Inhibition of histone deacetylase 3 via RGFP966 facilitates cortical plasticity underlying unusually accurate auditory associative cue memory for excitatory and inhibitory cue-reward associations

Precise Memory is Predicted by Learning-Induced Sensory System Neurophysiological Plasticity

“…Epigenetic mechanisms, such as histone deacetylase 3 (HDAC3), have been recently studied for their strong influence on the formation, strength, and persistence of long-term memory 36 , including for sensory cues 37 . Inhibition of class I HDACs like HDAC3, which releases HDAC-mediated constraints on gene expression, has been found to enhance the specificity of auditory memory across species 24,34,38 including humans 39 . Here, we confirm that HDAC3 inhibition enhances the frequency-specificity of auditory memory ( Fig.…”

“…Furthermore, a direct group comparison of ranked distributions of animals by the specificity of memory just reaches a statistical distinction between RGFP966 and vehicle-treated animals (Mann-Whitney one-tailed U-test(7,6)=8.0; p=0.050), which supports HDAC3 as a mechanism that drives memory in one direction towards specificity along a natural continuum of individual variability in memory. The link between HDAC3 and memory specificity revealed behaviorally is likely due to its role to promote the consolidation of learning experiences via frequency-specific auditory system neuroplasticity 24,35 .…”

“…HDAC3 inhibition has known sequelae in learning-induced plasticity at the level of the primary auditory cortex (A1) 24,35 . Thus, electrophysiological recordings in A1 were obtained outside of the training context, and following the Memory Test were to identify forms of A1 plasticity from the treated groups (RGFP966 vs. vehicle) to compare to a separate group of 5 naïve rats.…”

“…S3a,b). Therefore, though HDAC3 inhibition via RGFP966 does promote frequency-specific memory 24,35 (Fig. 2), this functional outcome may depend not just on the intervention alone, but on the ability of that intervention to facilitate the appropriate form, locus, and magnitude of auditory system plasticity that together provide sufficient neural substrates for the specificity of memory to reveal behaviorally.…”

“…However, to harness plasticity mechanisms in a useful way after the form of experience-induced plasticity between groups is identified, its function and magnitude of effect must be determined at the level of the individual.Previous work has identified distinct functions for different forms of auditory system plasticity related to the behavioral relevance of acoustic frequency 6,15-18 including at different time scales [19][20][21] . For example, in the auditory cortex, rapid changes in neural tuning properties correlate with selective attention to sound frequency during active tasks 21,22 , while long-term changes in tuning bandwidth may be related to frequency-specific memory over time 23,24 . Subcortical neurons in the lemniscal auditory nuclei also exhibit changes in tuning properties to represent behaviorally…”