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Voluntary Exercise Rescues the Spatial Memory Deficit Associated With Early Life Isoflurane Exposure in Male Rats

Chinn, Gregory A. MD, PhD; Sasaki Russell, Jennifer M. PhD; Banh, Esther T. BS; Lee, Saehee C. BA; Sall, Jeffrey W. PhD, MD

doi: 10.1213/ANE.0000000000004418
Neuroscience and Neuroanesthesiology: Original Laboratory Research Report

BACKGROUND: Early life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia.

METHODS: Postnatal day 7 male rats (P7) underwent isoflurane (Iso) or sham exposure and were subsequently weaned at P21. They were then singly housed in a cage with a running wheel or a fixed wheel. After 3 weeks of exercise, animals underwent behavioral testing for spatial and recognition memory assessments. Animals were killed at various time points to accomplish either bromodeoxyuridine (BrdU) labeling or quantitative real-time polymerase chain reaction (qRT-PCR) to quantify brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels.

RESULTS: Postweaning voluntary exercise rescued the long-term spatial memory deficit associated with perinatal Iso exposure. Iso-sedentary animals did not discriminate the goal quadrant, spending no more time than chance during the Barnes maze probe trial (1-sample t test, P = .524) while all other groups did (1-sample t test, PIso-exercise = .033; Pcontrol [Con]-sedentary = .004). We did not find a deficit in recognition memory tasks after Iso exposure as we observed previously. BrdU incorporation in the adult hippocampus of Iso-sedentary animals was decreased compared to sedentary controls (Tukey P = .005). Exercise prevented this decrease, with Iso-exercise animals having more proliferation than Iso-sedentary (Tukey P < .001). There was no effect of exercise or Iso on BDNF mRNA in either the cortex or hippocampus (cortex: FExercise[1,32] = 0.236, P = .631; FIso [1,32] = 0.038, P = .847; FInteraction [1,32] = 1.543, P = .223; and hippocampus: FExercise[1,33] = 1.186, P = .284; FIso [1,33] = 1.46, P = .236; FInteraction[1,33] = 1.78, P = .191).

CONCLUSIONS: Exercise restores BrdU incorporation and rescues a spatial memory deficit after early life anesthesia exposure. This demonstrates sufficiency of exercise alone in the context of environmental enrichment to recover a behavioral phenotype after a perinatal insult.

From the Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California.

Published ahead of print 8 January 2019.

Accepted for publication August 1, 2019.

Funding: This work was funded in part by National Institutes of Health (NIH) RO1GM112831 (J.W.S.), NIH University of California, San Francisco-Clinical and Translational Science Institute (UCSF-CTSI) Grant TL1 TR001871 (J.M.S.R.), and NIH T32 GM08440 (G.A.C.).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Gregory A. Chinn, MD, PhD, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 513 Parnassus Ave, Box 0542, San Francisco, CA 94143. Address e-mail to

Copyright © 2019 International Anesthesia Research Society
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