Variability of the time course of stimulus-specific adaptation in the inferior colliculus

Abstract

Stimulus-specific adaptation (SSA) is the ability of some neurons to respond better to rare than to frequent, repetitive stimuli. In the auditory system, SSA has been found at the level of the midbrain, thalamus, and cortex. While previous studies have used the whole overall neuronal response to characterize SSA, here we present a detailed analysis on the variations within the time course of the evoked responses. The extracellular activity of well isolated single neurons from the inferior colliculus (IC) was recorded during stimulation using an oddball paradigm, which is able to elicit SSA. At the same time, these responses were evaluated before, during, and after the microiontophoretic application of gabazine, a specific antagonist of GABA(A) receptors, to study the contribution of inhibition to the responses of these neurons. We then analyzed the difference signal (DS), which is the difference in the PSTH in response to rare and frequent stimuli. We found that, even in a sample of neurons showing strong SSA (i.e., showing larger preference for rare stimuli), the DS was variable and one third of the neurons contained portions that responded significantly better to the frequent stimuli than to the rare. This variability is not observed when averaging the responses of multiple cells. Furthermore, the blockade of GABA(A) receptors increased the number of neurons showing portions that responded better to the frequent stimuli, indicating that inhibition in the IC refines and sharpens SSA in the neural responses.

Keywords: GABA-A receptor; auditory; inhibition; microiontophoresis; single unit activity; stimulus-specific adaptation.

Figure 1

(A) In the oddball paradigm, a sequence is built containing two different stimuli, in this case, two pure tones at different frequencies (f₁, f₂). The stimuli are equally spaced, but their probabilities are different. One of the tones, the standard (blue), appears in 90% of the trials, while the other, called deviant (red), appears in the remaining 10%. A complimentary sequence is presented afterwards, with the probabilities of the stimuli reversed. Thus, comparisons can be drawn for each of the tones when they are presented as deviants or standards. (B,C) Left panels show examples of responses (PSTH) to one tone presented as standard (blue) or deviant (red). The difference signal (DS, green) was calculated as deviant–standard. We classified the shapes of the DS as monophasic (B) or multiphasic (C). The bin size for all the histograms in this study was 1 ms. The shaded background indicates the duration of the stimulus. Right panels show the cumulative functions of each corresponding DS. The raw cumulative sum function (gray) was smoothed, and the peaks and valleys (circles) were found (see “Materials and Methods”). The increasing sections between peaks (red) indicate portions were the DS is positive, while the decreasing sections indicate the negative portions of the DS. The extent of the negative portions was used to determine the type of DS. (D) Only DS values larger than the baseline DS were considered for the study. The positive (red) and negative (blue) portions of the DS were measured separately. The measurements included the latency and magnitude of the peaks (arrowheads), the duration and total area of each portion (red and blue areas), and the latency of the median spike (arrows). The horizontal dashed lines represent the threshold for the baseline activity, i.e., random fluctuations of the DS (mean + 3SD).

Figure 2

Grand average PSTH from the sample of neurons in the control (A) and gabazine (B) conditions. The red lines correspond to the responses to the deviant stimuli, while the blue lines represent the responses to the standard stimuli. The difference signal (DS; deviant-standard) is represented in green. The shaded background indicates the duration of the stimulus. The length of the histogram bins is 1 ms. (C) Distribution of the cases were the DS was classified as multiphasic. The Control and Gabazine groups indicate the number of cases that only presented a negative DS during one of those conditions. Both indicates the neurons that had a negative part in both conditions, while neurons that did not have a negative portion under any condition are labeled as None. (D) Distribution of the cases based on the firing pattern. S-S, both standard and deviant were sustained; S-O, only the deviant was onset; O-S, only the standard was onset; O-O, both the deviant and the standard were onset. (E,F) Examples from two different neurons during the control and gabazine conditions. In both cases, the DS type is monophasic during the control condition, but in (F) the DS type transforms to multiphasic during the gabazine condition. The insets show the cumulative function of the DS, used for the classification.

Figure 3

Duration of the DS (number of 1-ms bins where the response is significantly larger than the baseline DS). The duration of both the positive (A) and negative (B) parts of the DS increased during the application of gabazine. (C) Mean and standard deviation of the duration for all the cases pooled together, in the control (solid fill) and gabazine (pattern fill) conditions. (D) Mean and standard deviation of the duration, grouped by DS type. The duration of the negative part of the DS was shorter than the duration of the positive part for most neurons, both in the control (E) and the gabazine (F) conditions. The axes in these panels have been plotted at different scales for a better visualization of the data. (G) Mean and standard deviation of the different firing pattern groups for the monophasic or (H) multiphasic units, including units in both the control and gabazine conditions. Mono, monophasic; Multi, multiphasic. S-S, standard and deviant sustained; S-O, standard sustained and deviant onset; O-S, standard onset and deviant sustained; O-O, standard and deviant onset. Asterisks indicate p < 0.05. For all the scatter plots in this and similar figures, n = 92 unless stated otherwise. In this and similar figures, some of the significance brackets have been collapsed into a complex bracket, to reduce clutter. They indicate significant differences (p < 0.05) between the group at the square end and every group under an arrowhead.

Figure 4

Area (accumulated response) of the DS for each neuron, corrected for the baseline DS. The area of both the positive (A) and negative (B) portions of the DS increased during the gabazine condition. (C) Mean and standard deviation of the area for all the cases pooled together, in the control (solid fill) and gabazine (pattern fill) conditions. (D) Mean and standard deviation of the area, grouped by DS type. The area of the positive portions of the DS was larger than that of the negative ones for most neurons, both in the control (E) and the gabazine (F) conditions. The axes in these panels have been plotted at different scales for a better visualization of the data. (G) Mean and standard deviation of the different firing pattern groups for the monophasic or (H) multiphasic units, including units in both the control and gabazine conditions. The area ratio (negative area/positive area) (I) and the percentage of positive area (J) for each individual DS show that, while the amount of positive and negative DS portions changed during the gabazine condition, there was no clear trend. Mono, monophasic; Multi, multiphasic. S-S, standard and deviant sustained; S-O, standard sustained and deviant onset; O-S, standard onset and deviant sustained; O-O, standard and deviant onset. Asterisks indicate p < 0.05.

Figure 5

Peak firing rate of the DS for each neuron. The most positive (positive peak) and most negative (negative peak) values of the DS for each neuron are represented here in absolute value. The effect of removing GABA_A inhibition is depicted in (A) and (B). Both the positive peak rates (A) and the negative (B) tend to increase due to the application of gabazine, to the point of the appearance of negative parts in the DS where there was previously none in the control condition (B). (C) Mean and standard deviation of the peak firing rate for all the cases pooled together, in the control (solid fill) and gabazine (pattern fill) conditions. (D) Mean and standard deviation of the peak firing rate grouped by DS type. In the control condition (E), the peak positive DS extended over a wide range of values, while the negative peak was limited to much smaller rates. During the gabazine condition (F), both positive and negative peaks became slightly larger. In almost every case, the positive peak was much larger than the negative peak. The axes in these panels have been plotted at different scales for a better visualization of the data. (G) Mean and standard deviation of the different firing pattern groups for the monophasic or (H) multiphasic units, including units in both the control and gabazine conditions. Mono, monophasic; Multi, multiphasic. S-S, standard and deviant sustained; S-O, standard sustained and deviant onset; O-S, standard onset and deviant sustained; O-O, standard and deviant onset. Asterisks indicate p < 0.05.

Figure 6

The latency of the positive DS peak was relatively short (10–40 ms) and was little affected by gabazine (A), while the latency of the negative peak extended over a longer range of values (B). Some of the cases did not contain a negative part of the DS, so the corresponding latencies could not be calculated. The number of cases plotted is indicated inside each panel. (C) Mean and standard deviation of the latency of the peaks for all the cases pooled together, in the control (solid fill) and gabazine (pattern fill) conditions. (D) Mean and standard deviation of the latency of the peaks, grouped by DS type. In both the control (E) and the gabazine (F) condition, the latency of the positive DS peak was shorter than the latency of the negative peak for most neurons. (G) Mean and standard deviation of the different firing pattern groups for the monophasic or (H) multiphasic units, including units in both the control and gabazine conditions. Mono, monophasic; Multi, multiphasic. S-S, standard and deviant sustained; S-O, standard sustained and deviant onset; O-S, standard onset and deviant sustained; O-O, standard and deviant onset. Asterisks indicate p < 0.05.

Figure 7

Probability of occurrence of a positive (red) DS value or a negative one (blue) along time. Note how in the gabazine condition (B) the probabilities are higher and skewed toward longer latencies, compared to the control condition (A).