Abstract
Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV+ interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM+ interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV+ and SOM+ interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.
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Acknowledgements
We thank all members of the Lüthi laboratory and E. Schuman for discussions and critical comments on the manuscript. We would like to thank J. Lüdke, P. Argast and P. Buchmann for technical assistance. We further thank the Facility for Imaging and Microscopy at the FMI, in particular S. Bourke and M. Kirschmann, for their assistance in image acquisition and analysis. We also thank K. Deisseroth, E. Boyden, J. Huang, R. Sprengel and S. Arber for sharing materials and mouse lines. This work was supported by the Novartis Research Foundation, by the National Center of Competences in Research: ‘SYNAPSY — The Synaptic Bases of Mental Diseases’ (financed by the Swiss National Science Foundation) as well as by a SNSF core grant to A.L. S.B.E.W. is supported by a Schering Foundation Fellowship. J.J.L. is supported by a Swiss National Science Foundation Ambizione Fellowship. J.G. and G.A.J. are supported by EMBO Long-Term Fellowships and Marie Curie Action Fellowships.
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S.B.E.W. initiated the project, performed most experiments and data analysis, and wrote the manuscript. J.G. performed and analysed in vitro experiments and immunohistochemistry. P.T. performed and analysed immunohistochemistry. S.K. performed in vitro experiments and analysed subcellular targeting experiments. G.A.J. and R.W.F. performed and helped with data analysis. C.M. provided technical assistance. C.H. and I.E. helped to establish optogenetic manipulations and single-unit recordings. S.B.E.W., J.J.L. and A.L. conceived the project and wrote the manuscript. All authors contributed to the experimental design and interpretation, and commented on the manuscript.
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Extended data figures and tables
Extended Data Figure 1 Fibre and electrode placement sites and single-unit recording quality.
a, Position of electrode tips for single-unit recordings and of bilateral optic fibres for all PV–Cre and SOM–Cre animals used. b, Left, superimposed waveforms of three single units recorded on the same channel in the BLA of a PV–Cre animal. Right, spikes from individual units were sorted into clusters, using 3D principal component analysis. c, Recording quality was evaluated by calculation of J3 and Davies Bouldin validity index (DB) statistics for PV+ and SOM+ interneurons. To obtain control values two clusters were selected in the central noise cloud in channels without units. High J3 and low DB values indicate good isolation of single units. d, Left, principal component (PC) space cylinders to determine the stability of clustered waveforms during long-term recordings. Straight cylinders indicate stable recordings of the same set of single units. Right, superimposed waveforms recorded during the different sessions, used for the calculation of the PC space cylinders. e, For a quantitative evaluation of spike shape similarity over different recording days, we calculated linear correlation values for PV+ and SOM+ interneurons. As a control, we calculated the r values for waveforms of different random neurons. The maximum r value across recording sessions was used to quantify similarity (r = 1 indicates identical spike shapes). All PV+ and SOM+ interneurons had r values above 0.95, but only about 4% of the random comparisons. Values are mean ± s.e.m. *P < 0.05. Statistical analysis in Methods.
Extended Data Figure 2 Effects on freezing by baseline optogenetic stimulation and freezing for all behavioural groups.
a, Effects of optogenetic manipulations of PV+ or SOM+ cell activity on baseline freezing levels. Illumination patterns resemble stimulations during the CS in the conditioning paradigms (10 s of 300-ms blue light pulses at 0.9 Hz or 10 s continuous yellow light). b, Freezing values during fear retrieval for all behavioural groups with optogenetic PV+ or SOM+ cell manipulations during the CS, US or CS+US. Freezing levels are compared between the internal control CS1 and CS2 which was paired with optogenetic stimulation during the conditioning.
Extended Data Figure 3 Optogenetic identification and manipulation of PV+ and SOM+ interneurons.
a, b, Top left: ex vivo whole-cell patch clamp and cell-attached recordings of ChR2–mCherry-expressing PV+ (a) and SOM+ (b) BLA interneurons in amygdala slices. Top right: distinct firing patterns of PV+ (a) and SOM+ (b) cells in response to depolarizing somatic current injection. Bottom: PV+ (a) and SOM+ (b) cells fire brief bursts of action potentials in response to short blue light stimulation (468 nm, 5 ms, 10 mW) and show sustained firing during prolonged stimulation (468 nm, 300 ms, 10 mW, cell-attached recordings). c, Single-unit recordings of optogenetically identified PV+ (green) and SOM+ (red) interneurons upon 300-ms stimulation with blue (ChR2, top) or yellow (ARCH, bottom) light in behaving animals. Left: Z-scored activity. Right: firing frequency. d, Left: comparison of spontaneous and light-evoked superimposed average spike waveforms of all PV+ interneurons identified by optogenetic activation. Middle: linear correlations between spontaneous and light-evoked spikes were calculated for individual optogenetically identified PV+ interneurons. Only cells with r values above 0.95 were considered as directly light-activated. Right: jitter of first light-evoked spikes in identified PV+ cells. e, Change point analysis for determination of the latency of light-evoked activity changes. The cumulative sum of the activity of a neuron was calculated and the change point was determined. Shown is an example of ARCH-mediated inhibition for the entire illumination period (left) and at the light onset (right). The arrow indicates the change point. f, Expression of ChR2, co-expressed with Venus (green), is restricted to SOM+ interneurons (red). g, Specificity of opsin-expression. Left: examples of opsin expression in a PV–Cre (top) and a SOM–Cre (bottom) animal with immunohistochemistry (IHC) for the respective other interneuron marker. Right: quantification of co-localization of opsin-expressing and IHC-labelled cells. h, Light-induced changes in activity of SOM+ interneurons upon illumination with either blue or yellow light for activation of ChR2 or ARCH, respectively. i, Latencies and Z scores of light-induced activity changes in optogenetically identified SOM+ interneurons. j, Left: comparison of average waveforms of spontaneous and light-evoked spikes in SOM+ interneurons. Middle: linear correlations between spontaneous and light-evoked spikes in optogenetically identified SOM+ interneurons. Right: jitter of first light-evoked spikes in identified SOM+ cells.
Extended Data Figure 4 Physiological properties of PV+ and SOM+ interneurons and of non-light-responsive cells.
a, Distribution of physiological properties for optogenetically identified PV+ and SOM+ interneurons and for non-light-responsive cells. Spike half-width and spontaneous activity were compared for identified interneurons and for a population of simultaneously recorded non-light-responsive cells, which is mainly comprised of principal cells, but could also include unidentified interneurons. Squares indicate average values for the three groups. SOM+ interneurons cannot be separated from the non-light-responsive cells whereas PV+ cells are, on average, different from the other groups. b, Comparison of normalized spike waveforms of PV+ and SOM+ interneurons and non-light-responsive cells. c, Linear correlations of the spike waveforms between the different groups. d, Comparison of spike half-width and spontaneous activity of PV+ and SOM+ interneurons and non-light-responsive cells. Note the similarity of SOM+ interneurons with non-light-responsive cells. Values are mean ± s.e.m. *P < 0.05. Statistical analysis in Methods.
Extended Data Figure 5 US and CS responses in PV+ and SOM+ interneurons in the BLA.
a–d, Z-scored population activity (left) and firing frequency (right) for identified PV+ (green) and SOM+ (red) cells in response to the US (a, b) or the CS (c, d). Shown are the population responses for all cells (top graphs). The graphs below show population responses that were separated according to whether the cells showed inhibitory or excitatory responses to the stimuli. Cells were included in the stimulus inhibited group or stimulus excited group if their average Z-scored stimulus response was <0 or >0, respectively.
Extended Data Figure 6 Effects of optogenetic manipulations of PV+ interneuron activity on footshock responses of putative principal neurons.
a, Footshock-evoked responses in footshock-excited putative principal neurons with (blue or yellow) and without (black) optogenetic stimulation of PV+ interneurons. Cells are split based on being excited either exclusively during the footshock alone, exclusively during the footshock+light or during both conditions. b, Cumulative probability distributions of the average Z score of individual putative principal neurons during the footshock without (black) and with optogenetic manipulations of PV+ interneurons. c, Cumulative probability distributions of the change index (CI) as a measure for the light-induced changes in footshock responses for the different optogenetic interneuron manipulations. The change index is calculated as CI = (Z score(footshock+light)−Z score(footshock))/(Z score(footshock+light)+Z score(footshock)) (all Z scores are the averages of the shock response during the entire footshock). Shown are the distributions for the footshock-excited cells (black), for the footshock+light excited cells (blue or yellow), for cells which are excited in both conditions (green) and the weighted sum (grey). d, Left, comparisons of cumulative probability distributions for the differences in average footshock Z score during the entire footshock ((footshock+light) – footshock) in putative principal neurons for PV+ interneuron activation (blue) and inhibition (yellow). Right, comparisons of cumulative probability distributions for the change index of the footshock responses of putative principal neurons upon optogenetic activation (blue) or inhibition (yellow) of PV+ interneurons. e, Inhibition of BLA principal neurons during the US impairs fear acquisition. Principal neurons were selectively inhibited by expression of ARCH under the control of the CaMKII promoter and illumination with yellow light during the US. Values are mean ± s.e.m. **P < 0.01. Statistical analysis in Methods.
Extended Data Figure 7 Inhibitory inputs from PV+ to SOM+ as well as to unidentified GABAergic neurons.
a, Slice patch-clamp experiments. Left: BLA location of PV+ interneurons expressing ChR2–mCherry in acute slices of PV–Cre::GAD–EGFP animals. Right: whole-cell recording (middle) of neuron expressing GAD (top) but not ChR2 (bottom). (Original magnification: left: ×5, right: ×60.) b, Optogenetic stimulation of PV+ neurons resulted in inhibitory postsynaptic currents (IPSCs) in GAD–EGFP+ neurons (n = 26, 5-ms blue light). IPSCs reverse at about 0 mV (voltage clamp Cl− reversal potential, n = 4). c, Left: fractions of patched and identified SOM+ cells with and without detected PV+ input. Owing to potential wash-out of the antigen (SOM) during the whole-cell recordings, these data probably represent a solid lower bound rather than the actual connectivity rate (see Methods). Right: IPSC amplitude, peak latency after blue light onset and 10–90% rise time of PV inputs on all measured GABAergic (PV–GAD, n = 26) and somatostatin-positive (PV–SOM, n = 3) neurons, respectively. 1 SOM+ cell with PV inputs was tested with a current clamp internal at −40 mV and thus does not contribute to the statistics. d, e, Suppression of spikes in a SOM+ cell by optogenetic activation of PV+ cells. d, individual trials of somatic current injection into a SOM+ cell with and without PV+ activation. Red traces show spike failures on PV+ stimulation. e, overlay of current injections with spiking success and failures without (top) and with (bottom) simultaneous PV+ cell activation.
Extended Data Figure 8 PV+ and SOM+ interneurons contact different compartments of pyramidal neurons.
a, Maximum intensity projection (MIP) showing a biocytin-filled principal neuron (grey) and conditional expression of the presynaptic marker synaptophysin–GFP (Syn–GFP, red) in SOM+ interneurons in the BLA. b, Soma of the same principal neuron (grey) with expression of synaptophysin–GFP (red) selectively in SOM+ interneurons (MIP). Arrowhead points to 1 out of 7 identified synaptic contacts at the soma revealed by 3D analysis of confocal images. c, Dendritic branch located 200 μm distant from the soma (MIP, yellow rectangle in a). Arrowheads mark synaptic contacts of SOM+ interneurons with the principal neuron dendrite identified in 3D analysis. d, Single focal planes of contacts labelled in b, c. e, Biocytin-filled principal neuron and conditional synaptophysin–GFP expression (green) in PV+ interneurons in the BLA (MIP). f, Soma of the same principal neuron with presynaptic synaptophysin–GFP expression selectively in PV+ interneurons (MIP). Arrowheads point to 3 out of 53 synaptic contacts from PV+ interneurons identified in 3D analysis at this soma. g, Dendrite located 200 μm distant from the soma (MIP, yellow rectangle in e). Arrowhead marks a synaptic contact from PV+ interneurons. h, Single section images of appositions labelled in f, g. Scale bars: 100 μm (a, e), 5 μm (b, f), 2 μm (c, g) and 0.5 μm (d, h). i, Quantification of synaptic contacts from SOM+ and PV+ interneurons with the soma of principal neurons in the BLA. j, Number of extrapolated synaptic appositions from SOM+ and PV+ interneurons onto the estimated dendritic tree of principal neurons. k, Normalization of dendritic versus somatic appositions shows a highly significant difference between postsynaptic targeting of SOM+ and PV+ interneurons. l, Distance dependency of synaptic inputs from SOM+ (red, n = 8) and PV+ interneurons (green, n = 7) onto principal neuron dendrites. SOM+ interneurons preferentially target distal dendrites of principal neurons. All values are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001. Statistical analysis in Methods.
Extended Data Figure 9 Effects of optogenetic manipulations of PV+ or SOM+ interneuron activity on tone-evoked responses in putative principal neurons.
a, Tone-evoked responses in tone-excited putative principal neurons with (blue or yellow) and without (black) optogenetic stimulation of PV+ or SOM+ interneurons. Cells are split based on being tone excited either exclusively during the tone alone, exclusively during tone+light or in both conditions. b, Cumulative probability distributions of the change index (CI) as a measure for the light-induced changes in tone responses for the different optogenetic interneuron manipulations. The change index is calculated as CI = (Z score(tone+light) − Z score(tone))/(Z score(tone+light) + Z score(tone)) (all Z scores are the averages of the tone response during the pip). Shown are the distributions for the tone-excited cells (black), for the tone+light excited cells (blue or yellow), for cells which are excited in both conditions (green) and the weighted sum (grey). c, Comparisons of cumulative probability distributions for the change index of the tone responses of putative principal neurons upon optogenetic stimulation of PV+ or SOM+ cells.
Extended Data Figure 10 Effects of optogenetic manipulations of PV+ or SOM+ interneurons on spontaneous activity and burst firing of putative principal neurons.
a, Effects of optogenetic activation (top) or inhibition (bottom) of PV+ (grey) or SOM+ (black) cells on the spontaneous activity of putative principal neurons. b, Effects of optogenetic manipulations of PV+ or SOM+ cells on the burst frequency (top) and burst duration (bottom) in putative principal neurons. c, Comparisons of cumulative probability distributions for light-induced changes in spontaneous activity in putative principal neurons on optogenetic stimulation of PV+ or SOM+ interneurons. d, Comparisons of cumulative probability distributions for light-induced changes in burst rate in putative principal neurons on optogenetic stimulation of PV+ or SOM+ interneurons. Values are mean ± s.e.m. *P < 0.05, ***P < 0.001. Statistical analysis in Methods.
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Wolff, S., Gründemann, J., Tovote, P. et al. Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509, 453–458 (2014). https://doi.org/10.1038/nature13258
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DOI: https://doi.org/10.1038/nature13258
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