Historically, the overall aims of this project have been to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent and nonhuman primate models are tested in a variety of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include various nutritional, hormonal, neurotrophic, and pharmacological treatments. Multiple genotypes and genetically modified mice are examined to determine possible genetic involvement in age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rodents using manipulations of specific neurotransmitter and neuromodulatory systems. We have also used a toxin, STZ, to establish a model of diabetes in rats that markedly elevates blood glucose levels due to loss of insulin-producing pancreatic beta cells. We noted impaired maze learning in the STZ treated rats that could be attenuated by blocking production of corticosterone. We are also investigating the role of corticosterone in mediating the neuroprotective effects of calorie restriction. In vitro removal of corticosterone from neuronal cultures raised in serum obtained from rats on calorie restriction attenuated stress protection, so we are now conducting in vivo studies manipulating levels of corticosterone by removal of the adrenal glands. Studies of behavioral and neuromorphometric changes in mouse models of Alzheimers disease (AD) are also continuing. Regarding behavioral performance, we found that the ability to acquire a conditional taste aversion was impaired in a transgenic mouse model of AD. We have also established that a neurotoxin affecting the noradrenergic system, DSP-4, can accelerate neuropathology in a mouse model of AD, likely due to increased inflammation of the forebrain. We are conducting various studies to manipulate inflammation in this mouse model to affect the course of the pathology. Related investigations are aimed at documenting the potential neuropathological consequences of peripheral polysaccharide injection. Finally, extending earlier work in BNS, studies currently in progress will define the influence of common chemotherapy agents on learning and memory mediated by the hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000302-26
Application #
7963916
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2009
Total Cost
$286,116
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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