Research
Aging in Mouse Olfactory System

Investigator: John Larson, Ph.D.

The studies described in this proposal will investigate the effects of aging on the mouse olfactory system. Deficits in the sense of smell are common, and often severe, in human aging. However the neurobiological causes of these impairments are not known. The organization of the olfactory system is similar in all mammals; thus, an animal model of aging in this system is appropriate for neurobiological studies. But, in a larger sense, it is argued that the rodent olfactory system also represents a general model for the human declarative memory system, a system that is greatly impaired with aging and age-related neurological disorders. A model system in which the electrical activity of cells in defined neural circuits and networks can be related to both synaptic properties and manifestations of cognitive and memory functions in behavior would be a great asset in the analysis of the effects of aging on these functions. The studies in this pilot research program will test the feasibility of developing such a model. The mouse is selected for study in order to be able to exploit increasing advances in genetic engineering technology for the elucidation of molecular mechanisms of aging, the development of transgenic models of age-related neurological diseases, and the development of gene therapies for aging.

The olfactory learning system in rats shares a number of features in common with the human declarative memory system. These include nearly one-trial learning, rapid encoding, long-term memory, and high capacitiy for information storage without interference between items stored. It is assumed that olfactory learning in mice also shows these features. The studies outlined in Specific Aim One of the present proposal will test this and determine if these capabilities are degraded in aged mice. The rate of acquisition of new olfactory information, and the duration of its retention will be compared in young and aged animals.

It is hypothesized that olfactory memory, and declarative memory more generally, is encoded by specific changes in the strength of synaptic connections in specific brain networks by the mechanisms of long-term potentiation (LTP). The studies planned in Specific Aim Two will test for age-related deficits in LTP mechanisms in the primary olfactory region of the mouse cortex. The induction conditions for LTP, its magnitude, and the stability of synaptic potentiation will be compared in young and aged mice.

The production of LTP in olfactory cortex is hypothesized to be regulated by a system that generates the theta rhythm of cellular activity throughout the limbic system and is tied to the behavioral sampling of odor cues. The studies described in Specific Aim Three will test for effects of aging on this theta rhythm-generating system.

In summary, this program will combine behavioral and electrophysiological methods to characterize age-related changes in olfactory function in the mouse. The experiments described in this pilot research project will test the feasibility of the mouse olfactory system as a model for the understanding of the neurobiological mechanisms responsible for age-related declines in cognitive and memory function. If successful, this research will not only help explain age-related changes in olfactory function, but also create a model system for studying the cellular basis of behavior in general. Such a model is badly needed not only for aging research but also for evaluating the results of genetic manipulations (deletions, mutations, etc.) that have become such powerful tools in molecular biology. Thus we could potentially understand the effects of single gene changes on behavior by elucidating their consequences in cells, synapses, and circuits in the brain. Applied to the problem of aging, such an approach could also lead to new treatment strategies both for the treatment of age-related declines in neurological function and their prevention.