PROJECT SUMMARY / ABSTRACT Only 17% of the 466 million people worldwide who might benefit from hearing aids actually use one, imparting a large national and indeed worldwide cost on hearing and cognitive health. One reason for such low hearing-aid adoption rates is the unclear benefit they provide when listening in noisy environments. Difficulty hearing in noise typically begins in mid-life, often well before the onset of age-related hearing loss as measured by audiometry and is the primary hearing rehabilitation goal of individuals visiting audiology clinics. The contributions of dysfunctional central auditory processing towards the inability to hear in noise have received little attention compared to contributions of peripheral dysfunction. One likely contributor to the reduced ability to hear in noise as we age is loss of neuronal inhibition in the central auditory pathway, particularly auditory cortex (AC). Work in experimental animals has shown that both hearing loss and age, per se, are associated with reduced levels of the inhibitory neural transmitter GABA (gamma aminobutyric acid) in AC and other nuclei of the ascending auditory pathway. Such loss of neuronal inhibition likely has severe consequences for the ability to hear in noise via hyperexcitability of AC neurons. Hyperexcitability, defined as increased spontaneous or evoked firing rates, is hypothesized behaviorally to reduce the listener’s ability to suppress distracting acoustic input and focus on behaviorally relevant sounds. However, despite extensive animal work showing reduced GABA levels in AC, very few studies have directly examined this in humans. Even fewer have examined the role such reduced AC GABA levels might play in decreased hearing-in-noise ability. Here, we directly examine the relationship between age-related loss of inhibition in AC, AC hyperexcitability, and the ability to hear in noise. In Aim 1, we establish that age is indeed associated with reduced levels of GABA in human AC, while controlling for age-related hearing loss (Exps. 1A-1C). In Aim 2, we determine how reduced AC GABA levels manifest behaviorally for speech-in-noise perception (Exp. 2A) and behaviorally and neurophysiologically for detecting non-speech target sounds in noise (Exp. 2B). In Aim 3, we examine whether age-related changes in markers of AC hyperexcitability can be accounted for by loss of GABA at the circuit level through the use of biophysical modeling capable of identifying candidate circuit-level mechanisms. The results of this study will establish a combined imaging, physiological, and modeling framework for understanding the behavioral and neurophysiological consequences of loss of neuronal inhibition in human AC. Planned R01 work will solidify the link between AC GABA loss and difficulty hearing noise and identify candidate circuit-level mechanisms that can be further explored with animal models.