State-dependent gating of memory and plasticity in the aging brain - State-dependent gating of memory and plasticity in the aging brain Memory loss and sleep disturbances are among the most prevalent and debilitating health concerns in the aging population. Together they threaten the independence and quality of life of older adults and their families, costing the healthcare system over $800 billion worldwide. The long-term objective of this project is to understand the link between sleep disturbances and memory problems that arise during aging. Growing evidence suggests that sleep disturbances are a mediator of age-related memory problems. Previous work shows that sleep deprivation (SD) hampers memory function in animal models, and reduces the activity and connections of principal neurons in the hippocampus—a brain region crucial for memory processing. In addition, recent data show that SD increases the activity and connections of somatostatin-expressing (SST+) inhibitory interneurons. By altering the activity of SST+ cells, the hippocampal excitatory/inhibitory (E/I) balance shifts to a state incompatible with memory storage. E/I imbalance is also observed with aging. Nevertheless, how aging alters E/I balance to disrupt memory is still unknown. The overall objective of the current research is to test the hypothesis that sleep disturbances in aging result in memory impairments via effects on the function of SST+ interneurons. The central hypothesis is that age-related sleep disturbances alter the activity and/or connectivity of hippocampal SST+ interneurons, shifting the E/I balance, and causing memory problems. Using Brainbow labeling and patch- sequencing, Aim 1 will quantify the structure, function, and gene expression of hippocampal SST+ cells in aged versus adult mice, and test whether partial chronic SD or a sleep-promoting hypnotic treatment can worsen or rescue phenotypes associated with aging, respectively. From a training perspective, Aim 1 will facilitate development of new experimental and analytical skills, including collecting, analyzing, and modeling transcriptome data using bioinformatics. Aim 1 will also expand my conceptual background in the domain of aging, with opportunities to improve my science communication, mentoring, and grant writing skills. The mentoring team, composed of experts in the field of cognitive aging, bioinformatics, and sleep neurobiology, will facilitate these aspects of my career development at the University of Michigan, which is one of the world's leading research universities. During the independent phase, Aim 2 will assess how aging affects the cell type- specific transcriptome landscape with respect to memory function—using spatial transcriptomics—under conditions of ad lib, chronically disrupted, or hypnotic-augmented sleep. This analysis will provide greater insight into how aging and sleep affect biological pathways, including neuronal and glial cellular function. Together, the proposed research is the first to directly assess the relationship between sleep, memory, and E/I balance in the context of aging. Understanding how age-related sleep disturbances affect memory-processing brain circuits will lead to the development of new therapeutic strategies to mitigate or even prevent age-related cognitive decline.
