Synaptic and behavioral changes induced by hearing loss and Alzheimer's disease in the auditory brainstem.

In the auditory system, after sound is transduced by hair cells, the signal flows through a well-defined ascending route: cochlear nerve; cochlear nucleus; superior olivary complex (SOC); and inferior colliculus, before reaching higher processing areas. In mammals, signals from both ears must reach neurons in the SOC with high temporal precision so that binaural sound stimuli can be processed. An inability to encode and process accurately sound cues from both ears, especially in noisy environments, configures several forms of hearing loss (HL), a feature commonly associated with aging. Hearing impairment contributes to social isolation by burdening the individual with an exacerbated focus on processing speech. Social isolation reduces exposure to cognitive stimulation and may aggravate or even lead to instances of cognitive decline in those prone to it. Alzheimer’s disease (AD) is a progressively deteriorating condition that affects cognition globally. Importantly, AD is often associated with abnormal binaural hearing, especially in noisy environments. Thus, detecting early-onset deficits in binaural hearing and pairing it with AD likelihood is invaluable for guaranteeing quality of life for those at risk of eventually developing AD. This proposal aims to determine how auditory signal propagation is affected in different stages of AD progression associated with or without early HL. We will perform these studies using mouse models that develop early-onset AD (5xFAD) and HL (C57) to determine the changes in neuronal excitability and synaptic strength within the auditory brainstem that arise from the interaction of these conditions. We will focus on two specialized synapses in the auditory brainstem: the large calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) and the small bouton-type glycinergic and glutamatergic synapses of the lateral superior olive (LSO). These synapses are pivotal for the auditory brainstem circuits that compute sound source localization through binaural cues. In addition, we will study the binaural processing functionality using auditory brainstem recordings (ABRs) and behavioral studies such as the acoustic startle response (ASR). Preliminary data from our lab supports the hypothesis that healthy hearing delays AD progression at synaptic and behavioral levels. To further understand how this interaction may affect AD progression, we will use in vitro and in vivo approaches to 1) determine the underlying synaptic and neuronal changes in SOC circuits through single-cell patch clamp electrophysiology; 2) investigate non-invasively how sound processing is affected when AD and HL are associated, aiming for an early tool for AD forecasting; 3) correlate cellular, neuronal population and behavioral changes with aging in males and females. These results will provide novel insights into underlying functional deficits in AD development and its correlation with HL in different adult populations. The proposed studies will thus significantly enhance our fundamental understanding of AD and HL interactions in the mammalian brain. Project Number: 1R01AG091162-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: HENRIQUE VON GERSDORFF (+1 co-PI) | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $657,439 | Activity Code: R01 | Study Section: Auditory System Study Section[AUD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11227927