Mechanisms of Age-Related Cognitive Decline
 
Guiseppe P. Cortese^a, Andrew Olin^a, Kenneth O'Riordan^c, Rikki Hullinger^b, and Corinna Burger^a,b
aDepartment of Neurology, University of Wisconsin-Madison; ^bNeuroscience Training Program, University of Wisconsin-Madison; ^cPresent Address Department of Pharmacology & Therapeutics,Trinity College, Ireland
 
Currently, few molecular targets have been identified to treat age-related memory disorders such as mild cognitive impairment during normal aging, or Alzheimer's disease. We identified an isoform of the Homer1 gene,-Homer1c- that plays an important role in age-related learning. Our goal is to understand the molecular mechanisms of age-related learning and memory formation by studying the role of Homer1c in age-related cognitive decline. Environmental Enrichment (EE) preserves cognition in the senescent brain. Although humans with high cognitive activity have a lower risk for Alzheimer's disease, little is known concerning mechanisms giving rise to the functional benefits of EE. Rodent models of aging have been used to study the effects of environmental enrichment on cognition in normal aging and neurodegenerative disease. EE enhances performance in multiple well-established behavioral tasks, including the Morris Water Maze which measures spatial memory, and memory for objects and odors. Both spatial and object/odor memory decline with age in humans. In order to understand the molecular pathways involved in enhanced cognition and synaptic plasticity in EE in aged rats, we exposed aged rats to three different housing conditions: environmentally enriched (EE), socially enriched (SE), or standard housing (SC). We find that aged rats exposed to one month of environmental enrichment exhibit enhanced learning and memory in the Morris water maze and novel object recognition behavioral tasks. Moreover, we show that EE rats perform significantly better than SE or SC rats in the radial-arm water maze, and display enhanced metabotropic glutamate receptor-dependent long term potentiation (mGluR-LTP). Enhanced hippocampal function results from activity-dependent upregulation of mGluR5, Homer1c, and phospho-p70S6 kinase. These findings suggest a potential mechanism by which EE benefits overall cognition in the aging brain.
 
Funding: This research was supported by grant R01AG048172-03 to CB and in part by the Core Grant for Vision Research from the NIH to the University of Wisconsin-Madison (P30 EY016665).