Early exposure to general anesthesia impairs social and emotional development in rats
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.
KeywordsDevelopmental neurotoxicity Thigmotaxic behavior Social interactions Rodents Sex differences
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).
Compliance with Ethical Standards
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.
- 4.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 CrossRefGoogle Scholar
- 9.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 CrossRefGoogle Scholar
- 11.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 CrossRefGoogle Scholar
- 15.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 CrossRefGoogle Scholar
- 21.Johnston AL, File SE (1991) Sex differences in animal tests of anxiety. Physiol Behav 49:245-250Google Scholar
- 24.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 CrossRefGoogle Scholar
- 26.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 CrossRefGoogle Scholar
- 27.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 56:177-80Google Scholar
- 29.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 CrossRefGoogle Scholar
- 31.Jakuszkowiak-Wojten K, Landowski J, Wiglusz MS, Cubała WJ (2015) Impulsivity in anxiety disorders. A critical review. Psychiatr Danub 27(Suppl 1):S452–S455Google Scholar