For a given age or level of brain pathology, patients with higher educational status, occupational achievement, bilinguality, and school grades show fewer symptoms of dementia. Such factors have been lumped into a concept called ?Cognitive Reserve? (CR), which is the principal correlate of resilience against dementia and normal, age-related cognitive decline. CR ?may be based on more efficient utilization of brain networks or of enhanced ability to recruit alternate brain networks, or it may reflect intrinsic (innate) brain physiology differences; however, evidence indicates a major role of the degree of knowledge acquisition over the lifespan. But the linkages between enhanced experience and CR, and between CR and neurobiological function, need to be experimentally established. Does enhanced experience actually create CR? What are the neurobiological correlates of CR? Does CR actually preserve neurobiological function, such as the ability to retrieve recent activity patterns or the ability to rearrange synaptic connections, or is it merely a reflection of the complexity of patterns stored before the onset of brain pathology? As an animal proxy for CR, we will exploit a new method for environmental enrichment that we have developed, which produces striking improvements in at least five different tests of memory and cognitive function in normal mice. These improvements are significantly superior to classical environmental enrichment methods, allow for tight control of enrichment parameters and exercise variables, and last at least 6 months. Using advanced optical cellular activity imaging in freely behaving mice and neural ensemble recording methods in a VR apparatus we will assess the neurodynamic effects of EE in the hippocampus of normal mice and in an animal model of Alzheimer's disease (AD). We will study a range of hippocampal neurodynamics that are believed to reflect or to play a key role in memory processes. These parameters include hippocampal oscillations such as theta rhythm and sharp-wave-ripples (SWR), `place' cell population coding of environmental location, rate coding of changes in external inputs at a given location (?rate- remapping?), experience-dependent encoding of sequential experience, representational efficiency (sparse coding, log-normal firing rate distributions) and temporal stability, and post experience reactivation of recent memories during periods of rest. We will compare the effects of running the Enrichment Track with running on an Exercise Control Track. Parallel studies of the effects of Enrichment Track and Control Track on amelioration of cognitive/behavioral deficits in the same, 3xTg AD, mice are being conducted under separate support, which will enable us to assess which neural dynamic parameters best account for behavioral improvements and set the parameters for future within-subject experiments that would enable direct correlation and manipulation. CR is a significant factor not only in protection of cognitive capacity against brain pathology such as AD, but also against the changes that occur in normal, healthy aging. For these reasons, a complete understanding of the neurodynamics basis of CR is of paramount importance.

Public Health Relevance

Enhanced knowledge acquisition and lifestyle diversity is the basis of what is known as brain's 'Cognitive Reserve', which is the single best predictor of successful ageing and protection from the effects of degenerative or traumatic brain disorder. This proposal aims to deepen our understanding of how enriched experiences improve the brain function in health and disease conditions, particularly in the neurophysiological and information processing and storage functions of the hippocampal formation, the gateway to long-term semantic memory.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
Zip Code