ABSTRACT This application is in response to the Notice of Special Interest (NOT-AG-21-018) for Alzheimer's-focused administrative supplements for NIH grants. Our currently funded parent R01 titled `Spontaneous activity in the developing auditory system' does not currently focus on Alzheimer's disease (AD) or any of its related dementias. We propose to leverage our unique expertise in studying neuron and astrocyte activity patterns in the in vivo auditory system to extend Aims 2 and 3 of the parent R01 to determine how the progression of AD relevant pathologies influence cellular activity patterns and transcriptional phenotypes in sound processing centers. We will also determine if developmental disruptions in the stereotyped burst firing of neurons prior to hearing onset influences the progression of AD pathogenesis. Hearing loss is a major risk factor for developing dementias, including AD, and animal models of AD commonly develop auditory dysfunction at late stages of disease, suggesting that manifestation of disease reflects an interplay between cellular activity in auditory centers and AD progression, although the underlying mechanisms responsible for this link between hearing and disease have not been determined. Sensory systems provide the added opportunity to define how disease states alter neural processing in the intact brain. Notably, AD pathology is not limited to neurons. Astrocytes adapt to changes in neural activity and respond to disease by changing their molecular and functional properties (e.g. reactive astrogliosis), although how these phenotypic changes ultimately influence their behavior in vivo, particularly in AD, is poorly understood. Given the crucial roles of astrocytes in ion and neurotransmitter homeostasis, these reactive changes may profoundly impact local neural activity patterns and exacerbate pathology. In this supplement, we will determine how spontaneous and sound-evoked activity of both neurons and astrocytes is altered in the inferior colliculus and auditory cortex (two major processing centers in the auditory pathway), from early development (prior to pathology) through the onset of gross pathological changes (e.g., Aβ plaque formation). We will also determine how the transcriptional profiles of both neurons and astrocytes change with the progression of AD pathology in the auditory system to better define cell-type specific changes and identify potential therapeutic targets. Lastly, we will determine whether disruptions in early activity in the auditory system influences disease progression later in life. These studies will provide new insights into how AD influences network dynamics in the auditory system, and conversely how altered cellular activity influences disease progression, which could reveal novel risk factors for AD and new strategies for altering the trajectory of disease.