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

Abstract

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.

Figure 1.

Individual differences in auditory brainstem response plasticity predict sound-specific memory following identical learning experience. (A) Rats (n = 6) learn to associate a 5.0 kHz signal tone with an operant water reward. Individuals are trained to asymptotic performance. Error bars represent ±SEM. (B) Despite being trained with a single tone, the Memory Test reveals variability in how selective responses are to the training tone frequency (5.0 kHz). In fact, only one rat responded substantially more the signal tone versus other tone frequencies. Lines represent individual subjects. Solid lines represent individual subjects. The dashed line represents the Memory Test gradient if responses were equally distributed among all tone frequencies, which would indicate a completely generalized memory. (C) Tone-evoked auditory brainstem responses recordings were obtained from all subjects (n = 6) before (“pretraining,” gray) and after (“posttraining,” black) to determine learning induced changes in signal tone-evoked positive wave 1 (PW1) amplitude. Dashed boxes indicate PW1. Graphs depict data from two of six individuals. (D) There is a significant positive correlation between individual differences in PW1 amplitude changes and the percent of responses made to the signal tone during the Memory Test. Greater amplitude increases predict a greater percent of responses allocated to the signal tone frequency. (*) P < 0.05.

Figure 2.

Posttraining treatment with HDAC3 inhibitor RGF966 promotes frequency-specific memory. (A) RGFP966-treated rats (n = 6) exhibit a frequency-specific response distribution peaking at the signal tone frequency, while vehicle-treated rats (n = 7) exhibit a shallow response gradient. The dashed line represents the Memory Test gradient if responses were equally distributed among all tone frequencies, which would indicate a completely generalized memory. (B) Quantifying the shape of the response distribution using relative measures of responding to the signal tone versus other test tone frequencies reveals that RGFP966-treated animals behaviorally discriminate. They respond to the signal tone more than both distant (far) tones (left) and nearby tones (right). Vehicle-treated rats do not discriminate, responding equally to signal tone versus nearby or distant tones. (C) RGFP966 treatment significantly increases the proportion of individuals with frequency-specific memory type, compared with untreated individuals (n = 6). Vehicle treatment does not alter the distribution of memory phenotype. All error bars represent ±SEM. (*) P < 0.05.

Figure 3.

HDAC3 inhibition promotes learning-induced auditory system plasticity that is signal-specific. Panels represent sound-evoked neural responses from the auditory cortical (A,B) and auditory brainstem response (C,D) recordings. (A) Among auditory cortical sites tuned near the signal tone frequency (±1/3 octave), RGFP966-treated animals (n = 6 animals; 23 recording sites) showed significantly narrower tuning bandwidth at every sound level than vehicle-treated (n = 6 animals, out of 7; 44 recordings sites) and naïve animals (n = 5 animals; 28 recording sites). Bandwidth among vehicle-treated and naïve animals did not differ. There were no group differences in response threshold (dB SPL). (B) Tuning bandwidth between-groups was more similar among auditory cortical sites tuned far away from the signal tone frequency (+1.03–1.33 octaves); RGF966-treated rats only had narrower BW10 (n = 6 animals; 41 recording sites) than vehicle-treated rats (n = 6 animals; 50 recording sites), but were the same as naïve (n = 5 animals; 59 recording sites). (C) Left, Representative signal-tone evoked ABR traces from a single (out of 7) vehicle-treated subject recorded before (“pretraining,” gray) and after (“posttraining,” black). Right, Quantification of learning-induced PW1 amplitude changes in ABRs evoked by the 5.0 kHz signal tone, as well a near (5.946 kHz) and far (11.5 kHz) neighbor frequency. One-sample t-tests reveal no significant amplitude changes in 5.0 or 5.946 kHz evoked PW1, but a significant amplitude decrease in 11.5 kHz evoked PW1. (D) Left, Representative signal-tone evoked ABR traces from a single RGFP966-treated subject (out of 4) recorded before (pink) and after (red) training. Right, Quantification of learning-induced PW1 amplitude changes in ABRs evoked by the 5.0, 5.946, and 11.5 kHz, though none reached statistical significance. All error bars represent ±SEM. (*) P < 0.05, (**)P < 0.01, (***) P < 0.001. In (A,B), asterisks on the left represent comparisons between vehicle and RGFP966; on the right, naïve versus RGFP966. No significant differences were found between naïve and vehicle groups.

Figure 4.

Coordinated forms of auditory system plasticity are correlated with the frequency-specificity of auditory memory. (A) Greater amplitude gains in signal-tone evoked PW1 predict a greater percent of total responses to the signal tone frequency at Memory Test (n = 11). (B) Pretraining PW1 amplitude has no relationship with subsequent memory specificity (n = 13). (C) Greater neural contrast between the signal tone and a near neighbor tone (as measured by PW1 amplitude changes) predicts greater behavioral contrast (measured by difference in percent of bar presses) to that same pair of tones (n = 11). (D) Greater neural contrast between the signal tone and a distant neighbor tone also predicts greater behavioral contrast among that pair of tones (n = 11). (E) Narrower auditory cortical tuning bandwidth (BW20) for sites tuned near the signal tone correlates with a greater percentage of responses to the signal tone (n = 12. (F) Narrower auditory cortical tuning bandwidth (BW20) for sites tuned near the signal tone is predicted by greater amplitude gains in signal tone-evoked PW1 (n = 10). (*)P < 0.05, (**)P < 0.01, (***)P < 0.001.