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Aversive state processing in the posterior insular cortex

Abstract

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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Fig. 1: pIC activation drives aversive behaviors and avoidance.
Fig. 2: The pIC processes and regulates anxiety bidirectionally.
Fig. 3: The pIC mediates persistent anxiety.
Fig. 4: Sensory, emotional and bodily stimuli elicit insular activity.
Fig. 5: Whole-brain tracings of direct pIC inputs and outputs.
Fig. 6: Largely non-overlapping pIC neuronal subpopulations project to the CeA and NAcC.
Fig. 7: pIC input to the CeA governs defensive reactions, avoidance and anxiety-related behaviors.
Fig. 8: Distinct pIC outputs inhibit consumption upon the detection of homeostatic adversity or predator threat.

Data availability

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

Code availability

All custom-written analysis code is available from the corresponding author upon reasonable request.

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Acknowledgements

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.).

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Contributions

D.A.G. and N.G. designed the study and analyzed data. D.A.G., A.S.K., M.J. and A.M. performed optogenetic surgeries, behavior experiments and analyses. N.D. performed all two-photon imaging experiments and analyses, and helped with physiological recordings. R.R.C. and A.S.K. performed fiber photometry recordings. R.R.C., D.A.G. and A.S.K. performed photometry analyses. A.S.K. performed optrode recordings. N.R.V. assisted with behavior analysis and provided custom-written code. T.D.B. and A.P. helped with the histology. K.-K.C. provided rabies virus and shared expertise in monosynaptic tracing. D.A.G. performed all tracing experiments. D.A.G. and T.N.G. analyzed tracing experiments and performed immunohistochemistry. N.G. wrote the manuscript with input from all authors.

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Correspondence to Nadine Gogolla.

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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 information

Supplementary Information

Supplementary Figures 1–17.

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Supplementary Video 1

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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