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Prefrontal somatostatin interneurons encode fear memory

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.

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Fig. 1: Potentiation of synaptic transmission in prefrontal SST interneurons after cued fear learning.
Fig. 2: CS-related SST interneuron activity increases in tandem with memory acquisition.
Fig. 3: SST interneuron activity is necessary for memory expression and induces freezing in conditioned mice.
Fig. 4: SST interneuron activation and plasticity mediates memory formation.
Fig. 5: SST interneurons elicit relatively potent inhibition of PV interneurons, while PV interneurons preferentially inhibit PNs.
Fig. 6: SST interneuron-evoked freezing requires suppression of PV interneurons.
Fig. 7: Relative strength of BLA transmission onto prelimbic interneurons and PNs is modulated by learning.
Fig. 8: SST interneuron activation recruits a specific brain network in conditioned mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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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.

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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.

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Correspondence to Roger L. Clem.

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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

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