Extratelencephalic contributions to auditory categorization

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PROJECT SUMMARY Hearing loss occurs in ~80% of adults over 65 years of age and is considered to be the most heavily contributing modifiable risk factor to dementia. Alzheimer’s disease (AD) is the most common form of age-related dementia. Overwhelming recent evidence suggests an association between hearing loss, AD neuropathology, and memory function. Memory encoding is known to require an intact entorhinal-hippocampal circuit and this circuitry is severely affected in AD. Recent studies, including our own, have begun to tease apart the anatomical route that auditory information takes to reach the hippocampus (HPC) through the entorhinal cortex (EC). However, no study to date has comprehensively investigated how noise-induced hearing loss (NIHL) affects neuronal circuit integrity and integrated these findings into the neuropathological and behavioral changes observed in AD patients. To address this gap in knowledge, we will utilize a recently developed AD knock-in mouse model to determine (1) how NIHL and AD affects the flow of auditory information from the auditory cortex (ACtx) to the EC, (2) how NIHL and AD affect the time-course of cognitive decline during auditory decision making, and (3) whether NIHL accelerates accumulation of the pathological hallmarks of AD, neuroinflammation, and synaptic degeneration. We expect that NIHL will render the auditory information flow into the EC hyperactive, which will correlate with a diminished ability to remember and discriminate auditory stimuli and an exacerbation of AD neuropathology. By explicitly quantifying how NIHL and AD progression interact at the level of sensory information processing, cognitive function, and pathogenesis, these studies have the potential to unveil a much sought-after causal link between hearing loss and the pathophysiology of AD.