Over the past century, we have witnessed remarkable increases in the average life span. Unfortunately, increased longevity is not matched by the typical health span, and most elderly individuals will experience memory decline that interferes with their quality of life and ability to maintain independence. The hippocampus is critical for memory and is one of the brain regions vulnerable in advanced age and Alzheimer?s disease. Because onset of Alzheimer?s disease is generally after the age of 65, the biological foundations of this neurodegenerative disorder are compounded by normal age-associated declines that we do not fully understand. In fact, alterations in the hippocampal circuit with old age could either reflect synaptic senescence or adaptive plasticity compensating to normalize output. Unfortunately, we have insufficient information to distinguish between these two competing hypotheses that would lend to distinct treatment strategies. The long-term goal of the proposed research is to determine the alterations in hippocampal subregion interactions that underlie cognitive dysfunction. The primary objective of the current proposal is to determine how altered communication within the hippocampal circuit in old age produces memory deficits. Linking neurobiology directly to behavior, will allow us to determine if synaptic alterations are adaptive or the underlying cause of dysfunction. We will attain this by testing the central hypothesis that altered communication between CA3 and CA1 results from a deafferentation of the hippocampus from the entorhinal cortical (ERC), which leads to CA3 hyperexcitability. Old animals that maintain high performance, adapt to the loss of ERC input by weakening the CA3 to CA1 Schaffer collateral synapse to impede the propagation of aberrant activity. In contrast, aged animals will impairments show enhanced CA3-CA1 coupling. This hypothesis will be tested with the following specific aims: 1) Determine how CA3-CA1 neuron spike timing contributes to memory decline in old animals, 2) Determine the role of perforant path loss in intrinsic hippocampal dysfunction, and 3) Determine how changes in medial temporal lobe synchrony in old age map onto memory dysfunction. The rationale is that by elucidating how aging and disease influence systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, in our opinion, as neurophysiological techniques will be integrated with measures of behavior in young and aged rats in order to probe how local dysfunction manifests as network impairments or incites compensatory processes. The significance of the successful completion of this work will be to determine how distinct types of cellular dysfunction alter global circuit properties in order to identify and exploit network mechanisms to ultimately improve cognition.
The proposed research is relevant to public health because it provides an innovative approach for determining if age-related changes in the hippocampal circuit reflect adaptive plasticity or synaptic senescence. This will be achieved by linking local changes to overall synaptic function of hippocampal circuits. By understanding how local impairments alter systems-level network function, it will be possible to promote the development of interventions that broadly improve cognition in normal aging and Alzheimer?s disease and meet a mission of the NIA to advance our understanding of age-related cognitive decline.
|Nadel, L; Maurer, A P (2018) Recalling Lashley and Reconsolidating Hebb. Hippocampus :|
|Maurer, Andrew P; Burke, Sara N; Diba, Kamran et al. (2017) Attenuated Activity across Multiple Cell Types and Reduced Monosynaptic Connectivity in the Aged Perirhinal Cortex. J Neurosci 37:8965-8974|