Specific Early and Late Oddball-Evoked Responses in Excitatory and Inhibitory Neurons of Mouse Auditory Cortex

Neuronal adaptation during repeated standard tone presentation. A, Mean of filtered V_m responses for Exc, SST, and PV neurons for repeated stimulation with the same tone (colored average traces with shaded SEM range; responses were averaged from the initial 6 consecutive standard tone presentations during the oddball paradigm with P_Odd = 0.1, n = 20, 20, 12 for Exc, SST, and PV cells). Early and late time windows for analysis are indicated as black bars below voltage traces (0–0.1 s and 0.2–0.4 s after tone onset, respectively). Gray bars indicate tone durations. B, Equivalent mean of FR responses, showing rapid adaptation of Exc and SST neurons and a more gradual response decrease in PV neurons. C, Changes in V_m amplitude (mean ± SEM) as a function of tone number in the series of six tones. Peak and mean amplitudes, relative to baseline before the first tone, were analyzed for early (top) and late (bottom) time window, respectively. Note that baseline V_m for PV neurons was elevated due to spontaneous activity. D, FR changes as a function of tone number. Peak and mean amplitude of FR were quantified in early and late time window, respectively. Asterisks indicate significance of paired t test comparisons between responses evoked by the nth and the first tone. **p < 0.01 and *p < 0.05.

Oddball tones recover subthreshold and spiking responses of A1 neurons. A, Subthreshold V_m responses (mean ± SD) to pre-oddball standard (PreOdd; left) and oddball (Odd; right) tones for exemplary Exc, SST, and PV neurons with P_Odd = 0.1. B, Difference traces for the three example neurons shown in A. Peak amplitude within the early time window and mean amplitude during the late time window were computed for analysis. C, D, Corresponding mean FR changes (±SD) and FR difference traces for the same cells shown in A. E, Peak V_m response amplitude (ΔV_m) for the first standard tone (First), the pre-oddball standard and the oddball tone for the early (top) and late (bottom) time windows for all Exc, SST, and PV neurons. F, Box plot comparison of the adaptation index (d′_SSA), calculated for V_m depolarization in early (top) and late (bottom) time windows, across cell types and for three different oddball probabilities. G, Mean FR change (ΔFR) for first, pre-oddball, and oddball stimuli in early (top) and late (bottom) time windows for all Exc, SST, and PV neurons. H, Comparison of d′_SSA, calculated for FR change in early (top) and late (bottom) time windows, across cell types and for three different oddball probabilities. For E and G, bars and error bars represent mean ± SEM, with asterisks indicating statistical significance of two-sample comparisons between stimulus types. For F and H, top and bottom edges of boxes represent the first and third quartiles, and the middle line the median. Whiskers indicate 1.5 interquartile range and outliers are shown as red crosses. Top asterisks indicate outcome of one-sample right-tailed t test against the null hypothesis d′_SSA = 0. Bottom asterisks indicate statistical significance of two-sample comparisons between cell types. **p < 0.01, *p < 0.05.

Difference waveform depends on oddball probability and can be used to estimate response onsets. Traces in the top row show the difference traces (V_Diff) of mean oddball-evoked V_m response minus mean pre-oddball evoked V_m response for P_Odd = 0.1, 0.3, and 0.5 in the three cell types (grand averages from n = 20, 20, and 12 for Exc, SST, and PV cells, respectively). The corresponding first derivatives of the difference traces (dV_Diff/dt; smoothed by a moving average filter of 19 ms span at 1 kHz sampling rate) are shown in the bottom row. The onsets of the early responses can be estimated as the latency of the initial peaks of the first derivatives for P_Odd = 0.1 and 0.3 in all three neuronal types. The second local maxima of the first derivative, which are most prominent for P_Odd = 0.1 in Exc and PV cells, specify the onsets of the late components. Gray bars indicate tone duration and black bars the early and late time windows.

Cell-type-specific modulation of oddball tone responses by frequency preference. A, Grand average wave forms for oddball minus pre-oddball difference of the V_m changes evoked when oddball frequency matched the neuron's preferred (left) of nonpreferred (right) frequency. Gray bars indicate tone duration. Black bars represent the early and late component time windows. B, Comparisons of SSA index d′_SSA for V_m changes in response to oddballs of preferred (P) and nonpreferred (NP) frequency within early and late time windows. Boxplots were calculated as in Figure 3. C, D, Same as A and B, but for FR changes. E, Discriminability of tone frequency (f1 vs f2) for oddball compared with pre-oddball standard tones. Traces show averaged binned classification performance of a Bayesian classifier on V_m responses. Chance performance is 50%. Stars indicate significance of Odd versus PreOdd classification difference over the respective time windows (two-way repeated-measures ANOVA). **p < 0.01 *p < 0.05.

Subthreshold late oddball-response component carries signs of deviance detection. A, Schematic illustration of the relation between MS and oddball paradigm. In the MS condition, tones of frequencies f1 and f2 are presented within a pseudo-random sequence of tones of 15 different frequencies. Compared with the oddball condition, no regularity is established. Increased activity to oddballs compared with the same frequency tones in MS condition (MS tones) could indicate genuine deviance detection. B, Grand average V_m amplitudes and FR changes (both relative to baseline activity before each tone) for oddball (Odd; P_Odd = 0.1) and MS tones. Average responses are shown as colored lines and the SEM across each subpopulation as gray shades. Tone duration (0.1 s for both oddball and MS tones) is indicated as gray bars below traces and early and late time windows as black bars. C, D, Comparisons of peak V_m amplitudes (C) and FR changes (D) evoked by oddball and MS tones within early and late time windows. Bar graph indicates the averages and error bars indicate 1 SEM. *p < 0.05.

Oddball membrane potential responses are sensitive to NMDA receptor signaling in a cell-type-specific manner. A, B, Average V_m (A) and firing rate (B) in response to pre-oddball standard (PreOdd) and oddball (Odd; P_Odd = 0.1) tones in example Exc and PV cells with intracellular infusion of NMDA-receptor antagonist MK-801. Colored lines are shown as the average responses and colored shades as the SD for each neuron. Right panels indicate the grand mean difference responses (V_m, FR; oddball − pre-oddball). Solid lines represent the grand average response with MK-801 blockage (n = 11, 9 for Exc and PV cells), dashed lines those under control condition (n = 20, 12 for Exc and PV cells, respectively); colored shades indicate SEM across the subpopulation of each cell type. Tone duration is shown as gray bars and early and late time windows as black bars below traces. Note that MK-801 application leads to a clearly reduced difference waveform for V_m and spiking activity in pyramidal neurons. C, Comparisons of peak V_m amplitudes evoked by the first, pre-oddball standard and oddball tones within early and late time windows under intracellular MK-801 infusion. D, Comparisons of d′_SSA index computed from V_m between control condition and with MK-801 infusion for early and late responses. Data are shown with box plots as represented in Figure 3F,H. Lower stars indicate the outcome of one-sample right-tailed t test against zero and upper stars represent the results of two-sample comparisons between control and MK-801 treatment. E, F, Same as C and D but for FR changes. **p < 0.01, *p < 0.05.