This proposal will examine the relationship between diabetes-mediated impairments in insulin receptor (IR) signal transduction mechanisms, including insulin-stimulated protein phosphorylation and glucose transporter (GLUT) trafficking, and the development of cognitive deficits in diabetic subjects. The hippocampus is an important integration center for learning and memory in the mammalian central nervous system (CMS) and is particularly sensitive and responsive to changes in insulin concentrations. Insulin administration improves cognitive performance in a variety of physiological and pathophysiological settings, including diabetes. Conversely, decreases in IR expression and/or signaling may contribute to the development of diabetic encephalopathy, including cognitive deficits observed in type 1 subjects. Unlike the peripheral IR system, little is known about the functional role of IRs in the CMS and how the activity of the neuronal IR system may be impaired in diabetes phenotypes. In view of the emerging relationship between insulin and cognition and the importance of the hippocampus in cognition, the aims of this proposal are: 1) to establish the functional relationships of components of the IR system in the rat hippocampus, including phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase (MARK) signaling and the insulin-sensitive GLUTs; 2) to determine whether the neurological consequences of diabetes include impairments in IR expression and/or signaling; 3) to determine whether downregulation of IR expression in the rat hippocampus produces impairments in IR/PI3-K/MAPK signaling and GLUT trafficking, thereby providing a mechanistic basis for decreases in behavioral performance observed in experimental models of type 1 diabetes. Successful completion of these studies will: 1) determine the signal transduction mechanisms of the IR system in the brain; 2) provide insight into the mechanisms through which insulin enhances cognitive function in physiological settings; 3) provide a fundamental mechanistic bridge between impairments in IR expression and/or signaling and the morphological, electrophysiological and cognitive deficits associated with type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047728-03
Application #
7245901
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Mitler, Merrill
Project Start
2005-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$304,781
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Grillo, Claudia A; Piroli, Gerardo G; Lawrence, Robert C et al. (2015) Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity. Diabetes 64:3927-36
Reagan, Lawrence P (2012) Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications. Exp Neurol 233:68-78
Grillo, Claudia A; Piroli, Gerardo G; Kaigler, Kris F et al. (2011) Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats. Behav Brain Res 222:230-5
Tamashiro, K L; Sakai, R R; Shively, C A et al. (2011) Chronic stress, metabolism, and metabolic syndrome. Stress 14:468-74
Grillo, Claudia A; Piroli, Gerardo G; Evans, Ashlie N et al. (2011) Obesity/hyperleptinemic phenotype adversely affects hippocampal plasticity: effects of dietary restriction. Physiol Behav 104:235-41
Grillo, Claudia A; Piroli, Gerardo G; Junor, Lorain et al. (2011) Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus. Physiol Behav 105:138-44
Grillo, C A; Piroli, G G; Hendry, R M et al. (2009) Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res 1296:35-45
Wrighten, Shayna A; Piroli, Gerardo G; Grillo, Claudia A et al. (2009) A look inside the diabetic brain: Contributors to diabetes-induced brain aging. Biochim Biophys Acta 1792:444-53
Reagan, Lawrence P; Grillo, Claudia A; Piroli, Gerado G (2008) The As and Ds of stress: metabolic, morphological and behavioral consequences. Eur J Pharmacol 585:64-75
Reagan, Lawrence P (2007) Insulin signaling effects on memory and mood. Curr Opin Pharmacol 7:633-7

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