Aging is commonly associated with impaired memory, which is thought to result from altered synaptic connectivity and function in the medial temporal lobe (MTL), comprised of the hippocampus and medial temporal cortex (entorhinal, perirhinal and parahippocampal regions). Recent studies in rodent models and humans identified two particularly vulnerable elements within the MTL, the layer II pyramidal cells in the lateral entorhinal cortex, and GABAergic inhibitory interneurons in the dentate gyrus. These two neurons types are crucial for processing in the dentate gyrus (DG) subfield of the hippocampus. The lateral entorhinal cortex (LEC) cells, along with the medial entorhinal cortex (MEC), provide the bulk of the excitatory input to the granule cells in the DG. At the same time, the integrity of inhibitory circuits within the DG are important for ?sparse encoding? in DG contributing to pattern separation. Both, LEC cells and interneurons show early alterations in their molecular make-up during aging that are tightly coupled to memory loss. Notably, levetiracetam treatment (LEV), an intervention that restores mnemonic capabilities in elderly humans and rodents also restores molecular signs of dysfunction in LEC layer II neurons and dentate interneurons. The central goal of Project 3 will be to advance understanding of how aging affects the functionality and plasticity of these circuits at a synaptic level. Project 3 will combine optogenetics with synaptic electrophysiology for in vitro studies on the strength and function of the two entorhinal input streams (LEC and MEC), the local inhibitory connections in the DG, as well as on the effects of therapeutic interventions on these circuits. We hypothesize 1) that aging alters the functional balance of LEC and MEC inputs to DG in aged rats with cognitive impairment, contributing to the predominance of MEC processing over input from LEC as observed in the encoding properties of hippocampal neurons, 2) that inhibitory function in the DG is crucial for preservation of cognitive performance during aging and may be achieved in unimpaired aged rats in a compensatory manner that distinguishes those aged rats from young adults, and 3) LEV treatment improves cognitive performance by restoring functionality in the balance of EC inputs to granule cells, and/or by promoting compensatory changes in the inhibitory DG network. The proposed studies will provide the first comprehensive picture of how neurocognitive aging affects synaptic function in vulnerable DG/Hilar circuits, and will further our understanding of how therapeutic interventions can ameliorate the effects of aging on cognition.
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