HDAC3 inhibition harnesses learning-induced neurobiological mechanisms to enhance signal-in-noise responsivity in auditory cortex and behavior

Abstract

Auditory learning enables sound-selective enhancements in auditory cortical (AC) processing. Background noise can also alter sound-selective auditory responsivity. Yet, how learning can enhance AC processing in noise is unknown. Pharmacological inhibition of histone deacetylase 3 (HDAC3) via RGFP966 enhances learning and related AC plasticity, but its potential to support signal detection under degraded acoustic conditions is unclear. To determine if task learning supports tone-signal detection in a later background noise challenge, adult rats (Sprague-Dawley males) were trained in ideal quiet conditions to learn a tone-reward association while treated with RGFP966 (TRAINED+RGFP966, n=6). RGFP966 accelerated sound-reward learning relative to untreated rats (TRAINED, n=5), though all animals reached equivalent high levels of performance before further testing. Successful performance produced sound-specific enhancements in AC responses evoked by the learned tone, and a sound-general effect that suppressed responses to noise, relative to untrained rats (NAIVE, n=7). Notably, frequency-selective response biases were latent under quiet conditions and became robustly expressed under background noise, particularly in RGFP966-treated learners who acquired the task more rapidly. Increasing background noise abolished frequency-selective enhancements in tone-evoked AC activity, yet the learning-induced suppressive effect to noise was maintained. Behavioral detection of the learned tone across noise conditions mirrored AC tone-evoked response patterns. The findings demonstrate that learning can engage coordinated cortical mechanisms regulated by HDAC3 that selectively modify representations of behaviorally relevant signals. Further, auditory memory is dynamically gated by sensory context, relying on the stability of cortical decoding mechanisms to support listening in real-world environments. SIGNIFICANCE STATEMENTDifficulty hearing in noise is a widespread challenge, yet the cortical mechanisms that preserve meaningful sounds under noisy listening conditions remain unclear. We show that HDAC3 inhibition via the pharmacological inhibitor, RGFP966, accelerates auditory learning and strengthens cortical encoding of a learned tone while suppressing background noise activity in ways that predict improved behavioral detection. These findings reveal an experience-driven cortical mechanism that supports improved hearing in challenging listening environments, which may inform strategies for enhancing auditory learning and rehabilitation using HDAC3 drug-targets.