General anesthesia is typically considered to be a rapidly and completely reversible state. The demonstration of anesthetic preconditioning against ischemia makes it clear, however, that anesthetic agents can alter molecular and synaptic events in the central nervous system for days. Along similar lines, our research shows that in rodents general anesthesia produces enduring cognitive impairment, with the old recovering more slowly. The mechanisms of this post-anesthetic cognitive dysfunction are unclear but evidence points to lasting changes in processes involved in synaptic plasticity. We have evidence that the volatile anesthetic isoflurane produces profound and persistent down-regulation of drebrin, an F-actin binding protein involved in formation of dendritic spines and excitatory synapses, loss of dendritic spines, and reduced neuronal release of tPA, an enzyme that regulates synthesis of the neurotrophin BDNF, implying that isoflurane interferes with neurotrophic support and synaptogenesis. Moreover, isoflurane decreases proliferation of neural progenitors both in vitro and in vivo, possibly leading to reduced cellular plasticity in the mature brain. Accordingly, using in vitro models of cultured mature and immature neurons and hippocampal slices from young and old animals, as well as a behaviorally well-characterized in vivo model, we propose to systematically examine anesthetic effects on dendritic spine morphogenesis, synaptogenesis, and neurogenesis to test the hypotheses that isoflurane but not propofol 1. causes sustained disruption of mechanisms underlying spine and synapse formation;and 2. reduces the capacity for synaptic and cellular remodeling, particularly in the aged brain. There has been little attention to these aspects of anesthetic action previously and elucidating how general anesthetics interfere acutely and persistently with morphological and functional indices of synaptic communication may provide a morphological / molecular basis for their lingering short- and long-term effects on brain function. This proposal is a logical extension of our previous efforts and, by improving understanding of the impact of general anesthetics on the aged brain, may eventually help improve cognitive outcomes after surgery and general anesthesia in elders, the group most vulnerable to postoperative cognitive morbidity.

Public Health Relevance

These studies are designed to investigate the cause of persistent neuroplastic and cognitive changes in the aged brain following general anesthesia. This work may help to prevent or treat postoperative cognitive dysfunction in the aged.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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Brigham and Women's Hospital
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Culley, Deborah J; Fahy, Brenda G; Xie, Zhongcong et al. (2014) Academic productivity of directors of ACGME-accredited residency programs in surgery and anesthesiology. Anesth Analg 118:200-5
Tao, Guorong; Zhang, Jie; Zhang, Lei et al. (2014) Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3? activation in young mice. Anesthesiology 121:510-27
Crosby, Gregory; Davis, Peter J (2013) General anesthesia in infancy is associated with learning disabilities-or not. Anesth Analg 117:1270-2
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Culley, D J; Cotran, E K; Karlsson, E et al. (2013) Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro. Br J Anaesth 110 Suppl 1:i19-28
Crosby, Gregory; Culley, Deborah J (2011) Surgery and anesthesia: healing the body but harming the brain? Anesth Analg 112:999-1001
Palanisamy, Arvind; Baxter, Mark G; Keel, Pamela K et al. (2011) Rats exposed to isoflurane in utero during early gestation are behaviorally abnormal as adults. Anesthesiology 114:521-8
Crosby, Gregory; Culley, Deborah J; Hyman, Bradley T (2011) Preoperative cognitive assessment of the elderly surgical patient: a call for action. Anesthesiology 114:1265-8
Culley, Deborah J; Boyd, Justin D; Palanisamy, Arvind et al. (2011) Isoflurane decreases self-renewal capacity of rat cultured neural stem cells. Anesthesiology 115:754-63
Crosby, Gregory; Culley, Deborah J; Marcantonio, Edward R (2010) Delirium: a cognitive cost of the comfort of procedural sedation in elderly patients? Mayo Clin Proc 85:12-4

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