Grant: Project Grant

Although many people develop dementia with aging, the human brain possesses a capacity for remarkable resilience, as exemplified by individuals in their ninth decade of life with memory as good as that of cognitively average individuals in their 50s and 60s. Astoundingly, some of these SuperAgers show advanced Alzheimer's Disease (AD) brain pathologies. In our experimental rat colony, which has been genetically modified to develop AD pathologies, a minority of rats similarly do not develop progressive memory impairments. In the current proposal, we focus on elucidating the neuronal contributors of brain resilience. We speculate that a particularly propitious form of encoding function in the brain entails having a sizable population of neurons capable of contributing to the processing of a stimulus, but only a small proportion of that population being recruited into processing of the stimulus at any given instant - a population level manifestation of high volatility in individual neuron's responsivity across repeated stimuli. To test this hypothesis, we will leverage recently developed optical reporters of neuronal activity and ultra high-density electrophysiology to measure the volatility in neuronal responsivity across repeated stimulations in young vs. elderly animals. We will next investigate whether these neuronal engagement levels predict the susceptibility to acute injury induced by injecting a prominent AD neurotoxin directly into the brain. Finally, we will evaluate whether these imaging metrics, acquired in our rat model of AD prior to the onset of AD pathologies, accurately predict the latter life levels of memory impairment in individual animals. We anticipate our imaging tools will yield a useful metric for predicting susceptibility to dementia and guiding the development of interventions for delaying cognitive decline.