The aim of this project is 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 continued work examining the role of glutamate and nitric oxide in memory dysfunction. Nitric oxide enhances guanylate cyclase and production of the second messenger, cyclic guanosine monophosphate (cGMP), which in turn stimulates glutamate release. Inhibitors of cGMP-specific phosphodiesterase enzyme type 5 (PDE-5) can enhance cGMP activity. Sildenafil citrate, the main ingredient in Viagra, is one such PDE-5 inhibitor in clinical use for erectile dysfunction. In addition, clinical reports of persons using this compound have indicated cognitive effects which have been demonstrated in animal learning experiments. We are evaluating this compound and related compounds, such as vardenafil (Levitra) on maze performance in rats. We observed that sildenafil can attenuate a maze learning impairment in young rats induced by central antagonism of nitric oxide synthase, the enzyme involved in production of nitric oxide. We have confirmed that treatment of aged rats does not enhance maze learning but does enhance retention. We are currently evaluating the effects of glia derived neurotrophic factor (GDNF), which stimulates production of dopamine, on its ability to attenuate age-related declines in cognitive and motor performance in mice. ? ? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000302-25
Application #
7732194
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2008
Total Cost
$533,280
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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