The overall goal of this project is to determine the pathological consequences of chronic neuroinflammation associated with normal aging or enhanced by the infusion of lipopolysaccharide (LPS) upon ascending aminergic and cholinergic neurons within the brainstem of rats. A pro-inflammatory state has been described in the brains of patients with Alzheimer's disease, viral encephalitis, multiple sclerosis, AIDS and Parkinson's disease. The principle hypothesis of the current proposal is that the consequences of chronic neuroinflammation also underlie numerous other age-related degenerative diseases that involve the dopamine neurons in the SN, norepinephrine neurons in the LC, serotonergic neurons in the RN and the acetylcholine neurons in the LPT. The current proposal is designed to advance our understanding of the selective vulnerability of these brainstem regions to conditions that characterize age-associated disorders of these neural systems. The proposed studies are based upon the hypothesis that a major underlying problem in the age-associated loss of these neurons is the inflammation-induced elevation in extracellular glutamate and action of glutamate at NMDA channels. Clinical benefits would be achieved if one could modify the ability of glutamate to injure or destroy vulnerable neural systems. These studies will provide evidence that targeting the regulation of glutamate release or its actions within the synapse or calcium channels may produce clinical benefit for acute and chronic neurodegenerative disorders attributable to or exacerbated by brain inflammation.
Aim 1 will determine the time course and regional changes pro-inflammatory biomarkers and pathology.
Aim 2 will investigate the role of glutamate in the inflammation-induced degeneration of neurons within these brainstem nuclei.
Aim 3 will monitor second-by-second changes in extracellular glutamate levels within the discrete nuclei of the ascending systems following infusion of LPS into the 4th ventricle of young, adult and aged rats; these changes will be related to the degree of pathology expressed by each aminergic brainstem nuclei.
A pro-inflammatory state has been described in the brains of patients with Alzheimer's disease, viral encephalitis, multiple sclerosis, AIDS, and Parkinson's disease. The principle hypothesis of the current proposal is that the consequences of chronic neuroinflammation underlie the progression of these age-related degenerative diseases. The experiments proposed will investigate the consequences of long term brain inflammation on specific nuclei that are critical for normal cognitive processes, particularly those that fail with normal aging. In addition, these experiments will investigate potential ways to reverse the effects of the inflammation.
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