Senior Scholar Award in Aging
Jeff W. Lichtman, M.D., Ph.D.
Washington University
Joshua R. Sanes, Ph.D
Washington University

Time Lapse Imaging of Neurons as They Age

That the adult nervous system changes with age is beyond dispute: cognitive abilities deteriorate, reflexes worsen, and the incidence of neurodegenerative disease skyrockets. Yet, despite major advances in our understanding of the etiology of neurodegenerative disease, the neural underpinnings of normal aging remain a complete mystery. Without such knowledge, it will not be possible to determine the age-related mechanisms that increase susceptibility to pathological alterations. Struggling to understand Alzheimer’s disease, for example, without knowing how aging occurs in the normal brain is like trying to understand how cells become cancerous without knowing the basics about cell growth.

We propose studies that will close the gap between two major areas of research in aging: work at the molecular level (for example, identification of genes that affect aging) and at the macroscopic neural systems level (such as brain imaging and behavioral testing). Between these levels is the crucial middle ground of cellular changes that underlie age-related decline in brain function. It is the cell that is directly affected by molecular changes, and it is changes in cells that are responsible for system-wide physiological or behavioral changes. We will therefore apply new methods to address the cellular correlates of aging, some of which, we believe, will turn out to underlie age-related cognitive decline.

In one set of studies leading up to the present work, we generated transgenic mice in which fluorescent proteins of several colors (green, yellow, blue, and red) label whole neurons without harming the cells or the animals . In these animals, we can directly visualize distinctly marked neurons. In parallel, we developed vital imaging approaches using high sensitivity cameras, new confocal and two-photon microscopic techniques, and computational tools for image analysis. We will now combine these genetic and imaging technologies for time-lapse imaging of aging neurons in vivo. We will begin with simple and accessible preparations --neuromuscular junctions and autonomic ganglia-- and proceed to the far more complex circuits of the brain. Ultimately, we will be able to find out how dendritic and axonal arbors of neurons change with age, how the dynamics of synapse formation and elimination change with age, whether synaptic loss is gradual or abrupt and whether the lifetime of an individual synapse varies with age.

Contact Dr. Lichtman.

Contact Dr. Sanes.