The long-term goal of the PI is develop into an academic anesthesiologist with an independent research program focused on anesthetics and neural development. This proposal outlines a career development plan that includes didactic and laboratory based instruction in neural development and stem cell biology. During its course the PI will obtain several new skills necessary to compete for independent funding in this field in the future. The research and didactic program will be carried out at the University of California, San Francisco in the department of Anesthesia and Perioperative Care, one of the top departments in this field. All general anesthetics act in part at GABA or NMDA receptors and recent research has identified an important role for GABA and NMDA mediated signals in growth and differentiation of neural progenitor cells (NPCs). Therefore, volatile anesthetics acting at these known and other unknown sites may alter proliferation, differentiation and survival of NPCs with implications for long-term effects on CNS function. Neurogenesis in the hippocampal dentate gyrus is necessary for certain types of learning and memory. Our preliminary data show isoflurane decreases proliferation of NPCs both in vitro and in vivo and in rodents and we have observed a hippocampal cognitive deficit 3 weeks to 8 months after isoflurane exposure. We propose that long-term hippocampal-based cognitive deficits following anesthesia are a consequence of anesthetic induced changes in hippocampal NPCs. We will test the hypothesis that anesthetics induce cell cycle exit and premature differentiation in NPCs.
Aim 1 will focus on mechanisms of anesthetic action on NPCs in vitro.
Aim 2 will investigate changes in the cyto-architecture of the hippocampal dentate gyrus after anesthetic exposure in vivo. Together these aims will begin to define the effect of anesthetics on hippocampal development.

Public Health Relevance

Recent identification of long-term cognitive deficits following general anesthesia in neonatal animals has caused significant concern for clinical practice. This proposal seeks to understand how anesthetics alter neural development and neural precursors in the hippocampus. )

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM086511-03
Application #
8212430
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2010-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$119,610
Indirect Cost
$8,860
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lee, Bradley H; Hazarika, Obhi D; Quitoriano, Gabe R et al. (2014) Effect of combining anesthetics in neonates on long-term cognitive function. Int J Dev Neurosci 37:87-93
Lee, Bradley H; Chan, John Thomas; Hazarika, Obhi et al. (2014) Early exposure to volatile anesthetics impairs long-term associative learning and recognition memory. PLoS One 9:e105340
Stratmann, Greg; Lee, Joshua; Sall, Jeffrey W et al. (2014) Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology 39:2275-87
Lee, Bradley H; Chan, John Thomas; Kraeva, Ekaterina et al. (2014) Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females. Neuropharmacology 83:9-17
Ramage, T M; Chang, F L; Shih, J et al. (2013) Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats. Br J Anaesth 110 Suppl 1:i39-46
Dubowitz, G; Breyer, K; Lipnick, M et al. (2013) Accuracy of the Lifebox pulse oximeter during hypoxia in healthy volunteers. Anaesthesia 68:1220-3
Sall, Jeffrey W; Leong, Jason (2013) Technical communication: stability of propofol in polystyrene-based tissue culture plates. Anesth Analg 117:65-7
Feiner, John R; Rollins, Mark D; Sall, Jeffrey W et al. (2013) Accuracy of Carboxyhemoglobin Detection by Pulse CO-Oximetry During Hypoxemia. Anesth Analg :
Lin, Nan; Moon, Tiffany S; Stratmann, Greg et al. (2013) Biphasic change of progenitor proliferation in dentate gyrus after single dose of isoflurane in young adult rats. J Neurosurg Anesthesiol 25:306-10