Abstract
Theories stipulate that memories are encoded within networks of cortical projection neurons. Conversely, GABAergic interneurons are thought to function primarily to inhibit projection neurons and thereby impose network gain control, an important but purely modulatory role. Here we show in male mice that associative fear learning potentiates synaptic transmission and cue-specific activity of medial prefrontal cortex somatostatin (SST) interneurons and that activation of these cells controls both memory encoding and expression. Furthermore, the synaptic organization of SST and parvalbumin interneurons provides a potential circuit basis for SST interneuron-evoked disinhibition of medial prefrontal cortex output neurons and recruitment of remote brain regions associated with defensive behavior. These data suggest that, rather than constrain mnemonic processing, potentiation of SST interneuron activity represents an important causal mechanism for conditioned fear.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Holtmaat, A. & Caroni, P. Functional and structural underpinnings of neuronal assembly formation in learning. Nat. Neurosci. 19, 1553–1562 (2016).
Kandel, E. R., Dudai, Y. & Mayford, M. R. The molecular and systems biology of memory. Cell 157, 163–186 (2014).
Josselyn, S. A., Köhler, S. & Frankland, P. W. Finding the engram. Nat. Rev. Neurosci. 16, 521–534 (2015).
Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014).
Rashid, A. J. et al. Competition between engrams influences fear memory formation and recall. Science 353, 383–387 (2016).
Siwani, S. et al. OLMα2 cells bidirectionally modulate learning. Neuron 99, 404–412.e3 (2018).
Stefanelli, T., Bertollini, C., Lüscher, C., Muller, D. & Mendez, P. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron 89, 1074–1085 (2016).
Wolff, S. B. et al. Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509, 453–458 (2014).
Corcoran, K. A. & Quirk, G. J. Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J. Neurosci. 27, 840–844 (2007).
Rudy, B., Fishell, G., Lee, S. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61 (2011).
Kim, D. et al. Distinct roles of parvalbumin- and somatostatin-expressing interneurons in working memory. Neuron 92, 902–915 (2016).
Arruda-Carvalho, M. & Clem, R. L. Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding. J. Neurosci. 34, 15601–15609 (2014).
Lucas, E. K., Jegarl, A. M., Morishita, H. & Clem, R. L. Multimodal and site-specific plasticity of amygdala parvalbumin interneurons after fear learning. Neuron 91, 629–643 (2016).
Graziane, N. & Dong, Y. Electrophysiological Analysis of Synaptic Transmission (Humana Press, 2016).
Herry, C. & Johansen, J. P. Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654 (2014).
Amano, T., Unal, C. T. & Paré, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci. 13, 489–494 (2010).
Asede, D., Bosch, D., Lüthi, A., Ferraguti, F. & Ehrlich, I. Sensory inputs to intercalated cells provide fear-learning modulated inhibition to the basolateral amygdala. Neuron 86, 541–554 (2015).
Namburi, P. et al. A circuit mechanism for differentiating positive and negative associations. Nature 520, 675–678 (2015).
Pattwell, S. S., Bath, K. G., Casey, B. J., Ninan, I. & Lee, F. S. Selective early-acquired fear memories undergo temporary suppression during adolescence. Proc. Natl Acad. Sci. USA 108, 1182–1187 (2011).
Tsvetkov, E., Carlezon, W. A., Benes, F. M., Kandel, E. R. & Bolshakov, V. Y. Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala. Neuron 34, 289–300 (2002).
Zhou, Y. et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat. Neurosci. 12, 1438–1443 (2009).
Clem, R. L. & Huganir, R. L. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010).
Pi, H. J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).
Fenno, L. E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).
Senn, V. et al. Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81, 428–437 (2014).
Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008).
Burgos-Robles, A. et al. Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment. Nat. Neurosci. 20, 824–835 (2017).
Klavir, O., Prigge, M., Sarel, A., Paz, R. & Yizhar, O. Manipulating fear associations via optogenetic modulation of amygdala inputs to prefrontal cortex. Nat. Neurosci. 20, 836–844 (2017).
Little, J. P. & Carter, A. G. Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala. J. Neurosci. 33, 15333–15342 (2013).
Cruikshank, S. J., Urabe, H., Nurmikko, A. V. & Connors, B. W. Pathway-specific feedforward circuits between thalamus and neocortex revealed by selective optical stimulation of axons. Neuron 65, 230–245 (2010).
McGarry, L. M. & Carter, A. G. Inhibitory gating of basolateral amygdala inputs to the prefrontal cortex. J. Neurosci. 36, 9391–9406 (2016).
Lee, S., Kruglikov, I., Huang, Z. J., Fishell, G. & Rudy, B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat. Neurosci. 16, 1662–1670 (2013).
Garcia-Junco-Clemente, P. et al. An inhibitory pull–push circuit in frontal cortex. Nat. Neurosci. 20, 389–392 (2017).
Ibrahim, L. A. et al. Cross-modality sharpening of visual cortical processing through layer-1-mediated inhibition and disinhibition. Neuron 89, 1031–1045 (2016).
Letzkus, J. J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480, 331–335 (2011).
Beas, B. S. et al. The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nat. Neurosci. 21, 963–973 (2018).
Do-Monte, F. H., Quiñones-Laracuente, K. & Quirk, G. J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015).
Stamatakis, A. M. & Stuber, G. D. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat. Neurosci. 15, 1105–1107 (2012).
Tovote, P. et al. Midbrain circuits for defensive behaviour. Nature 534, 206–212 (2016).
Johnson, P. L. & Shekhar, A. Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J. Neurosci. 26, 7093–7104 (2006).
Arruda-Carvalho, M., Wu, W. C., Cummings, K. A. & Clem, R. L. Optogenetic examination of prefrontal-amygdala synaptic development. J. Neurosci. 37, 2976–2985 (2017).
Xu, W. & Südhof, T. C. A neural circuit for memory specificity and generalization. Science 339, 1290–1295 (2013).
Yavorska, I. & Wehr, M. Somatostatin-expressing inhibitory interneurons in cortical circuits. Front. Neural Circuits 10, 76 (2016).
Muñoz, W., Tremblay, R., Levenstein, D. & Rudy, B. Layer-specific modulation of neocortical dendritic inhibition during active wakefulness. Science 355, 954–959 (2017).
Li, K., Nakajima, M., Ibañez-Tallon, I. & Heintz, N. A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167, 60–72.e11 (2016).
Nakajima, M., Görlich, A. & Heintz, N. Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159, 295–305 (2014).
Kluge, C., Stoppel, C., Szinyei, C., Stork, O. & Pape, H. C. Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity. Learn. Mem. 15, 252–260 (2008).
Einstein, E. B. et al. Somatostatin signaling in neuronal cilia is critical for object recognition memory. J. Neurosci. 30, 4306–4314 (2010).
Xu, H. et al. A disinhibitory microcircuit mediates conditioned social fear in the prefrontal cortex. Neuron 102, 668–682.e5 (2019).
Keum, S. et al. A missense variant at the Nrxn3 locus enhances empathy fear in the mouse. Neuron 98, 588–601.e5 (2018).
Yaeger, C. E., Ringach, D. L. & Trachtenberg, J. T. Neuromodulatory control of localized dendritic spiking in critical period cortex. Nature 567, 100–104 (2019).
Kvitsiani, D. et al. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498, 363–366 (2013).
Calipari, E. S. et al. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward. Proc. Natl Acad. Sci. USA 113, 2726–2731 (2016).
Gunaydin, L. A. et al. Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014).
Lagerlöf, O. et al. The nutrient sensor OGT in PVN neurons regulates feeding. Science 351, 1293–1296 (2016).
Acknowledgements
We thank S. Bayshtok and E. Beckett for their expert technical assistance, behavioral scoring and assistance with experimenter blinding; C. Román-Ortiz for help with the optogenetic behavioral manipulations; and D. Cai for comments on the manuscript. These experiments were supported by funds from National Institute of Mental Health grant nos. RO1 MH105414, RO1 MH116145 and R21 MH114170 to R.L.C, and grant no. F32 MH115688 to K.A.C.
Author information
Authors and Affiliations
Contributions
K.A.C. and R.L.C. initiated the project. R.L.C. supervised the research. K.A.C. and R.L.C. designed the experiments. K.A.C. performed the research and data analysis. R.L.C. and K.A.C. wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature Neuroscience thanks Mario Penzo for his contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary Figs. 1–17.
Rights and permissions
About this article
Cite this article
Cummings, K.A., Clem, R.L. Prefrontal somatostatin interneurons encode fear memory. Nat Neurosci 23, 61–74 (2020). https://doi.org/10.1038/s41593-019-0552-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-019-0552-7
This article is cited by
-
Reactivation of encoding ensembles in the prelimbic cortex supports temporal associations
Neuropsychopharmacology (2024)
-
Modulation of learning safety signals by acute stress: paraventricular thalamus and prefrontal inhibition
Neuropsychopharmacology (2024)
-
A distinct cortical code for socially learned threat
Nature (2024)
-
Human iN neuronal model of schizophrenia displays dysregulation of chromogranin B and related neuropeptide transmitter signatures
Molecular Psychiatry (2024)
-
Synaptic configuration and reconfiguration in the neocortex are spatiotemporally selective
Anatomical Science International (2024)