2006 AFAR Research Grant: Aging, Cytokines, and Depressive Behavior

Please give a brief summary of your AFAR research project.
It is known that the elderly have a higher incidence of depressive disorders concomitant with illness or infection; however, the mechanisms involved are not well understood. To address this issue we have designed behavioral and biochemical experiments using a mouse model of aging to determine if age-associated changes in the brain are permissive to the onset of depression following activation of the peripheral innate immune system. We hypothesize that a heightened inflammatory cytokine response in the brain disrupts normal serotonin metabolism and results in long-lasting depressive symptoms. In the first aim we will delineate if inflammatory cytokine pathways promote protracted depressive symptoms by impairing serotonin metabolism and neurogenesis in the hippocampus of aged mice following peripheral lipopolysaccharide (LPS) challenge. In the second aim we will determine if attenuating LPS-induced microglial cell activation blocks prolonged neuroinflammation and prevents depressive behavior in mice. These initial studies are important in enhancing our understanding of how age-related changes in the brain lead to impaired immunity and neurobehavioral complications in the elderly.

What problems are you addressing and what specific questions will your research seek to answer?
It is known that older individuals have a higher incidence of mental health complications concomitant with illness or infection, but the mechanisms involved are not well understood. The overall objective of this project is to test the hypothesis that activation of the peripheral immune system in the aged promotes an exaggerated inflammatory response in the brain that disrupts the signaling of the neurotransmitter serotonin and causes long-lasting depressive complications. This project will aim to answer (a) if prolonged neuroinflammation impairs serotonin metabolism and neurogenesis in the hippocampus of aged mice and (b) if microglial cell hypersensitivity to peripheral immune activation is a critical factor for the prolonged neuroinflammtion and behavior complications in the aged.

What aspects of your project are most interesting from a scientific point of view?
The most interesting aspect to me is the idea that excessive or prolonged exposure to inflammatory cytokines within the brain can profoundly influence normal neurotrophic and neurotransmitter signaling. This is significant because disruption of these pathways may underlie mental health complications associated with inflammatory conditions.

What are the implications of your research for age-related diseases and disorders?
Prolonged inflammation, especially in the brain can be deleterious to both mental and physical health. The goal of this project is to better understand the biochemistry that underlies why the neuroinflammatory response to immune activation leads to prolonged depressive behavior in aged mice. We hope by delineating the mechanism involved that we will (a) gain a better understanding of the relationship between neuroinflammation and depression in the aged and (b) begin to identify potential targets to prevent or treat neurobehavioral deficits in a susceptible elderly population.

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