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Cellular and oscillatory substrates of fear extinction learning

Nature Neuroscience volume 20, pages 1624–1633 (2017)Cite this article

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Abstract

The mammalian brain contains dedicated circuits for both the learned expression and suppression of fear. These circuits require precise coordination to facilitate the appropriate expression of fear behavior, but the mechanisms underlying this coordination remain unclear. Using a combination of chemogenetics, activity-based neuronal-ensemble labeling and in vivo electrophysiology, we found that fear extinction learning confers on parvalbumin-expressing (PV) interneurons in the basolateral amygdala (BLA) a dedicated role in the selective suppression of a previously encoded fear memory and BLA fear-encoding neurons. In addition, following extinction learning, PV interneurons enable a competing interaction between a 6–12 Hz oscillation and a fear-associated 3–6 Hz oscillation within the BLA. Loss of this competition increases a 3–6 Hz oscillatory signature, with BLA→medial prefrontal cortex directionality signaling the recurrence of fear expression. The discovery of cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV interneurons could inform therapies aimed at preventing the pathological recurrence of fear following extinction learning.

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Figure 1: BLA PV interneurons selectively suppress conditioned fear behavior and neuronal ensembles following extinction.
Figure 2: Structured perisomatic inhibition selectively silences BLA fear neurons during post-extinction retrieval.
Figure 3: BLA PV interneurons control the balance between two functionally opposed low-frequency oscillations.
Figure 4: BLA PV interneurons enable competition between 3–6 Hz and 6–12 Hz oscillations.
Figure 5: BLA PV interneurons participate in a reciprocal BLA–mPFC circuit.
Figure 6: Silencing BLA PV interneurons shifts mPFC ensemble dynamics.
Figure 7: BLA PV interneurons control directionality of 3–6 and 6–12 Hz oscillations following extinction.

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Acknowledgements

We thank B. Roth (UNC Vector Core) and E. Callaway (Salk Institute) for reagents. We thank A. Poulopoulos and T. Papouin for discussions and critical reading of the manuscript. We thank J. Sasaki Russell and S. Viola for technical assistance. This work was supported in part by grants to L.G.R. (NIH R01 MH104589) and J.M. (NIH R01 NS102937), and by the Tufts Center for Neuroscience Research (NIH P30 NS047243). P.D. was supported by the Synapse Neurobiology Training Program (NIH T32 NS061764) and the Medical Scientist Training Program at Tufts University (NIH T32 GM008448).

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Authors and Affiliations

  1. Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA

    Patrick Davis, Yosif Zaki, Jamie Maguire & Leon G Reijmers

  2. Medical Scientist Training Program and Graduate Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA

    Patrick Davis

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Contributions

P.D., J.M., and L.G.R. conceived and designed the experiments. P.D. and Y.Z. executed the experiments. P.D., Y.Z., and L.G.R. analyzed the experiments. P.D. and L.G.R. wrote the manuscript.

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Correspondence to Leon G Reijmers.

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Integrated supplementary information

Supplementary Figure 1 Selective expression of hM4Di-mCherry in BLA PV interneurons mediates behavioral effect.

a) Representative 10x confocal z-stack of BLA showing selective expression of hM4Di-mCherry in parvalbumin-positive (PV) interneurons (red: mCherry, green: parvalbumin). b) Quantification of % overlap between hM4Di-mCHerry and PV (n = 10 mice). c-f) The number of tagged GFP+ neurons did not differ between VEH and CNO injected mice (c, unpaired t-test: t(13) = 0.7906, P = 0.4433, VEH n = 7 mice, CNO n = 8 mice; d, unpaired t-test: t(10) = 0.2709, P = 0.7920, VEH n = 7 mice, CNO n = 5 mice; C3 L2-3, Mann-Whitney test: U = 21, P = 0.8981, VEH n = 5 mice, CNO n = 9 mice; e, L5-6, Mann-Whitney test: U = 21, P = 0.8981, VEH n = 5 mice, CNO n = 9 mice; f, L2-3, Mann-Whitney test: U = 20, P = 0.7972, VEH n = 5 mice, CNO n = 9 mice; C4 L5-6, Mann-Whitney test: U = 22, P > 0.9999, VEH n = 5 mice, CNO n = 9 mice;). g) Mice exhibit increasing freezing levels as conditioning progresses on day 1, and decreasing freezing levels as extinction progresses on days 2-3 (Wilcoxon matched-pairs FC1 versus EXT1: W = 435, P < 0.0001, n = 29 mice; Wilcoxon matched-pairs EXT1 versus EXT8: W = -435, P < 0.0001, n = 29 mice). h) Mice freeze more during retrieval after CNO injection regardless of order of trials (CNO first, Wilcoxon matched-pairs: W = -75, P = 0.0015, n = 13 mice; VEH first, Wilcoxon matched-pairs: W = 77, P = 0.0264, n = 16 mice). i) CNO has no effect on behavior in animals not expressing hM4Di (SHAM injection) (Wilcoxon matched-pairs: W = 7, P = 0.7344, n = 9 mice). j) Mice exhibit increased freezing levels after CNO injection compared to VEH injection in the EXT-tagged group (Wilcoxon matched-pairs: W = 75, P = 0.0059, n = 13 mice). All box plot graphs show median (line inside box), 25% and 75% percentiles (box edges), and minimum and maximum values (error bars).

Supplementary Figure 2 Perisomatic analysis of BLA ensembles.

a) Example 40x confocal z-stack showing extraction of hM4Di-mCHerry perisomatic signal (middle) from nuclear ZIF signal (right) using DAPI mask. INSET: Example GFP+ neuron displayed in left panels. b) Representative ZIF+ and ZIF- nuclei in BLA of CNO- and VEH-injected mice demonstrating relationship between perisomatic puncta and ZIF expression. c) The amount of perisomatic mCherry around tagged GFP+ neurons, normalized within each mouse to perisomatic mCherry around GFP- neurons, was similar in FC-tagged and EXT tagged mice (unpaired t-test: t(16) = 0.04475, P = 0.9649, FC-tagged n = 8 mice, EXT-tagged n = 10 mice). Box plot graph shows median (line inside box), 25% and 75% percentiles (box edges), and minimum and maximum values (error bars).

Supplementary Figure 3 Oscillatory states following fear conditioning and following fear extinction.

a) Location of electrode tips in BLA (left), and mPFC (right), with example images of nissl-stained tissue showing electrode sites. b) Freezing data (minutes 2-3) from fear conditioning and extinction trials of mice used for LFP recordings (Wilcoxon matched-pairs FC1 versus EXT1: W = 64, P = 0.0020, n = 11 mice). c) Averaged power spectra across freezing and non-freezing bouts during EXT1 trials (BLA n = 11, mPFC n = 9; shaded bands mark standard error of mean). d) Averaged power spectra of post-extinction retrieval trials following vehicle or CNO injection (BLA n = 11, mPFC n = 9; shaded bands mark standard error of mean). e) Example of a VEH injected mouse demonstrating a correlation between BLA 3-6 Hz / 6-12 Hz power ratio and freezing during 12 time bins within a post-extinction retrieval trial (linear regression: F(1,10) = 19.68, P = 0.0013, n = 12 bins of 20 seconds each). f) The averaged within-trial Pearson’s correlation coefficients, calculated as in e), was significantly higher than zero in the VEH and CNO groups, but not in the EXT1 group (EXT1 Wilcoxon Signed Rank Test with theoretical median = 0: W = 13, P = 0.4961, n = 9 mice; VEH Wilcoxon Signed Rank Test with theoretical median = 0: W = 30, P = 0.0391, n = 8 mice; CNO Wilcoxon Signed Rank Test with theoretical median = 0: W = 55, P = 0.0020, n = 10 mice). g) CNO increases 3-6 / 6-12 Hz power ratio within bouts of freezing in both BLA (Wilcoxon matched-pairs: W = 66, P = 0.0010, n = 11), and in mPFC (Wilcoxon matched-pairs: W = 45, P = 0.0039, n = 9). h) Following fear conditioning, but before extinction takes effect (EXT1 trial), there is a trend for a larger mPFC lead in the 3-6 Hz band during the first 5 seconds following onset of freezing (3-6 Hz paired t-test: t(20) = 1.825, P = 0.0830, n = 21 mice; 6-12 Hz paired t-test: t(20) = 0.5692, P = 0.5756, n = 21 mice). i) Following fear conditioning, but before extinction takes effect (EXT1 trial), there is a trend for an increased probability that mPFC will lead BLA in the 3-6 Hz band, but not in the 6-12 Hz band (3-6 Hz Wilcoxon matched-pairs: W = 19, P = 0.0625, n = 8; 6-12 Hz Wilcoxon matched-pairs: W = -10, P = 0.1250, n = 8). All box plot graphs show median (line inside box), 25% and 75% percentiles (box edges), and minimum and maximum values (error bars).

Supplementary Figure 4 Example LFP traces filtered at different frequency ranges.

a) Example traces collected in the BLA during the first extinction trial on day 2 (EXT1), with red bar indicating freezing epochs. b) Example traces collected in the BLA during the first extinction trial on day 2 (EXT1), with red bar indicating freezing epochs. c) Example traces simultaneously collected in the BLA and mPFC during a post-extinction retrieval trial, with red bar indicating freezing epoch.

Supplementary Figure 5 Cross-correlation between 3–6 Hz and 6–12 Hz does not correlate with 6–12 Hz power.

a) Data from 10s bins from an example mouse demonstrating lack of correlation between 6-12 Hz power and 3-6 Hz: 6-12 Hz cross-correlation coefficients (VEH Pearson r = -0.08202, P = 0.8105, n = 11 bins of 10 seconds each; CNO Pearson r = 0.1049, P = 0.7731, n = 10 bins of 10 seconds each). b) Averaged Pearson’s correlation coefficients, calculated as in a), do not differ from zero in the VEH and CNO groups (VEH Wilcoxon Signed Rank Test with theoretical median = 0: W = -25, P = 0.2227, n = 10 mice; CNO Wilcoxon Signed Rank Test with theoretical median = 0: W = 7, P = 0.7520, n = 10 mice). c) Data from same analysis as in a) normalized to within-trial values and pooled together from all retrieval trials (VEH, linear regression: F(1,101) = 0.7014, R^2 = 0.0069, P = 0.4043, n = 103 bins of 10 sec each from 11 mice; CNO, linear regression: F(1,95) = 0.08185, R^2=0.0008, P = 0.7754, n = 97 bins of 10 sec each from 11 mice). Box plot graph shows median (line inside box), 25% and 75% percentiles (box edges), and minimum and maximum values (error bars).

Supplementary Figure 6 Granger causality analysis supports BLA→mPFC directionality in the 3–6 Hz range during post-extinction freezing.

a-b) Examples of Granger causality analysis for two post-extinction retrieval trials of the same mouse (a), first 2 minutes of the retrieval trial following vehicle injection; b), first 2 minutes of the retrieval trial following CNO injection; red boxes: periods of >50% freezing per bin; nDTF: normalized Directed Transfer Function). c) Granger causality when mice were freezing during post-extinction retrieval was significantly higher in BLA→mPFC than mPFC→BLA direction in the 4-8 Hz range (n = 7 mice; repeated measures two-way ANOVA: frequency F(14,84) = 4.889, P < 0.0001, direction F (1,6) = 10.34, P = 0.0182, frequency x direction F (14,84) = 2.947, P = 0.0011; Sidak's multiple comparisons tests used for comparing BLA→mPFC versus mPFC→BLA direction at single frequencies; shaded bands mark standard error of mean). d) Granger causality when mice were not freezing during post-extinction retrieval was significantly higher in BLA→mPFC than mPFC→BLA direction in the 5-8 Hz range (n = 7 mice; repeated measures two-way ANOVA: frequency F (14,84) = 3.918, P < 0.0001, direction F (1,6) = 4.796, P = 0.0711, frequency x direction F (14,84) = 2.725, P = 0.0024; Sidak's multiple comparisons tests used for comparing BLA→mPFC versus mPFC→BLA direction at single frequencies; shaded bands mark standard error of mean). e) During freezing epochs, but not during no freezing epochs, BLA→mPFC directionality was stronger in the 3-6 Hz range than in the 6-12 Hz range (n = 7 mice; freezing: paired t-test, t(6) = 4.83, P = 0.0029; no freezing: paired t-test, t(6) = 1.776, P = 0.1260). f) Freezing was associated with a higher relative BLA lead at 4 Hz (n = 7 mice; repeated measures two-way ANOVA: frequency F (14,84) = 3.167, P = 0.0005, freezing F (1,6) = 1.578, P = 0.2557, frequency x freezing F (14,84) = 2.089, P = 0.0203; Sidak's multiple comparisons tests used for comparing freezing versus no freezing at single frequencies; shaded bands mark standard error of mean). g) Freezing was associated with a higher relative 3-6 Hz BLA lead (n = 7 mice: Wilcoxon matched-pairs: W = -26, P = 0.0313). h) The CNO-induced increase in freezing correlated with the CNO-induced increase in relative 3-6 Hz BLA lead (n = 9 mice; linear regression: F(1,7) = 16.91, P = 0.0045). **** P < 0.0001, *** P < 0.001, ** P < 0.01, * P < 0.05. All box plot graphs show median (line inside box), 25% and 75% percentiles (box edges), and minimum and maximum values (error bars).

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Davis, P., Zaki, Y., Maguire, J. et al. Cellular and oscillatory substrates of fear extinction learning. Nat Neurosci 20, 1624–1633 (2017). https://doi.org/10.1038/nn.4651

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