Research ReportEffects of isoflurane or propofol on postnatal hippocampal neurogenesis in young and aged rats
Introduction
A rising number of clinical studies suggest that anesthesia and surgery could be risk factors for later cognitive impairment, especially in the young (Johnson et al., 2002, Loepke and Soriano, 2008, Sun, 2010) and aged brain (Abildstrom et al., 2000, Moller et al., 1998, Canet et al., 2003, Monk et al., 2008). Moreover, recent in vitro (Liang et al., 2008, Xie et al., 2007, Xie and Xu, 2012) and in vivo (Popic et al., 2012, Yu et al., 2013; Zhao et al., 2010) studies suggest an anesthetic-induced neurotoxic effect on both of these age groups (Culley et al., 2007). However, it remains unclear whether these cognitive changes are due to the effects of surgery or anesthesia.
Postnatal generation of neurons occurs throughout life in two brain regions (Altman and Das, 1965, Kempermann and Gage, 2000), the subventricular zone of the lateral ventricle, where it has been suggested that neurons migrate into the olfactory bulb and are involved in olfactory memory (Pignatelli and Belluzzi, 2010, Sultan et al., 2010); and the subgranular zone of the dentate gyrus (DG) of the hippocampus where neurons appear to be involved in spatial learning and memory (Dupret et al., 2008, Kempermann, 2002). Generation of new neurons in the DG has been shown of key importance to hippocampal function, and has been shown to be involved in spatial memory (Broadbent et al., 2004, Moscovitch et al., 2005) suggesting that anesthetics may act on hippocampal neurogenesis to affect hippocampal dependent cognitive functions. Recently, there has been an increase in studies looking at the anesthetics effects on neurogenesis in vivo (Stratmann et al., 2009, Stratmann et al., 2010; Zhu et al., 2010) and in vitro (Culley et al., 2011, Sall et al., 2009, Zhao et al., 2013), but results differ from each other mainly because of anesthetic agent, dose, and age group being studied. Consequently, it is critical to gain more insight on the effects of anesthetics on hippocampal neurogenesis.
A time line of neuronal precursor maturation in the DG has been suggested by Ming and Song (2005), while details regarding this differentiation and maturation remain to be resolved, the timing of differentiation and maturation, based on developmental markers, appears to be consistent (Bonaguidi et al., 2012, Ming and Song, 2005). Postnatal hippocampal neurogenesis is a multistep process that involves proliferation of neural progenitor cells, followed by the differentiation to a neuronal phenotype, migration during the late phase of differentiation, neuronal maturation and synaptic integration of the these cells into the existing hippocampal circuitry (Ming and Song, 2005, Piatti et al., 2006). These developmental stages can be identified by cell morphology and the expression of developmentally regulated markers (Kempermann et al., 2004, Ming and Song, 2005). Some nascent cells also differentiate into astrocytes that populate the DG (Palmer et al., 2000), and stimuli that affect postnatal neurogenesis also affect gliogenesis (Kempermann et al., 2002).
Based on the suggested timeline of neuronal precursor development in the DG (Ming and Song, 2005); in the present study, we investigated the effects of two commonly used anesthetics, the inhaled anesthetic isoflurane and the intravenous anesthetic propofol, on nascent cells undergoing proliferation, early (4-day-old cells), late (8-day-old cells) differentiation, and maturation (21-day-old cells) in the DG of young (3 mo) and aged (21 mo) rats at the time of exposure to anesthesia. Anesthetic-induced alteration of any stage of postnatal hippocampal neurogenesis may, in part explain, the resulting cognitive impairment surgery and anesthesia.
Section snippets
Results
The results of these experiments are presented in Table 1 (isoflurane) and Table 2 (propofol). Young animals had a statistically greater amount of cell proliferation in the DG than aged animals (F3,7=8.57, p<0.0001 and F3,7=28.93, p<0.0001 for isoflurane and propofol, respectively). Similarly, we found a decrease in the number of nascent cells undergoing early differentiation (F2,11=16.61, p<0.0001 and F2,11=59.75, p<0.0001 for isoflurane and propofol, respectively), late differentiation (F7,11
Discussion
The experiments reported here showed an agent and age dependent effect of isoflurane and propofol on nascent cells in the DG of young and aged rats. Specifically, isoflurane decreased the number of maturing neurons in the DG born 21 days prior to anesthesia exposure in aged, but not young, rats, while propofol decreased the number of differentiating neurons in the DG born 4 and 8 days prior to anesthesia exposure in young, but not aged, rats (see Fig. 4). We also confirmed previously published
Animals
Young (3 month-old) and aged (20 month-old) Male Fisher 344 (F344) rats (Harlan, Indianapolis, IN) were used in this study. Rats were pair-housed in environmentally controlled conditions (12:12 h light: dark cycle at 21±1 °C) and provided food and water ad lib. This study was conducted in accordance with the National Institute of Health Guide and Use of Laboratory Animals, and was approved by the Institutional Animal Care and Use committee of the University of South Florida, College of Medicine.
Experimental design
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Current affiliation: University of Miami, USA.