Research Article

Insular cortex processes aversive somatosensory information and is crucial for threat learning

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Science  31 May 2019:
Vol. 364, Issue 6443, eaaw0474
DOI: 10.1126/science.aaw0474

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Fear behavior and the insular cortex

Threat learning is important to avoid dangers in the environment. The amygdala is a brain structure involved in the formation of threat memories. How unconditioned stimulus information reaches the amygdala remains unclear. Berret et al. found that independent subpopulations of neurons in the insular cortex project either to the lateral or the central amygdala and drive threat learning and fear-associated responses, respectively. Neurons in the posterior insula adapted their response patterns to conditioned stimulus presentation during fear conditioning and maintained this pattern at retrieval. Multisensory integration in the insula thus contributes to the storage and retrieval of threat memories.

Science, this issue p. eaaw0474

Structured Abstract


Animals and humans need to learn about potential dangers in the environment to guarantee survival. This threat learning can be studied in laboratory animals with fear conditioning paradigms, in which an innocuous sensory event such as a tone [the conditioned stimulus (CS)] comes to predict a potentially harmful event such as a footshock [the unconditioned stimulus (US)]. During threat learning, an association between the sensory representations of the CS and US is formed in a brain area called the amygdala, especially in the lateral amygdala (LA). However, the synaptic pathways that carry information about a footshock to the LA are unknown. More generally, it has not been addressed which brain area(s) upstream of the amygdala process aversive somatosensory events and conduct this information to the amygdala.


To address this question, we took advantage of optogenetic approaches in behaving mice. We concentrated on the insular cortex, which is known to send axons to the amygdala and to respond to tones and somatosensory stimulation. Mice were trained to acquire a fear response, assessed as immobility (freezing), when a tone was paired with a mild footshock. Our principal approach was to use an inhibitory optogenetic protein to suppress action potential (AP) firing in insula neurons or in the axons connecting the insula with the amygdala. We hypothesized that if the insula sends information about the US to the amygdala, then this manipulation should suppress threat learning.


Silencing AP activity in the posterior insular cortex suppressed acute fear behavior and strongly impaired the formation of threat memories 1 day later, when tones were applied alone. Anatomical tracing and ex vivo electrophysiological experiments then showed that two largely separate neuron populations in the insular cortex form strong excitatory synapses with neurons in the LA or the central amygdala (CeA). Silencing the projection from the insular cortex to the CeA during the US reduced acute fear behavior, whereas silencing the projection to the LA impaired the formation of a threat memory 1 day later but left acute fear behavior unchanged. Complementary experiments with an excitatory optogenetic protein showed that activation of the insular neurons that target the CeA (CeA projectors) rapidly initiated immobility, but this manipulation did not result in an aversive memory. Conversely, optogenetic activation of the LA projectors paired with a tone led to strong aversive behaviors and, on the next day, to escape-like behaviors when the tone was presented alone, showing that stimulation of LA projectors creates an aversive memory. In vivo recordings showed that about one-quarter of the neurons in the posterior insular cortex responded to footshocks (the US). A similar but not completely overlapping neuron population acquired a response to the tones when these were reinforced by footshocks during the threat learning paradigm. Finally, silencing the posterior insular cortex during tone presentation on the retrieval day revealed a contribution of the insula to threat memory retrieval.


The insular cortex is intricately involved in processing aversive somatosensory information. Silencing the posterior insular cortex largely removes the aversive quality of footshock stimulation, thus suppressing an essential drive for learning about such harmful events. The insular cortex routes information to specific amygdalar subdivisions and can thus drive temporally separate components of fear behavior. Furthermore, the insula forms associations between innocuous and harmful sensory events and, together with the LA, is necessary for the retrieval of threat memories. Taken together, the posterior insula processes aversive somatosensory events and contributes to elaborate their negative valence.

Optogenetic studies to determine aversive signaling in brain areas upstream of the amygdala.

Optogenetic silencing of the insula during the footshock leads to reduced threat learning (left). Largely separate neuron populations of the insular cortex project to the LA (red neurons) and the CeA (green neurons) (middle). Selective silencing of the projection to either the CeA or LA impairs different phases of threat learning (right).


Learning about threats is essential for survival. During threat learning, an innocuous sensory percept such as a tone acquires an emotional meaning when paired with an aversive stimulus such as a mild footshock. The amygdala is critical for threat memory formation, but little is known about upstream brain areas that process aversive somatosensory information. Using optogenetic techniques in mice, we found that silencing of the posterior insula during footshock reduced acute fear behavior and impaired 1-day threat memory. Insular cortex neurons respond to footshocks, acquire responses to tones during threat learning, and project to distinct amygdala divisions to drive acute fear versus threat memory formation. Thus, the posterior insula conveys aversive footshock information to the amygdala and is crucial for learning about potential dangers in the environment.

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