Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways

PERI (Perirhinal area) MBA:922 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Perirhinal cortex neurons were retrogradely labelled by monosynaptic rabies tracing from both insular projector populations, with comparable amounts for the two.

Fig. 7b, c

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ORB (Orbital area) MBA:714 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Rabies-virus monosynaptic tracing from accumbens-projecting insular neurons labelled many presynaptic cells in the orbitofrontal cortex, significantly more than were labelled from amygdala-projecting insular neurons.

Fig. 7a–c

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AI (Agranular insular area) MBA:95 projects to CEA (Central amygdalar nucleus) MBA:536 · Mouse

Retrograde tracer injected into the central amygdala labelled insular cortex neurons, mainly in layer 5 with an additional population in layer 2/3; these cells were largely separate from accumbens-projecting IC cells.

Supplementary Fig. 5a–e; Results (Nonoverlapping IC-CeA and IC-NAc projectors)

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PL (Prelimbic area) MBA:972 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Prelimbic cortex cells were also labelled as presynaptic partners of amygdala-projecting insular neurons, although at a lower level than for accumbens-projecting insular neurons.

Fig. 7b, c

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MO (Somatomotor areas) MBA:500 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Somatomotor cortex contained rabies-labelled presynaptic neurons of both insular projection populations, with no significant difference between them.

Fig. 7b, c

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AI (Agranular insular area) MBA:95 projects to ACB (Nucleus accumbens) MBA:56 · Mouse

Retrograde virus injected into the nucleus accumbens labelled a distinct set of insular cortex neurons, concentrated in layer 5 with additional cells in layer 6, with little overlap with amygdala-projecting IC neurons.

Supplementary Fig. 5a–e

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AI (Agranular insular area) MBA:95 projects to ACB (Nucleus accumbens) MBA:56 · Mouse

Synaptophysin-tdTomato labelling of IC neurons tagged during extinction learning revealed axonal boutons preferentially in the nucleus accumbens rather than the central amygdala.

Fig. 3g–i; Supplementary Fig. 4

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SS (Somatosensory areas) MBA:453 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Rabies-labelled presynaptic neurons were found in somatosensory cortex for both insular projection populations, with a trend toward more input onto amygdala-projecting insular neurons (P = 0.052).

Fig. 7b, c

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AI (Agranular insular area) MBA:95 projects to CEA (Central amygdalar nucleus) MBA:536 · Mouse

Cre-dependent synaptophysin-tdTomato expressed in FosTRAPed insular cortex neurons tagged during fear learning labelled presynaptic boutons predominantly in the central amygdala, showing that fear-memory-associated IC neurons send axons there.

Fig. 3e–i; Supplementary Fig. 4

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AI (Agranular insular area) MBA:95 functionally connects to ACB (Nucleus accumbens) MBA:56 · Mouse

Optogenetic stimulation of insular axon terminals in the nucleus accumbens produced excitatory postsynaptic currents in accumbens neurons, which were suppressed by tetanus toxin expression in the presynaptic IC neurons.

Fig. 5b

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ECT (Ectorhinal area) MBA:895 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Ectorhinal cortex supplied rabies-labelled monosynaptic inputs to both amygdala- and accumbens-projecting insular neurons, with no difference between groups.

Fig. 7b, c

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BLAa (Basolateral amygdalar nucleus, anterior part) MBA:303 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Among subcortical inputs, the anterior basolateral amygdala contained more rabies-labelled neurons presynaptic to accumbens-projecting insular neurons than to amygdala-projecting ones.

Results (whole-brain input mapping); Supplementary Fig. 22

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CEA (Central amygdalar nucleus) MBA:536 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Rabies tracing showed more presynaptic neurons in the central amygdala for amygdala-projecting insular neurons than for accumbens-projecting insular neurons.

Results (whole-brain input mapping); Supplementary Fig. 22

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AI (Agranular insular area) MBA:95 functionally connects to CEA (Central amygdalar nucleus) MBA:536 · Mouse

Blue-light activation of ChR2-expressing insular axon terminals in the central amygdala evoked excitatory postsynaptic currents in recorded CeA neurons; these currents were strongly reduced when tetanus toxin light chain was expressed in the same IC neurons.

Fig. 5b

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AI (Agranular insular area) MBA:95 functionally connects to CEA (Central amygdalar nucleus) MBA:536 · Mouse

Photostimulating the terminals of the same intersectionally labelled insular neurons failed to evoke excitatory currents in central amygdala neurons, confirming the pathway's selectivity for the accumbens.

Supplementary Fig. 25

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ORB (Orbital area) MBA:714 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Rabies tracing from amygdala-projecting insular neurons also labelled orbitofrontal cortex input cells, but fewer than for accumbens-projecting insular neurons.

Fig. 7b, c

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ORB (Orbital area) MBA:714 synapses onto AI (Agranular insular area) MBA:95 · Mouse

Anterograde transsynaptic AAV1 expressing Flp injected into the orbitofrontal cortex drove recombination in postsynaptic insular cortex neurons, which could then be targeted for further manipulation.

Fig. 7f; Supplementary Fig. 24b

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ORB (Orbital area) MBA:714 functionally connects to AI (Agranular insular area) MBA:95 · Mouse

Stimulating orbitofrontal axons in insular slices produced excitatory currents in about two thirds of recorded amygdala-projecting insular neurons, with a higher inhibitory-to-excitatory ratio than in accumbens-projecting neurons.

Supplementary Fig. 23c–f

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AI (Agranular insular area) MBA:95 functionally connects to ACB (Nucleus accumbens) MBA:56 · Mouse

Insular neurons labelled by the intersectional strategy as receiving orbitofrontal input and projecting to the accumbens produced excitatory postsynaptic currents in accumbens neurons when their terminals were photostimulated.

Supplementary Fig. 25

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