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Comparative Study
. 2007 May 30;27(22):5958-66.
doi: 10.1523/JNEUROSCI.5218-06.2007.

Processing of temporal unpredictability in human and animal amygdala

Cyril Herry  1 , Dominik R Bach, Fabrizio Esposito, Francesco Di Salle, Walter J Perrig, Klaus Scheffler, Andreas Lüthi, Erich Seifritz
Affiliations
Comparative Study

Processing of temporal unpredictability in human and animal amygdala

Cyril Herry et al. J Neurosci. .

Abstract

The amygdala has been studied extensively for its critical role in associative fear conditioning in animals and humans. Noxious stimuli, such as those used for fear conditioning, are most effective in eliciting behavioral responses and amygdala activation when experienced in an unpredictable manner. Here, we show, using a translational approach in mice and humans, that unpredictability per se without interaction with motivational information is sufficient to induce sustained neural activity in the amygdala and to elicit anxiety-like behavior. Exposing mice to mere temporal unpredictability within a time series of neutral sound pulses in an otherwise neutral sensory environment increased expression of the immediate-early gene c-fos and prevented rapid habituation of single neuron activity in the basolateral amygdala. At the behavioral level, unpredictable, but not predictable, auditory stimulation induced avoidance and anxiety-like behavior. In humans, functional magnetic resonance imaging revealed that temporal unpredictably causes sustained neural activity in amygdala and anxiety-like behavior as quantified by enhanced attention toward emotional faces. Our findings show that unpredictability per se is an important feature of the sensory environment influencing habituation of neuronal activity in amygdala and emotional behavior and indicate that regulation of amygdala habituation represents an evolutionary-conserved mechanism for adapting behavior in anticipation of temporally unpredictable events.

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Figures

Figure 1.
Figure 1.
Schematic of auditory stimulation time series with predictable and unpredictable timing of the sound pulses. The randomized pulse sequence (bottom) was generated from the regular sequence (top) by a random temporal shift of each single pulse. The randomly selected temporal shift is confined to an interval σ with uniform probability within σ (see Materials and Methods for details).
Figure 2.
Figure 2.
Increased c-Fos induction by unpredictably timed sound pulse stimulation in the lateral and basal amygdala. a, c-Fos induction in the LA, BA, and central (CE) nuclei of the amygdala, ventral auditory cortex (AUv), medial division of the medial geniculate nucleus of the thalamus (MGm), ventral hippocampus (HCv), and primary motor cortex (M1) quantified 30 min (n = 4–5 per group) and 120 min (n = 4–6 per group) after the start of unpredictably timed sound pulse stimulation (stim). Results are expressed as a percentage of the number of c-Fos-positive cells induced by predictably timed sound pulse stimulation (Pred. tone). All p < 0.05 (Scheffé's F test). *p < 0.05; **p < 0.01. b, c, Photomicrographs illustrating increased c-Fos levels in the LA 120 min after the start of unpredictably versus predictably timed sound pulse stimulation. d, e, Photomicrographs illustrating increased c-Fos levels in the BA 30 min after the start of unpredictably versus predictably timed sound pulse stimulation.
Figure 3.
Figure 3.
Differential neural activity during unpredictably and predictably timed sound pulse stimulation in BLA neurons. a, Recording sites in the BLA. b, Waveforms of a representative neuron recorded during predictably and unpredictably timed sound pulse stimulation. c, Raster plot and peristimulus time histogram (PSTH) illustrating sound pulse-evoked activity of a representative neuron recorded in the BLA during predictably (top) and unpredictably (bottom) timed sound pulse stimulation (bins of 20 ms). The red transparent box indicates time of sound pulse stimulation. d, Group PSTHs showing increased Z score for basolateral neurons recorded during unpredictably (red bars) versus predictably timed (blue bars) sound pulse stimulation (bins of 20 ms; n = 28; p = 0.007, 2-tailed paired t test on the average Z score 0–80 ms after sound pulse onset). The red box indicates time of sound pulse stimulation. e, Sound pulse-evoked neural responses (plotted as the percentage of the Z score of the first 2 sound pulses) during predictable (blue symbols) and unpredictable (red symbols) sound pulse sequence stimulation. During predictably timed but not during unpredictably timed sound pulse stimulation, neural responses exhibit rapid and significant habituation (predictable: F (27,4) = 2.83, p = 0.03; unpredictable: F (27,4) = 0.17, p = 0.95; 1-way ANOVA with repeated measures on the average Z score 0–80 ms after sound pulse onset). Pred., Predictably timed; Unpred., unpredictably timed.
Figure 4.
Figure 4.
Unpredictably timed sound pulse sequence stimulation induces anxiety-like and avoidance behavior in mice. a, Unpredictably timed sound pulse stimulation decreases time spent on open arms of the EPM (unpredictable vs silent control period: n = 5, p = 0.005, paired t test; predictable vs silent control period: n = 5, p = 0.649, paired t test; unpredictable vs predictable: n = 5 per group, p = 0.021, unpaired t test; **p < 0.01). b, No difference in locomotor activity was measured by the mean speed (centimeters per second) during unpredictably and predictably timed sound pulse stimulation (unpredictable vs silent control period: n = 8, p = 0.246, paired t test; predictable vs silent control period: n = 8, p = 0.704, paired t test; unpredictable vs predictable: n = 8, p = 0.205, paired t test; **p < 0.01). c, Top, Unpredictably timed sound pulse stimulation induces avoidance behavior in a two-compartment place-aversion paradigm. Systematic exposure to unpredictably timed sound pulse stimulation in the preferred compartment (and predictably timed stimulation in the nonpreferred compartment) leads to progressive avoidance of the preferred compartment [n = 5; F (2,16) = 39.82; p < 0.001, 2-way ANOVA with repeated measures (interaction between group × time point)]. Direct comparison between predictably and unpredictably timed sound pulse stimulations shows a significant difference for the first and the last time points (F (1,8) = 60.04, p < 0.001 and F (1,8) = 16.37, p < 0.01, Scheffé's F test). Bottom, Same as top panel, except that during training, unpredictably timed sound pulse stimulation was delivered in the nonpreferred compartment (n = 6). Mice continued to spend more time in the preferred compartment if it was associated with predictably timed sound pulses [F (2,20) = 1.57, p = 0.23, 2-way ANOVA with repeated measures (interaction between group × time point)]. No stim., No stimulation; Unpred., unpredictably timed; Pred., predictably timed; Pref. comp., preferred compartment; Non-pref. comp., nonpreferred compartment.
Figure 5.
Figure 5.
Effects of auditory stimulation with sequence of unpredictably timed sound pulses on human brain activity and behavior. a, fMRI yields sustained amygdala activity during 60 s stimulation with a sequence of temporally unpredictable compared with predictable sound pulses. Shown is a coronal slice (y, −11 mm) of Talairach-transformed anatomical MRI brain scan (averaged across all subjects) with a statistical parametric map superimposed [balanced random-effects GLM contrast; voxel-level threshold, p uncorrected < 0.001; cluster-level threshold (111 mm3), p corrected < 0.05; color gradient, t (19) values ]. b, Timeline of visual dot-probe task measuring attention toward threat information. The task was performed during presentation of sequences of predictably and unpredictably timed sound pulses. After the presentation of a fixation cross (950 ms) and two modified Ekman faces (Büchel et al., 1998), subjects had to respond by key press to the position of a dot appearing at the position of one of the two faces. c, The bias index served as a quantitative measure of attention toward threat information in the visual dot probe; it was calculated as RT difference between trials with the dot appearing in the angry face's position (congruent) and those with the dot in the opposite position (incongruent). The presentation of sequences with unpredictable sound pulse timing during the dot probe task produced an increase in bias index (mean ± SEM; *F (1,34) = 7.04; p = 0.01), indicating unpredictability-related enhanced (anxiety-like) attention toward angry faces. Unpred, Unpredictably timed; Pred, predictably timed.
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