Agency: National Institute of Nursing Research, $62,190, F31NR010853

Project Period: July 1, 2008 to June 30, 2010

Mentor: Irwin Lucki, PhD; Co-Mentor: Marilyn S. Sommers, PhD

ABSTRACT

The applicant seeks a training opportunity that will prepare her to successfully engage in research that elucidates aspects of the relationship between mental and physical health. The concept of mind-body interaction recognizes that mental and physical health influence one another, although the mechanisms responsible for these influences are still unknown. The applicant will use a rodent model of diabetes induced by the drug streptozotocin (STZ), to examine how a physical condition might precipitate affective and neurological changes. Studies directed at determining the underlying neurobiological alterations occurring during diabetes will lead to better predictors of risk as well as identifying rational targets of new therapies to manage biobehavioral complications of this common disease. The effect of diabetes on neural function will be evaluated through behavioral tests and measurement of hippocampal neurogenesis. The core hypothesis of this proposal is that reduced neurogenesis resulting from diabetes is produced, in whole or in part, by dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis with concomitant elevations of the hormone corticosterone (CORT). Suppression of hippocampal neurogenesis, known to result from persistent CORT elevations, may be associated with increased vulnerability to depression and cognitive deficits. The mechanism underlying suppressed neurogenesis in diabetes models is not known. However, it is known that increased CORT decreases neurogenesis, and diabetes models are associated with increased levels of circulating CORT. Using a 2x2 factorial design, this study will determine whether diabetes-related CORT elevation mediates changes in behavior and/or neurogenesis. If the results obtained in this study support the hypothesis that HPA axis dysregulation and excess CORT contribute to diabetesrelated suppression of hippocampal cell proliferation, and if controlling CORT levels restores neurogenesis and improves behavioral and cognitive deficits, then a new pharmacologic target will have been identified. This will be an innovative avenue of investigation with a potential pathway that leads to brain-related diabetic complications. Manipulation of this pathway may increase the quality of life of patients suffering from diabetes through preserving cognitive function and limiting psychological and mood alterations. This proposed training will take place at the University of Pennsylvania under the mentorship of Drs. Irwin Lucki and Marilyn Sommers. During this fellowship, the applicant will develop and conduct an innovative program of neuroscience research that will identify pharmacological targets and ways to improve the quality of life of those with diabetes and comorbid neurologically based complications.