Altered regulation of the hypothalamic-pituitary-adrenalcortical axis (HPAA), including hippocampal function, has been identified for both endocrine and neurotransmitter systems with age. Corticosteroids are among the hormonal factors identified to modulate the HPAA with aging, including an age-dependent decline in corticosteroid binding sites in the hippocampus. Similarly, alterations in neurotransmitter function in the HPAA with age include the decline of hippocampal serotonin (5- hydroxytryptamine; 5-HT) neuronal systems. Recent investigations of possible 5-HT/corticosteroid interactions in the mammalian central nervous system have identified the ability of this neurotransmitter afferent input to modulate the expression of corticosteroid receptor function in the hippocampus. However, the physiological and pharmacological consequences of this interaction on aging of the HPAA remain to be addressed. A series of experiments will address the hypothesis that age-related alterations in serotonergic function modulate the corticosteroid-induced decline of hippocampal cell function. The cellular and molecular alterations in 5-HT and corticosteroid function, including mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), will be investigated by a multidisciplinary analysis of CAI and CA3 hippocampal fields in 3,12, 18 and 24 month old female Fischer 344 rats. The regulation of 5-HT and corticosteroid function will be addressed using in vivo and in vitro cellular electrophysiological recording techniques, neurochemical radioligand binding techniques as well as application of Northern blot and in situ hybridization techniques. Particular emphasis will be placed on assessment of changes for multiple 5-HT (5-HT1A, 5-HT2, 5-HT3) and corticosteroid (MR and GR) receptors by evaluation age-related changes in RNA species and levels for these receptors. In addition, studies of the depletion of 5-HT on age-related changes in corticosteroid hippocampal responses will provide new insights into the nervous/endocrine system interactions that underlie both normal aging and pathological changes found in Alzheimer' disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
United States
Zip Code
Hegde, Muralidhar L; Mantha, Anil K; Hazra, Tapas K et al. (2012) Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases. Mech Ageing Dev 133:157-68
Tann, Anne W; Boldogh, Istvan; Meiss, Gregor et al. (2011) Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5'-EXO/endonuclease) in their repair. J Biol Chem 286:31975-83
Zhang, Haihong; Xie, Chenghui; Spencer, Horace J et al. (2011) Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. Am J Pathol 178:1715-27
Szczesny, Bartosz; Tann, Anne W; Mitra, Sankar (2010) Age- and tissue-specific changes in mitochondrial and nuclear DNA base excision repair activity in mice: Susceptibility of skeletal muscles to oxidative injury. Mech Ageing Dev 131:330-7
Szczesny, Bartosz; Tann, Anne W; Longley, Matthew J et al. (2008) Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 283:26349-56
Szczesny, Bartosz; Mitra, Sankar (2005) Effect of aging on intracellular distribution of abasic (AP) endonuclease 1 in the mouse liver. Mech Ageing Dev 126:1071-8
Choksi, K B; Boylston, W H; Rabek, J P et al. (2004) Oxidatively damaged proteins of heart mitochondrial electron transport complexes. Biochim Biophys Acta 1688:95-101
Garg, Nisha; Gerstner, Arpad; Bhatia, Vandanajay et al. (2004) Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways. Biochem J 381:743-52
Szczesny, Bartosz; Hazra, Tapas K; Papaconstantinou, John et al. (2003) Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci U S A 100:10670-5
Bhakat, Kishor K; Izumi, Tadahide; Yang, Suk-Hoon et al. (2003) Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. EMBO J 22:6299-309

Showing the most recent 10 out of 80 publications