Cell type specific vulnerability to aging

Johns Hopkins University, Baltimore MD

Investigators

Linked publications, trials & patents

Abstract

Project Summary: Cognitive decline is an already significant and increasing public health issue. Multiple factors contribute to cognitive decline. In particular, hearing is central to human communication and age-related hearing loss (ARHL, presbycusis) by itself is a common ailment due to age-related changes along the auditory pathway. Both hearing loss and aging are associated with cognitive decline, increasing the risk for Alzheimer's disease (AD). In many cases of presbycusis peripheral function is normal, pointing to a large role of central auditory system dysfunctions. However, the age-related changes in the central nervous system that underlie these functional deficits are largely unknown due to the functional and molecular complexity of central circuits. This lack of knowledge precludes targeted interventions. We hypothesize that the key changes in normal aging and AD in the central nervous system is the dedifferentiation of neurons, that is the loss of their functional, transcriptional, and connectional identities, and that this dedifferentiation occurs more rapidly in AD. We test this hypothesis by a series of molecular and cellular neuro-imaging experiments in both aged animals and an AD model, which explores the molecular, connectomic, and physiological correlates of ARHL and identifies precisely which auditory cortical circuits are impacted by aging. Based on preliminary data showing that lifelong auditory training can prevent at least some of the age-related changes in A1, we then develop therapeutic strategies through plasticity induced by engagement of cognitive functions. To achieve our goals, we integrate at the level of single cells across large scale single-nucleus RNAseq, spatially resolved STARmap in situ sequencing, next-generation barcode-based connectomics, and in vivo 2-photon imaging. We also use training procedures to reverse some of the age-related changes.