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. 2015 Sep 23;35(38):13124-32.
doi: 10.1523/JNEUROSCI.0914-15.2015.

Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation

Kasia M Bieszczad  1 , Kiro Bechay  2 , James R Rusche  3 , Vincent Jacques  3 , Shashi Kudugunti  3 , Wenyan Miao  3 , Norman M Weinberger  4 , James L McGaugh  2 , Marcelo A Wood  5
Affiliations

Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation

Kasia M Bieszczad et al. J Neurosci. .

Abstract

Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.

Keywords: auditory cortex; chromatin modification; cortical plasticity; epigenetics; histone acetylation; memory.

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Figures

Figure 1.
Figure 1.
Protocol and timeline for auditory learning, memory testing and determining A1 plasticity. A, RGFP966 kinetics in auditory cortex. The effective 10 mg/kg dose of RGFP966 (a selective HDAC3 inhibitor) was established by Malvaez et al. (2013) and confirmed here to penetrate the blood–brain barrier (Cmax = 415 ng/g ± 120 at 30 min; Cmax = 1065 ng/g ± 163 at 75 min; Cmax = 451 ng/g ± 54 at 4 h). Its action in rat auditory cortex occurs with similar pharmacokinetics to treatments with RGFP966 that are known to modulate memory formation and persistence (Malvaez et al., 2013). Data shown are mean ± SEM (N = 3 untrained animals) for each time point. Inset, Chemical structure of RGFP966. B, All animals were trained to associate sound with reward in an instrumental conditioning paradigm (sound-reward training). Signal A was a pure tone (5.0 kHz, 70 dB SPL) that predicted the availability of reward after a bar-press response. Signal B was a sound typical of behavioral training equipment that was produced by a mechanical lever holding reward; it predicted the immediate delivery of reward on correct trials (1–2 kHz). After training, the frequency specificity of associative memory was determined using various test tones (including Signal A, 5.0 kHz, and Signal B, 1.1 kHz) to indicate which frequency elicited reward-related bar-pressing behavior (memory test). Rewards were omitted during this session. Frequency tuning and tonotopic representation in A1 were determined by electrophysiological recording (A1 mapping). C, Performance on the auditory association task was not affected by RGFP966. There are no significant differences between groups before treatment with RGFP966 (days 1–4) and after treatment (days 5–8; before, RGFP966, 8.5 ± 2.5% vs vehicle, 6.4 ± 1.4%; p = 0.248; after, RGFP966, 33.3 ± 6.4% vs vehicle, 26.6 ± 5.2%; p = 0.101; N = 6 for each group). Likewise, asymptotic levels of performance immediately preceding the memory test are not significantly different between groups (RGFP966, N = 6, 51.1 ± 6.5% vs vehicle, N = 6, 57.4 ± 6.5%; p = 0.284). RGFP966 similarly did not affect the memory test session, which was without any rewards, as determined by a reinstatement session (i.e., a session identical to training and with rewards) the day immediately following the memory test (i.e., on day n + 2; RGFP966, 54.3 ± 7.8% vs vehicle, 60.0 ± 9.9%; p = 0.345; N = 6 for each group).
Figure 2.
Figure 2.
RGFP966 enables highly specific memory and A1 plasticity. A, Behavior. The latency to bar press for each test tone frequency was determined in each group to indicate which frequencies best elicited reward-related behavior. Rats treated with RGFP966 (N = 6) were faster to respond than performance-matched rats treated with vehicle alone (N = 6) to frequencies associated with reward (Signal A) and reward delivery [Signal B; Z-score for paired difference in latency to respond to each test frequency; calculated as RGFP966 minus vehicle, responses to 1.1 kHz (Signal B) were on average 1.25 ± 0.7 s significantly faster, p = 0.030; responses to 2.4 kHz were 0.26 ± 0.5 s faster, p = 0.280; responses to 5.0 kHz (Signal A) were 0.75 ± 0.3 s significantly faster, p = 0.003; responses to 10.6 kHz were 0.75 ± 0.3 s faster, p = 0.380; responses to 22.4 kHz were 0.42 ± 0.5 s slower, p = 0.830), which indicates the formation of a more highly specific memory for acoustic frequency with RGFP966. Inset, Mean (±SE) bar-press latencies show group response gradients for the RGFP966 (N = 6) and vehicle (N = 6) groups, without respect to performance-matched pairs. B, Sound frequency representation in A1. Rats treated with RGFP966 had greater expansions of best frequency areas in A1 to overrepresent sound frequencies near the reward, Signal A (5.0 kHz; in the 4.0–6.3 kHz frequency band) and reward delivery signal, Signal B (1.1 kHz; in the 1.0–1.6 kHz frequency band). Asterisks indicate frequency bands that were significant with both paired (sign test) and unpaired (Mann–Whitney–Wilcoxon) one-sided tests after Holm–Bonferroni correction (p values for sign test/Mann–Whitney–Wilcoxon tests are indicated in parentheses): 1.0–1.6 kHz, 4.8 ± 2.6% significant increase in A1 area (p = 0.002/p = 0.004); 1.6–2.5 kHz, 6.9 ± 4.8% less A1 area (p = 0.984/p = 0.479); 2.5–4.0 kHz, 3.7 ± 2.4% less A1 area (p = 0.891/p = 0.418); 4.0–6.3 kHz, 4.1 ± 2.4% significant increase in A1 area (p = 0.022/p = 0.010); 6.3–10 kHz, 3.5 ± 3.2% increase in A1 area (p = 0.328/p = 0.016); 10–15.9 kHz, 0.7 ± 1.5% increase in A1 area (p = 0.219/p = 0.366); 15.9–25.2 kHz, 1.2 ± 3.1% increase in A1 area (p = 0.086/p = 0.116); 25.2–39.9 kHz, 0.9 ± 3.2% less A1 area (p = 0.445/p = 0.334). C, Sound level representation in A1. Analysis of best frequency areas of A1 representation between groups (y-axis) across various sound levels (x-axis) revealed that frequency-specific expansion for Signal A in rats treated with RGFP966 occurred only in the representation of the best frequency determined at 70 dB SPL, i.e., at the unique sound level of Signal A. The expansion of Signal B occurred across all sound levels. Asterisks indicate that sound levels that were significantly increased in RGFP966-treated rats using both paired (sign test) and unpaired (Mann–Whitney–Wilcoxon) one-sided tests after Holm–Bonferroni correction (p values for the sign test/Mann—Whitney–Wilcoxon tests are indicated in parentheses): for Signal A, 70 dB, 4.1 ± 2.4% significant increase in A1 area (p = 0.027/p = 0.030); 60 dB, 4.2 ± 2.3% significant increase in A1 area (p = 0.027/p = 0.044); 50 dB, 0.02 ± 2.5% nonsignificant change in A1 area (p = 0.055/p = 0.089); 40 dB, 2.9 ± 2.2% decrease in A1 area (p = 0.056/p = 0.084); for Signal B: 70 dB, 4.8 ± 2.6% significant increase in A1 area (p = 0.004/p = 0.004); 60 dB, 8.0 ± 5.0% significant increase in A1 area (p = 0.041/p = 0.041); 50 dB, 4.7 ± 3.6% significant increase in A1 area (p = 0.029/p = 0.036); 40 dB, 4.3 ± 3.8% significant increase in A1 area (p = 0.014/p = 0.041). Mean differences between six pairs of RGFP966- and vehicle-treated animals (total N = 12) are shown (±SE). Note that the study design did not permit detection of significant differences between Signal A and Signal B in the identified behavioral and neural response changes between groups. Thus, the report focuses on RGFP966 versus vehicle treatment effects with respect to frequency specificity per se.
Figure 3.
Figure 3.
RGFP966 enables highly specific cortical remodeling that changes the landscape of sound representation in A1. A, Tonotopic plasticity in A1. Representative maps show sound frequency representation in A1 for a pair of performance-matched rats (+VEH, treated with vehicle treated during training; +RGFP966, treated with RGPF966 during training). Maps were constructed using Voronoi tessellation algorithms that circumscribe and denote CF tuning by colored polygons (cool colors show low CFs, whereas warmer colors show higher CFs). Note the general progression of CFs from posterior to anterior sites across the cortical surface. Solid lines outline cortical areas that represent a quarter-octave range around the Signal A frequency. Likewise, stippled lines outline cortical areas that represent a quarter-octave range around Signal B. Ruler bar shows 1.0 mm across the AP and DV surfaces, as indicated. B, Signal-specific map reorganization. Cortical remodeling induced by RGFP966 in A1 enables expansions (shown in red shading) in the representation of reward-predicting auditory cues, here shown as the difference in the amount of percentage increase in A1 tonotopic representation across different frequency ranges (x-axis) at different sound levels (y-axis). Rats treated with RGFP966 show enhanced specificity of A1 reorganization relative to vehicle-treated rats (increases greater than vehicle controls indicated by red shading and decreases less than controls by blue). Maximal expansion in A1 representation occurs for the identity of specific reward signals, e.g., sound Signal A (5 kHz, 70 dB, shown by the solid circle) and Signal B (1–2 kHz, indicated by the thick solid line). Note that this figure combines and expands the data shown in Figure 2.
Figure 4.
Figure 4.
RGFP966 enables highly specific cortical remodeling: reduced tuning bandwidth. A second form of A1 representational plasticity reduces tuning bandwidth only in neurons tuned near an auditory signal associated with reward. Panels show tuning curve means of populations of neurons with CFs tuned within the range indicated in the lower left. All bandwidths are shown in decibel level relative to CF threshold. Asterisks in the middle panel indicate significant decreases in bandwidth (Mann–Whitney test, p < 0.05), which occurred for sites tuned near Signal A at 30 dB (∼0.5 octave decrease in tuning bandwidth) and 40 dB (∼1.0 octave decrease in tuning bandwidth) above threshold. Detection of changes in bandwidth for Signal B were not possible in this dataset due to a sampling floor effect on the low-frequency side of the Signal B frequency range.
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