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October 22, 2005
2:00:00 PM - 4:00:00 PM
Hall C4
General Anesthesia and Neurogenesis in Adult Brain
Deborah J. Culley, M.D., Rustam Y. Yukhananov, M.D., Ph.D., Gregory Crosby, M.D.
Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts, United States
INTRODUCTION. General anesthesia and surgery are associated with early cognitive impairment in both young and aged patients (1). In the laboratory, we have demonstrated that general anesthesia with 1.2% isoflurane-70% nitrous oxide impairs acquisition of spatial memory subsequently (2,3), suggesting that general anesthesia has a persistent effect on memory. However, the neurobiological mechanisms of the impairment are unknown. Recent evidence indicates that the adult brain retains the capacity to make new neurons. This neurogenesis is robust but limited in adult brain to the subventricular zone and the dentate gyrus of the hippocampus, where it appears to play an important role in learning and memory (4). Thus, we hypothesized that postanesthetic learning impairment reflects altered neurogenesis during general anesthesia.

METHODS. To test this hypothesis, we investigated the effect of isoflurane-nitrous oxide anesthesia on incorporation of bromodeoxyuridine (BrdU), a thymidine analogue widely employed to study neurogenesis because it labels only those cells in the S-phase of cell division, in adult (6 mo old), male Fisher 344 rats. The studies adhered to institutional and APS/NIH guidelines for the care of animals. Rats were acclimatized to the lab for 1 week and then received 300 mg/kg BrdU intraperitoneally. Five minutes later, rats were placed in a Plexiglas box containing either 1.2% isoflurane-70% nitrous oxide-30% oxygen (N = 5) or 30% oxygen alone (N = 5). Rats breathed spontaneously and mean arterial pressure was measured intermittently by tail cuff; rectal temperature was maintained at 37 ± 0.5 oC. Animals were sacrificed 4 h later and the brain removed and frozen. Serial 12 μm frozen sections were taken through the entire hippocampus and BrdU labeled cells were detected immunohistochemically using standard procedures. BrdU+ cells were counted with a light microscope in the granular cell layer of the hippocampal dentate gyrus by a blinded observer. Counts were obtained at fixed anterior – posterior distances from 7 sections per rat. Data were analyzed with Student's t test.

RESULTS. In control rats, there were 3.2 ± 0.7 (Mean ± SD). BRDU+ cells per section in the granular cell layer of the dentate gyrus. Given that the rat hippocampus is approximately 3.5 mm in length, this calculates to nearly 1000 BRDU+ cells per dentate gyrus per rat. Anesthetized rats had 3.5 ± 0.7 in the dentate gyrus and there was no difference compared to the control group.

CONCLUSIONS. These data show that the birth of new cells in the dentate gyrus of the hippocampus of adult rats is robust and not altered during general anesthesia with isoflurane-nitrous oxide. Thus, it is unlikely that postanesthetic learning impairment is due to a lower rate of cell birth in this particular neurogenic region of the adult brain. However, this study investigated only one aspect of neurogenesis. Such newly born cells must survive and differentiate into neurons before they can participate in learning and memory, a process that takes 2-3 weeks. Therefore, we can not exclude the possibility that general anesthesia affects survival and maturation of newly born cells in the adult brain.

1. Lancet 1998; 351: 857 – 61

2. Anesthesiology 2004; 100: 309 – 14

3. Anesth. Analg 2004; 99: 1393 – 7

4. Nature 2001; 410: 372 – 6

Anesthesiology 2005; 103: A124