Neural System Dynamics & Gene Expression Supporting Successful Cognitive Aging

PI: Barnes, Carol A.
PROJECT SUMMARY {See instructions):
This proposal applies a novel set of cognitive, neurobiological and molecular profiling approaches to the
question of how to understand the concept of cognitive reserve in a rodent model of aging. An integrated
set of experiments is proposed designed lo assess, mechanisms underlying differential cognitive trajectories
observed over the lifespan of the rat at three different phases of the lifespan, young adult, middle age, and
old. The experiments take advantage of technologies that cannot be used in humans at present, as well as
those that can (such as cognitive tests and MRl imaging methods). These methods have not been applied in
combination in the rodent previously, and involve high resolution MRl Imaging ofthe entire brain, cognitive
tests that examine domains relevant to 8 brain regions in the temporal and frontal lobes (hippocampal
regions CAI, CA3, dentate gyrus and the subiculum; temporal lobe regions perirhinal cortex and medial
entorhinal cortex; frontal lobe regions anterior cingulate and prelimbic cortex), behavior-induced, single cell
gene expression imaging in these 8 regions, and in 4 hippocampal subregions cell-specific whole
transcriptome analyses. These procedures will be conducted in rats that are chosen on the basis of
possessing behavioral performance scores that are high, average or low with respect to performance
distributions from young, middle-aged and old rats. The present experiments have the potential to identify
cell-specific RNA transcripts and behavior-activated circuits in brain regions that are critical for cognition, and
that define how individuals segregate along a cognitive competence continuum throughout life. The
combination of these methods will enable identification of those variables that are associated with more or
less successful cognitive aging trajectories - a fundamental necessity if effective treatments are to be
developed. The specific goals of this project are approached experimentally under two main aims. AIM 1 is
to identify transcriptional patterns in hippocampal subregions that are associated with differential cognitive
aptitudes across the lifespan. AIM 2 is to identify behavior-induced activity patterns in temporal and frontal
lobe circuits associated with differential cognitive abilities, to identify what circuit characteristics are
associated with successful cognitive outcomes during aging and the extent to which temporal and frontal
lobes age independently. Together, the data collected in these experiments should identify targets useful in
the development of strategies to optimize cognition during aging.
RELEVANCE (See instructions):
The goal of this project Is to uncover critical genetic and circuit characteristics that increase the probability
that an individual will maintain high levels of cognition across the lifespan. When the mechanisms conducive
to high levels of behavioral function are well enough understood to be effectively manipulated, strategies for
altering the trajectories of age-related declines can then be implemented. This is likely to have enormous
impact on productivity and independence of elderly populations.