Triggering behavioral adaptation upon the detection of adversity is crucial for survival. The insular cortex has been suggested to process emotions and homeostatic signals, but how the insular cortex detects internal states and mediates behavioral adaptation is poorly understood. By combining data from fiber photometry, optogenetics, awake two-photon calcium imaging and comprehensive whole-brain viral tracings, we here uncover a role for the posterior insula in processing aversive sensory stimuli and emotional and bodily states, as well as in exerting prominent top-down modulation of ongoing behaviors in mice. By employing projection-specific optogenetics, we describe an insula-to-central amygdala pathway to mediate anxiety-related behaviors, while an independent nucleus accumbens-projecting pathway regulates feeding upon changes in bodily state. Together, our data support a model in which the posterior insular cortex can shift behavioral strategies upon the detection of aversive internal states, providing a new entry point to understand how alterations in insula circuitry may contribute to neuropsychiatric conditions.
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We thank A. Ghanem (Ludwig Maximilians University) for producing modified rabies viruses; W. Denk, I. Grundwald-Kadow, R. Klein and R. Portugues for critical reading of earlier versions of this manuscript; K. Deisseroth (Stanford University) for optogenetic and Cre-dependent AAV constructs and the UNC Vector Core for viral packaging; F. Lyonnaz for managing the animal colony; and C. Weiand for technical assistance. This study was supported by the Max Planck Society, the Deutsche Forschungsgemeinschaft (SPP1665 to K.-K.C., D.A.G. and N.G.), funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-2017-STG, grant agreement 758448 to N.G.), a German–Israeli Foundation grant (to N.G. and N.R.V., grant I-1301-418.13/2015) and the ANR-DFG project SafeNet (project no. 391081777 to N.G. and A.S.K.).
The authors declare no competing interests.
Peer review information: Nature Neuroscience thanks Wulf Haubensak and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Figures 1–17.
Optogenetic stimulation of posterior insular cortex. The video provides representative examples of behaviors elicited in a typical sequence upon bilateral ChR2-mediated optogenetic pIC stimulation at 20 Hz (1-s stimulation, 5-ms pulses).
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Gehrlach, D.A., Dolensek, N., Klein, A.S. et al. Aversive state processing in the posterior insular cortex. Nat Neurosci 22, 1424–1437 (2019). https://doi.org/10.1038/s41593-019-0469-1
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