, Jerussi TP (1983) Sexual dimorphism in rats with respect to locomotor activity and circling behavior. Pharmacol Biochem Behav 18:725–729. https://doi.org/10.1016/0091-3057(83)90014-X
Russell PA (1977) Sex differences in rats’ stationary exploration as a function of stimulus and environmental novelty. Anim Learn Behav 5:297–302. https://doi.org/10.3758/BF03209243
Viola TW, Wearick-Silva LE, Creutzberg KC, Kestering-Ferreira É, Orso R, Centeno-Silva A, Albrechet-Souza L, Marshall PR et al (2018) Postnatal impoverished housing impairs adolescent risk-assessment and increases risk-taking: a sex-specific effect associated with histone epigenetic regulation of Crfr1 in the medial prefrontal cortex. Psychoneuroendocrinology 99:8–19. https://doi.org/10.1016/j.psyneuen.2018.08.032
de Vocht F, Suderman M, Tilling K, Heron J, Howe LD, Campbell R, Hickman M, Relton C (2018) DNA methylation from birth to late adolescence and development of multiple-risk behaviours. J Affect Disord 227:588–594. https://doi.org/10.1016/j.jad.2017.11.055
Dalla Massara L, Osuru HP, Oklopcic A, Milanovic D, Joksimovic SM, Caputo V, DiGruccio MR, Ori C et al (2016) General anesthesia causes epigenetic histone modulation of c-Fos and brain-derived neurotrophic factor, target genes important for neuronal development in the immature rat hippocampus. Anesthesiology 124:1311–1327. https://doi.org/10.1097/ALN.0000000000001111
Imhof JT, Coelho ZM, Schmitt ML, Morato GS, Carobrez AP. (1993) Influence of gender and age on performance of rats in the elevated plus maze apparatus. Behav Brain Res 56:177-80
Kodama M, Satoh Y, Otsubo Y, Araki Y, Yonamine R, Masui K, Kazama T (2011) Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology 115:979–991. https://doi.org/10.1097/ALN.0b013e318234228b
Xu C, Tan S, Zhang J, Seubert CN, Gravenstein N, Sumners C, Vasilopoulos T, Martynyuk AE (2015) Anesthesia with sevoflurane in neonatal rats: developmental neuroendocrine abnormalities and alleviating effects of the corticosteroid and Cl − importer antagonists HHS Public Access. Psychoneuroendocrinology 60:173–181. https://doi.org/10.1016/j.psyneuen.2015.06.016
Mejia-Toiber J, Boutros N, Markou A, Semenova S (2014) Impulsive choice and anxiety-like behavior in adult rats exposed to chronic intermittent ethanol during adolescence and adulthood. Behav Brain Res 266:19–28. https://doi.org/10.1016/J.BBR.2014.02.019
Jakuszkowiak-Wojten K, Landowski J, Wiglusz MS, Cubała WJ (2015) Impulsivity in anxiety disorders. A critical review. Psychiatr Danub 27(Suppl 1):S452–S455
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Dere E, Topic B, De Souza Silva MA et al (2002) The graded anxiety test: a novel test of murine unconditioned anxiety based on the principles of the elevated plus-maze and light-dark test. J Neurosci Methods 122:65–73
File S, Gonzalez LE, Gallant R (1999) Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety. Neuropsychopharmacology 21:312–320. https://doi.org/10.1016/S0893-133X(99)00028-7
Cruz AP, Frei F, Graeff FG (1994) Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49:171–176
Supported in part by funds from the Department of Anesthesiology at the University of Colorado Anschutz Medical campus, R0144517, R0144517-S, R01 GM118197, R01 GM118197-S, R21 HD080281, and March of Dimes National Award, USA (to VJT) and Harold Carron and CU Medicine Endowments (to VJT).
The experiments were approved by the Animal Use and Care Committee of the University of Virginia, Charlottesville, VA. Treatment of rats adhered to the NIH Guide for the Care and Use of Laboratory Animals.
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Diana, P., Joksimovic, S.M., Faisant, A. et al. Early exposure to general anesthesia impairs social and emotional development in rats. Mol Neurobiol 57, 41–50 (2020). https://doi.org/10.1007/s12035-019-01755-x
- Developmental neurotoxicity
- Thigmotaxic behavior
- Social interactions
- Sex differences