Article | Published:

Encoding of danger by parabrachial CGRP neurons

Nature volume 555, pages 617622 (29 March 2018) | Download Citation

Abstract

Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (CGRPPBN neurons) relay sensory signals that contribute to satiation and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most CGRPPBN neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRPPBN neurons prevent overeating. CGRPPBN neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of CGRPPBN neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRPPBN neurons promote affective-behavioural states that limit harm in response to potential threats.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

References

  1. 1.

    The house alarm. Cell Metab. 23, 754–755 (2016)

  2. 2.

    & Efferent connections of the parabrachial nucleus in the rat. Brain Res. 197, 291–317 (1980)

  3. 3.

    , , & Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013)

  4. 4.

    , , & Parabrachial CGRP neurons control meal termination. Cell Metab. 23, 811–820 (2016)

  5. 5.

    , & Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nat. Commun. 7, 11905 (2016)

  6. 6.

    Gastrointestinal mechanisms of satiation for food. Physiol. Behav. 81, 249–273 (2004)

  7. 7.

    , , , & Elucidating an affective pain circuit that creates a threat memory. Cell 162, 363–374 (2015)

  8. 8.

    , , & Central amygdala PKC-δ+ neurons mediate the influence of multiple anorexigenic signals. Nat. Neurosci. 17, 1240–1248 (2014)

  9. 9.

    & Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol. Psychiatry 21, 450–463 (2016)

  10. 10.

    et al. High-speed, miniaturized fluorescence microscopy in freely moving mice. Nat. Methods 5, 935–938 (2008)

  11. 11.

    et al. Miniaturized integration of a fluorescence microscope. Nat. Methods 8, 871–878 (2011)

  12. 12.

    & The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J. Neurophysiol. 63, 473–490 (1990)

  13. 13.

    , & The parabrachial area: electrophysiological evidence for an involvement in visceral nociceptive processes. J. Neurophysiol. 71, 1646–1660 (1994)

  14. 14.

    , , , & Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake. Nat. Neurosci. 20, 1722–1733 (2017)

  15. 15.

    , , & Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82, 522–536 (2014)

  16. 16.

    et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009)

  17. 17.

    , & Neurotoxins affecting neuroexocytosis. Physiol. Rev. 80, 717–766 (2000)

  18. 18.

    et al. Linking genetically defined neurons to behavior through a broadly applicable silencing allele. Neuron 63, 305–315 (2009)

  19. 19.

    et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014)

  20. 20.

    et al. A central neural circuit for itch sensation. Science 357, 695–699 (2017)

  21. 21.

    . et al. Efficient and accurate extraction of in vivo calcium signals from microendoscope video data. eLife (in the press)

  22. 22.

    et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015)

  23. 23.

    & Lateral parabrachial nucleus lesions in the rat: neophobia and conditioned taste aversion. Brain Res. Bull. 55, 359–366 (2001)

  24. 24.

    , & Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J. Neurosci. 35, 4582–4586 (2015)

  25. 25.

    , & Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci. 16, 317–331 (2015)

  26. 26.

    & Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 153, 1–26 (1978)

  27. 27.

    , & The pattern of brain c-fos mRNA induced by a component of fox odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), in rats, suggests both systemic and processive stress characteristics. Brain Res. 1025, 139–151 (2004)

  28. 28.

    , , & Transcription factor modulation and expression in the rat auditory brainstem following electrical intracochlear stimulation. Exp. Neurol. 175, 226–244 (2002)

  29. 29.

    , & Integrative responses of neurons in parabrachial nuclei to a nauseogenic gastrointestinal stimulus and vestibular stimulation in vertical planes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R965–R975 (2012)

  30. 30.

    et al. Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. J. Neurosci. 33, 7627–7640 (2013)

  31. 31.

    et al. Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat. Neurosci. 19, 734–741 (2016)

  32. 32.

    et al. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016)

  33. 33.

    , , & Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350 (2013)

  34. 34.

    et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013)

  35. 35.

    , , , & Basolateral to central amygdala neural circuits for appetitive behaviors. Neuron 93, 1464–1479.e5 (2017)

  36. 36.

    , , & Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841 (2015)

  37. 37.

    , & Afferent connections of the parabrachial nucleus in C57BL/6J mice. Neuroscience 161, 475–488 (2009)

  38. 38.

    et al. Elucidation of the anatomy of a satiety network: Focus on connectivity of the parabrachial nucleus in the adult rat. J. Comp. Neurol. 524, 2803–2827 (2016)

  39. 39.

    & Mechanisms of fear extinction. Mol. Psychiatry 12, 120–150 (2007)

  40. 40.

    et al. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat. Neurosci. 20, 934–942 (2017)

  41. 41.

    et al. Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses. Nat. Protocols 11, 566–597 (2016)

Download references

Acknowledgements

Research was supported by a fellowship grant from Hope Funds for Cancer Research (C.A.C.), a National Institutes of Health (NIH) training grant (C.W.R., T32DK007247), and an NIH grant (R.D.P., R01-DA24908). Inscopix provided the calcium imaging equipment via their DECODE program. We thank C. de Solages and L. Cardy (Inscopix) for advice regarding calcium imaging, Y. S. Jo for help with conditioning equipment, M. Chiang for maintaining the mouse colony, and S. Han for making the GCaMP6m virus.

Author information

Affiliations

  1. Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA

    • Carlos A. Campos
    • , Anna J. Bowen
    • , Carolyn W. Roman
    •  & Richard D. Palmiter

Authors

  1. Search for Carlos A. Campos in:

  2. Search for Anna J. Bowen in:

  3. Search for Carolyn W. Roman in:

  4. Search for Richard D. Palmiter in:

Contributions

C.A.C. designed and conducted the calcium imaging studies. A.J.B. performed the stereotaxic surgeries for loss-of-function studies. C.A.C. and A.J.B. designed and conducted the fear studies. C.A.C. and C.W.R. designed and conducted the itch studies. R.D.P. provided guidance and resources. C.A.C. wrote the manuscript with input from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carlos A. Campos or Richard D. Palmiter.

Reviewer Information Nature thanks C. Alexander and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains the detailed statistical analysis.

Videos

  1. 1.

    CGRPPBN neurons in anesthetized mice are activated by tail pinch

    This is an unprocessed video file from calcium imaging.

  2. 2.

    CGRPPBN neurons are inhibited before food consumption

    Calcium recording was processed using CNMF, and the fluorescence of each neuron was normalized to its own maximum fluorescence intensity in the video.

  3. 3.

    CGRPPBN neurons are active during exploration of novel, palatable food

    Calcium recording was processed using CNMF, and the fluorescence of each neuron was normalized to its own maximum fluorescence intensity in the video. Video is 2x speed.

  4. 4.

    CGRPPBN neurons are active during exploration of novel marble

    Calcium recording was processed using CNMF, and the fluorescence of each neuron was normalized to its own maximum fluorescence intensity in the video. Video is 2x speed.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature25511

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.