Linking molecules, circuits and behavior to promote plasticity and memory in the aging brain

Advances in disease prevention and therapeutics have enabled humans to live longer than ever before. We now face the challenge of increasing health span in a comparable manner. How can we help people maintain the normal mental function needed to support multifaceted, independent lifestyles for as long as possible? The cognitive changes that develop with normal advanced aging are poorly understood, and we currently lack effective therapies to slow decline. We know that age-related changes in the brain occur at the molecular, circuit and behavioral levels, so we must investigate each of these scales and understand how changes at one level relate to changes at others. We aim to understand the links between molecular, circuit and behavioral alterations that occur with age, with a longer-term goal of developing effective treatments that will help maintain cognitive function during aging.

We will focus on a set of neural circuits in the medial temporal lobe, including the entorhinal cortex (EC), the dentate gyrus (DG), and hippocampal regions CA3 and CA1, all of which are strongly affected by aging. These regions are critical for learning and remembering past experiences and using them to inform future decisions. Extensive work from our labs and others provides insight into how the EC, DG and hippocampus maintain neural representations of experiences and how local circuits within these regions contribute to forming memories and using those memories to make decisions. We will use cutting-edge electrophysiological and analytical tools to map how neural representations in the EC and in CA1, the primary output region of the hippocampus, change with age. Further, we will examine gene expression in different types of neurons in the EC and CA1 and explore how gene expression influences electrical activity and behavior. Our group has previously shown that connections between DG and CA3 interneurons decline with age, and that reversing this decline improves memory. We will look for the molecular mechanisms underlying plasticity in this circuit, as well as the molecular factors that may play central roles in age-related changes in the EC and CA1 regions.