HDAC3阻害は、聴覚野と行動における信号対雑音応答性を高めるために学習誘発性の神経生物学的メカニズムを活用する

Auditory learning enables sound-guided behavior and sound-specific enhancements in auditory cortical (AC) processing. Background noise can also alter sound-specific auditory responsivity. Yet, the potential enhancing effects of learning on AC processing in noise is unknown. Pharmacological inhibition of histone deacetylase 3 (HDAC3) by RGFP966 has been shown to improve AC coding when administered during various auditory learning paradigms. Here, adult rats (Sprague-Dawley males) were trained in ideal quiet conditions to learn a tone-reward associative task while treated with RGFP966 (TRAINED+RGFP966, n = 6) to determine if learning-related effects on AC could support tone-signal detection in a later background noise challenge. RGFP966 accelerated sound-reward learning relative to a trained but untreated group of rats (TRAINED, n = 5), though all animals ultimately reached equivalent high levels of performance prior to testing. Training produced a sound-specific enhancement in AC responses evoked by the signal tone, and a sound-general effect that suppressed responses during steady-state noise, relative to untrained rats (NAÏVE, n = 7). Effects were strongest when training was with RGFP966 administration and scaled with increasing signal-to-noise (SNR). High levels of background noise abolished sound-specific enhancements in tone-signal evoked AC activity, yet the general suppressive effect to noise was maintained. Remarkably, behavioral responses to the signal tone in different SNRs recapitulated AC patterns of tone-evoked responding. Overall, rapid auditory learning facilitated by RGFP966 yields AC plasticity that can improve signal detection. Learning-induced mechanisms appear to shape cortical decoding mechanisms that selectively enhance representations of signal sounds and suppress the effects of background noise.

Difficulty 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 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.