? """"""""Healthy"""""""" aging is associated with widespread changes in the CNS that include alterations in neurotransmitter systems, synaptic plasticity, and hippocampal neurogenesis. These changes make the aged brain more """"""""fragile"""""""" and may account for development of age-related cognitive dysfunction. Elderly patients frequently require surgery and anesthesia but may suffer prolonged cognitive impairment as a result. However, the mechanisms involved are unknown and the role of anesthetic agents is unclear. Using a well-established behavioral model, we have demonstrated that an uncomplicated general anesthetic with isoflurane-nitrous oxide produces long-lasting impairment in memory for an established spatial task in aged rats and isoflurane alone disrupts the ability of young and old rats to learn a new task. Moreover, these changes are associated with reduced phosphorylation of a nuclear protein involved in memory, a decrease in a dendritic marker of synaptic plasticity, and an increase in neurogenesis in young adult rats but no change or a decrease in aged rats. This suggests that general anesthesia could be a factor in human postoperative cognitive dysfunction and that anesthetic-induced changes in memory processing may explain the impairment. The objectives of this proposal are to characterize the mechanisms of anesthesia-related cognitive impairment and to define the neurobiological basis of it. We will use selective anesthetic and non-anesthetic agents to manipulate GABA and glutaminergic tone, in conjunction with behavioral testing and neurochemistry, to systematically investigate the relationship between prolonged post-anesthetic changes in spatial memory and alterations in cholinergic neurotransmission, synaptic plasticity, and neurogenesis. From this analysis, we expect to be able to draw inferences about whether post-anesthetic impairment is a function of the receptor characteristics of the agents, an imbalance between excitatory and inhibitory neurotransmission, or the state of anesthesia. We will investigate mechanisms of prolonged post-anesthetic learning impairment by examining relationships between anesthetic pharmacology, age, and mediators or makers of learning and memory. As such, these experiments will clarify how general anesthesia produces persistent cognitive impairment in aging, enhance understanding of anesthetic effects on memory, and potentially lead to methods to mitigate the cognitive morbidity associated with anesthesia and surgery. ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Wagster, Molly V
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Brigham and Women's Hospital
United States
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Palanisamy, Arvind; Crosby, Gregory; Culley, Deborah J (2017) EARLY gestational exposure to isoflurane causes persistent cell loss in the dentate gyrus of adult male rats. Behav Brain Funct 13:14
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Zhang, Guohua; Dong, Yuanlin; Zhang, Bin et al. (2008) Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci 28:4551-60
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Baxter, Mark G; Murphy, Kathy L; Crosby, Gregory et al. (2008) Different behavioral effects of neurotoxic dorsal hippocampal lesions placed under either isoflurane or propofol anesthesia. Hippocampus 18:245-50
Culley, Deborah J; Xie, Zhongcong; Crosby, Gregory (2007) General anesthetic-induced neurotoxicity: an emerging problem for the young and old? Curr Opin Anaesthesiol 20:408-13
Xie, Zhongcong; Dong, Yuanlin; Maeda, Uta et al. (2007) The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci 27:1247-54
Culley, Deborah J; Raghavan, Sumati V; Waly, Mostafa et al. (2007) Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg 105:83-8

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