Memory specific to temporal features of sound is formed by cue-selective enhancements in temporal coding enabled by inhibition of an epigenetic regulator

Abstract

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and its substrates in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory formation (LTM). Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM that is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was unusually specific to the AM rate paired with reward. Unusually sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system: stronger phase-locking that was specific to the rewarded AM rate was revealed in both the surface-recorded frequency following response (FFR) and auditory cortical multiunit activity in rats treated with the HDAC3-inhibitor. Furthermore, HDAC3inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats) that generalized across different AM rates. Stronger signal-specific phase-locking correlated with individual behavioral differences in memory specificity for the AM signal. Together, these findings support that epigenetic mechanisms regulate activity-dependent processes that enhance discriminability of sensory cues encoded into LTM in both spectral and temporal domains, which may be important for remembering spectrotemporal features of sounds, e.g., as in human voices and speech. SIGNIFICANCE STATEMENTEpigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of histone deacetylase 3 (HDAC3) in a sensory model of learning to reveal, for the first time, its ability to enable unusually precise memory for amplitude modulated sound cues. In so doing, we uncover neural substrates for memorys "specificity" for temporal sound cues. Memory specificity was supported by auditory cortical changes in temporal coding, including greater response consistency and stronger phase-locking. HDAC3 appears to regulate effects across domains that determine specific cue saliency for behavior. Thus, epigenetic players may gate how sensory information is stored in long-term memory and can be leveraged to reveal the neural substrates of sensory details stored in memory.