Oxidative stress is thought to be a factor in the behavioral decline that occurs when the brain ages or is damaged in some conditions or diseases. In Alzheimer?s disease (AD), in particular, there are a number of clear-cut indications that oxidative stress plays a role in neurodegeneration. Among the neurons that are compromised in this disease, the basal forebrain cholinergic neurons seem to be particularly vulnerable. These neurons are important in regulating neurotransmission in the hippocampus and cortex, in circuits known to be important in cognition. Other brain cholinergic neurons, like those in the brainstem, seem to be relatively preserved in AD. The latter cholinergic neurons express the enzyme nitric oxide synthase (c-NOS), an enzyme that produces a free radical that could endanger the cell. Thus, the c-NOS phenotype appears to endow neurons with a paradoxical resistance to oxidative stress and/or disease. Our laboratory combines molecular, biochemical, and anatomical approaches to quantitate the levels of expression of candidate genes at the mRNA and protein level, in cholinergic neurons in the brain and in culture, currently with a special emphasis on mechanisms of resistance to oxidative stress. We use in situ hybridization histochemistry, Western blotting, immunocytochemistry, RT/PCR, and other similar methods. The laboratory is currently funded by the Mayo Foundation, and by grants from the National Institute on Aging.