Memory Specific to Temporal Features of Sound Is Formed by Cue-Selective Enhancements in Temporal Coding Enabled by Inhibition of an Epigenetic Regulator.

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 substrates of memory 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 (LTM) formation. Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM, which 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. Adult male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. 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 and auditory cortical multiunit activity in rats treated with the HDAC3 inhibitor. Furthermore, HDAC3 inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats), which generalized across different AM rates. Stronger signal-specific phase locking correlated with individual behavioral differences in memory specificity for the AM signal. 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, for example, as in human voices and speech.SIGNIFICANCE STATEMENT Epigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of HDAC3 in a sensory model of learning to reveal the ability of HDAC3 to enable precise memory for amplitude-modulated sound cues. In so doing, we uncover neural substrates for memory's 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.

Precise memory for pure tones is predicted by measures of learning-induced sensory system neurophysiological plasticity at cortical and subcortical levels.

Despite identical learning experiences, individuals differ in the memory formed of those experiences. Molecular mechanisms that control the neurophysiological bases of long-term memory formation might control how precisely the memory formed reflects the actually perceived experience. Memory formed with sensory specificity determines its utility for selectively cueing subsequent behavior, even in novel situations. Here, a rodent model of auditory learning capitalized on individual differences in learning-induced auditory neuroplasticity to identify and characterize neural substrates for sound-specific (vs. general) memory of the training signal's acoustic frequency. Animals that behaviorally revealed a naturally induced signal-"specific" memory exhibited long-lasting signal-specific neurophysiological plasticity in auditory cortical and subcortical evoked responses. Animals with "general" memories did not exhibit learning-induced changes in these same measures. Manipulating a histone deacetylase during memory consolidation biased animals to have more signal-specific memory. Individual differences validated this brain-behavior relationship in both natural and manipulated memory formation, such that the degree of change in sensory cortical and subcortical neurophysiological responses could be used to predict the behavioral precision of memory.

Input from the medial geniculate nucleus modulates amygdala encoding of fear memory discrimination.

Generalization of fear can involve abnormal responding to cues that signal safety and is common in people diagnosed with post-traumatic stress disorder. Differential auditory fear conditioning can be used as a tool to measure changes in fear discrimination and generalization. Most prior work in this area has focused on elevated amygdala activity as a critical component underlying generalization. The amygdala receives input from auditory cortex as well as the medial geniculate nucleus (MgN) of the thalamus, and these synapses undergo plastic changes in response to fear conditioning and are major contributors to the formation of memory related to both safe and threatening cues. The requirement for MgN protein synthesis during auditory discrimination and generalization, as well as the role of MgN plasticity in amygdala encoding of discrimination or generalization, have not been directly tested. GluR1 and GluR2 containing AMPA receptors are found at synapses throughout the amygdala and their expression is persistently up-regulated after learning. Some of these receptors are postsynaptic to terminals from MgN neurons. We found that protein synthesis-dependent plasticity in MgN is necessary for elevated freezing to both aversive and safe auditory cues, and that this is accompanied by changes in the expressions of AMPA receptor and synaptic scaffolding proteins (e.g., SHANK) at amygdala synapses. This work contributes to understanding the neural mechanisms underlying increased fear to safety signals after stress.

Rumination and self-reflection in stress narratives and relations to psychological functioning.

The longitudinal study aims to expand what is known about the costs and benefits of narrating stressful experiences by exploring changes in rumination within the narrative process and comparing it to changes in self-reflection. Rumination (e.g., brooding, self-criticism, and negative emotions) and self-reflection were measured in stress narratives of 56 college students. There were several goals: (1) examine changes in narrative rumination and narrative self-reflection over 3 days of writing, (2) examine the relations among the changes in narrative rumination variables and narrative self-reflection and (3) examine how changes in narrative rumination and narrative self-reflection relate to multiple measures of psychological functioning. Overall, individuals increased self-reflection over the 3-day writing task. Individuals who increased ruminative brooding across the 3 days of writing showed lower ego identity development (short term and long term) and self-esteem (short term), while increased self-criticism was positively correlated with identity distress (short term). Implications of the different aspects of narrative rumination, specifically in the context of stressful experiences, are discussed.

Sensory cortical and subcortical auditory neurophysiological changes predict cue-specific extinction behavior enabled by the pharmacological inhibition of an epigenetic regulator during memory formation.

Extinction learning and memory have been broadly investigated at both behavioral and neural levels, but sensory system contributions to extinction processes have been less explored. Using a sound-reward extinction paradigm in male rats, we reveal both cortical and subcortical forms of plasticity associated with the cue-specificity of behavioral extinction memory. In the auditory cortex, frequency tuning narrowed by up to two-thirds of an octave around the remembered extinguished sound cue. Subcortical signals revealed in the auditory brainstem response (ABR) in the same animals developed smaller amplitudes of some (but not all) ABR peaks evoked by the extinguished sound frequency. Interestingly, treatment with an inhibitor of histone deacetylase 3 (HDAC3-i) facilitated both auditory cortical tuning bandwidth changes and changes in subcortical peak amplitude evoked only by the extinguished sound frequency. These neurophysiological changes were correlated to each other, and to the highly precise extinction behavior enabled by HDAC3-i (compared to vehicle controls). Thus, we show for the first time that HDAC3 regulates the specificity of sensory features consolidated in extinction memory. Further, the sensory cortical changes in tuning bandwidth recapitulate known effects of blocking HDAC3 to enhance cue specificity in other behavioral tasks. Therefore, the findings demonstrate how some forms of sensory neuroplasticity may encode specific sensory features of learning experiences in order to enable cue-specific behaviors.

Sex differences in auditory processing vary across estrous cycle.

In humans, females process a sound's harmonics more robustly than males. As estrogen regulates auditory plasticity in a sex-specific manner in seasonally breeding animals, estrogen signaling is one hypothesized mechanism for this difference in humans. To investigate whether sex differences in harmonic encoding vary similarly across the reproductive cycle of mammals, we recorded frequency-following responses (FFRs) to a complex sound in male and female rats. Female FFRs were collected during both low and high levels of circulating estrogen during the estrous cycle. Overall, female rodents had larger harmonic encoding than male rodents, and greater harmonic strength was seen during periods of greater estrogen production in the females. These results argue that hormonal differences, specifically estrogen, underlie sex differences in harmonic encoding in rodents and suggest that a similar mechanism may underlie differences seen in humans.