Aversive state processing in the posterior insular cortex


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.


  1. 1.

    Lovett-Barron, M. et al. Ancestral circuits for the coordinated modulation of brain state. Cell 171, 1411–1423 (2017).

  2. 2.

    Zelikowsky, M. et al. The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress. Cell 173, 1265–1279 (2018).

  3. 3.

    Contreras, M., Ceric, F. & Torrealba, F. Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 318, 655–658 (2007).

  4. 4.

    Kurth, F., Zilles, K., Fox, P. T., Laird, A. R. & Eickhoff, S. B. A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis. Brain Struct. Funct. 214, 519–534 (2010).

  5. 5.

    Critchley, H. D., Wiens, S., Rotshtein, P., Öhman, A. & Dolan, R. J. Neural systems supporting interoceptive awareness. Nat. Neurosci. 7, 189–195 (2004).

  6. 6.

    Craig, A. D. Interoception: the sense of the physiological condition of the body. Curr. Opin. Neurobiol. 13, 500–505 (2003).

  7. 7.

    Simmons, W. K. et al. Keeping the body in mind: insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness. Hum. Brain Mapp. 34, 2944–2958 (2013).

  8. 8.

    Allen, G. V., Saper, C. B., Hurley, K. M. & Cechetto, D. F. Organization of visceral and limbic connections in the insular cortex of the rat. J. Comp. Neurol. 311, 1–16 (1991).

  9. 9.

    Cechetto, D. F. & Saper, C. B. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J. Comp. Neurol. 262, 27–45 (1987).

  10. 10.

    Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. Neurosci. 3, 655–666 (2002).

  11. 11.

    Tan, L. L. et al. A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity. Nat. Neurosci. 20, 1591–1601 (2017).

  12. 12.

    Gogolla, N., Takesian, A. E., Feng, G., Fagiolini, M. & Hensch, T. K. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905 (2014).

  13. 13.

    Livneh, Y. et al. Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546, 611–616 (2017).

  14. 14.

    Singer, T., Critchley, H. D. & Preuschoff, K. A common role of insula in feelings, empathy and uncertainty. Trends Cogn. Sci. 13, 334–340 (2009).

  15. 15.

    Etkin, A., Büchel, C. & Gross, J. J. The neural bases of emotion regulation. Nat. Rev. Neurosci. 16, 693–700 (2015).

  16. 16.

    Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).

  17. 17.

    Grupe, D. W. & Nitschke, J. B. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat. Rev. Neurosci. 14, 488–501 (2013).

  18. 18.

    Nagai, M., Kishi, K. & Kato, S. Insular cortex and neuropsychiatric disorders: a review of recent literature. Eur. Psychiatry 22, 387–394 (2007).

  19. 19.

    Downar, J., Blumberger, D. M. & Daskalakis, Z. J. The neural crossroads of psychiatric illness: an emerging target for brain stimulation. Trends Cogn. Sci. 20, 107–120 (2016).

  20. 20.

    Goodkind, M. et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 72, 305–315 (2015).

  21. 21.

    Namkung, H., Kim, S.-H. & Sawa, A. The insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci. 40, 200–207 (2017).

  22. 22.

    Casanova, J. P. et al. A role for the interoceptive insular cortex in the consolidation of learned fear. Behav. Brain Res. 296, 70–77 (2016).

  23. 23.

    Berret, E. et al. Insular cortex processes aversive somatosensory information and is crucial for threat learning. Science 364, eaaw0474 (2019).

  24. 24.

    Contreras, M. et al. A role for the insular cortex in long-term memory for context-evoked drug craving in rats. Neuropsychopharmacology 37, 2101–2108 (2012).

  25. 25.

    Foilb, A. R., Flyer-Adams, J. G., Maier, S. F. & Christianson, J. P. Posterior insular cortex is necessary for conditioned inhibition of fear. Neurobiol. Learn. Mem. 134, 317–327 (2016).

  26. 26.

    Christianson, J. P. et al. Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol. Psychiatry 70, 458–464 (2011).

  27. 27.

    Rogers-Carter, M. M. et al. Insular cortex mediates approach and avoidance responses to social affective stimuli. Nat. Neurosci. 21, 404–414 (2018).

  28. 28.

    Hanamori, T., Kunitake, T., Kato, K. & Kannan, H. Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats. J. Neurophysiol. 79, 2535–2545 (1998).

  29. 29.

    Oppenheimer, S., Gelb, A, Girvin, J. & Hachinski, V. Cardiovascular effects of human insular cortex stimulation. Neurology 42, 1727–1732 (1992).

  30. 30.

    Yasui, Y., Breder, C. D., Safer, C. B. & Cechetto, D. F. Autonomic responses and efferent pathways from the insular cortex in the rat. J. Comp. Neurol. 303, 355–374 (1991).

  31. 31.

    Chen, X., Gabitto, M., Peng, Y., Ryba, N. J. P. & Zuker, C. S. A gustotopic map of taste qualities in the mammalian brain. Science 333, 1262–1266 (2011).

  32. 32.

    Pastuskovas, C. V., Cassell, M. D., Johnson, A. K. & Thunhorst, R. L. Increased cellular activity in rat insular cortex after water and salt ingestion induced by fluid depletion. Am. J. Physiol. Integr. Comp. Physiol. 284, R1119–R1125 (2003).

  33. 33.

    Reimer, J. et al. Pupil fluctuations track fast switching of cortical states during quiet wakefulness. Neuron 84, 355–362 (2014).

  34. 34.

    Wickersham, I. R., Finke, S., Conzelmann, K.-K. & Callaway, E. M. Retrograde neuronal tracing with a deletion-mutant rabies virus. Nat. Methods 4, 47–49 (2007).

  35. 35.

    Shi, C. J. & Cassell, M. D. Cortical, thalamic, and amygdaloid connections of the anterior and posterior insular cortices. J. Comp. Neurol. 399, 440–468 (1998).

  36. 36.

    Mufson, E. J., Mesulam, M.-M. & Pandya, D. N. Insular interconnections with the amygdala in the rhesus monkey. Neuroscience 6, 1231–1248 (1981).

  37. 37.

    Namburi, P., Al-Hasani, R., Calhoon, G. G., Bruchas, M. R. & Tye, K. M. Architectural representation of valence in the limbic system. Neuropsychopharmacology 41, 1697–1715 (2015).

  38. 38.

    Floresco, S. B. The nucleus accumbens: an interface between cognition, emotion, and action. Annu. Rev. Psychol. 66, 25–52 (2015).

  39. 39.

    Fadok, J. P., Markovic, M., Tovote, P. & Lüthi, A. New perspectives on central amygdala function. Curr. Opin. Neurobiol. 49, 141–147 (2018).

  40. 40.

    Schiff, H. et al. An insula–central amygdala circuit for guiding tastant-reinforced choice behavior. J. Neurosci. 38, 1418–1429 (2018).

  41. 41.

    Avery, J. A. et al. Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula. Biol. Psychiatry 76, 258–266 (2014).

  42. 42.

    Paulus, M. P. & Stein, M. B. Interoception in anxiety and depression. Brain Struct. Funct. 214, 451–463 (2010).

  43. 43.

    Fitzgerald, P. B., Laird, A. R., Maller, J. & Daskalakis, Z. J. A meta-analytic study of changes in brain activation in depression. Hum. Brain Mapp. 29, 683–695 (2008).

  44. 44.

    Peng, Y. et al. Sweet and bitter taste in the brain of awake behaving animals. Nature 527, 512–515 (2015).

  45. 45.

    Wang, L. et al. The coding of valence and identity in the mammalian taste system. Nature 558, 127–131 (2018).

  46. 46.

    Castro, D. C. & Berridge, K. C. Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula. Proc. Natl Acad. Sci. USA 114, E9125–E9134 (2017).

  47. 47.

    Damasio, A. & Carvalho, G. B. The nature of feelings: evolutionary and neurobiological origins. Nat. Rev. Neurosci. 14, 143–152 (2013).

  48. 48.

    LeDoux, J. Rethinking the emotional brain. Neuron 73, 653–676 (2012).

  49. 49.

    Naqvi, N. H. & Bechara, A. The hidden island of addiction: the insula. Trends Neurosci. 32, 56–67 (2009).

  50. 50.

    Wekselblatt, J. B., Flister, E. D., Piscopo, D. M. & Niell, C. M. Large-scale imaging of cortical dynamics during sensory perception and behavior. J. Neurophysiol. 115, 2852–2866 (2016).

  51. 51.

    Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013).

  52. 52.

    Labouèbe, G., Boutrel, B., Tarussio, D. & Thorens, B. Glucose-responsive neurons of the paraventricular thalamus control sucrose-seeking behavior. Nat. Neurosci. 19, 999–1002 (2016).

  53. 53.

    Felix-Ortiz, A. C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).

  54. 54.

    Gardner, M. P. H. & Fontanini, A. Encoding and tracking of outcome-specific expectancy in the gustatory cortex of alert rats. J. Neurosci. 34, 13000–13017 (2014).

  55. 55.

    Pachitariu, M. et al. Suite2p: beyond 10,000 neurons with standard two-photon microscopy. Preprint at biorXiv https://www.biorxiv.org/content/10.1101/061507v2 (2017).

  56. 56.

    Franklin, K. B. J. & Paxinos, G. Paxinos and Franklin’s The Mouse Brain in Stereotaxic Coordinates 4th edn (Academic Press, 2012).

  57. 57.

    Do, J. P. et al. Cell type-specific long-range connections of basal forebrain circuit. eLife 5, 1–18 (2016).

  58. 58.

    Watabe-Uchida, M., Zhu, L., Ogawa, S. K., Vamanrao, A. & Uchida, N. Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74, 858–873 (2012).

  59. 59.

    Grider, M. H., Chen, Q. & Shine, H. D. Semi-automated quantification of axonal densities in labeled CNS tissue. J. Neurosci. Methods 155, 172–179 (2006).

  60. 60.

    Taniguchi, H. et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71, 995–1013 (2011).

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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.).

Author information

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.

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 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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