Studies in outbred Long Evans rats have contributed to the identification of a neurobiological basis for cognitive impairment in the aged brain of otherwise healthy laboratory animals. Within the medial temporal lobe memory system the selective loss of perforant path connections and an altered condition of the network it innervates in the dentate gyrus (DG) and CA3 region are hallmarks of rats that age with memory impairment. In contrast, that network is relatively maintained in aged rats with preserved cognitive function, including anatomical integrity of the perforant path and a balance of computational properties for pattern separation and pattern completion in DG/CA3 that resembles young adults. A unique feature of this network is the integration of new DG neurons in the adult brain. No studies have yet examined that integration in the context of brain aging. The proposed research in Project 2 will complement studies in the other projects by examining whether the integration of newly DG generated neurons aligns with individual differences in cognitive outcomes. Unimpaired aged rats, consistent with young adults may show a predominant role for the lateral entorhinal cortex (LEC) in the integrating network. Because the circuit integration of new DG neurons involves other elements that strongly differentiate cognitive outcomes, such as hilar interneurons, CA3 neurons, and basal forebrain cholinergic projections, we will determine whether a broad difference in the circuit integration of new DG neurons occurs in impaired and unimpaired aged rats. In addition to a better understanding of the basis for age-related impairment, the findings will be informative about the condition of the aged brain that maintains a high-level of cognitive capacity, e.g. testing the hypothesis that such animals (but not impaired aged cohorts) integrate a complement of new DG neurons in a manner similar to young. Additional studies in this project will further test whether an impoverished integration in impaired aged rats can be improved by a therapeutic treatment that has been shown to boost molecular markers in key monosynaptic afferents in the entorhinal cortex and DG/hilus. Those findings, together with studies in Project 1 and 3, will address an emerging hypothesis in this research program that a failure through the LEC steam of information processing disproportionately contributes to memory impairment in the aged brain. Alongside better maintenance of those properties in aged unimpaired rats, research in this model suggests that adjustments in the aging brain, which are distinct from young adults, contribute to preserving cognitive function. Project 2 will further examine whether unimpaired aged rats engage greater inhibitory control over the entorhinal/DG/CA3 network as suggested by our findings. Neural overactivity in the brains of impaired aged rats, and a parallel condition detected by functional imaging in studies of human aging/MCI suggest that recruitment of inhibitory control in unimpaired aged rats could play an adaptive beneficial role in neurocognitive aging.
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