Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Functional consequences of neuropeptide and small-molecule co-transmission

Key Points

  • The fundamental variables of small-molecule–neuropeptide co-transmission, including the potential degrees of freedom at particular presynaptic and postsynaptic profiles, and the impact of presynaptic neuron firing rate, modulatory state and extracellular peptidase activity, act to increase the complexity of synaptic transmission.

  • There is considerable diversity in the consequences for synaptic transmission resulting from small-molecule–neuropeptide co-transmission at identified synapses, and their impact on behaviour. One highlight is that the various mechanisms by which this co-transmission influences synapses (for example, convergent or divergent co-transmission, firing rate-dependent co-transmitter release, and so on) are shared across invertebrate and vertebrate species.

  • Using exogenously applied neuropeptides has provided many insights into their modulatory actions, but this approach also has limitations and can lead to erroneous conclusions, as illustrated by studies in the crustacean stomatogastric ganglion that compare the influence of exogenous versus neuronally released neuropeptides from identified neurons.

  • Extending small-molecule–neuropeptide co-transmission studies from individual synapses to their impact on microcircuits, results from the crustacean stomatogastric system are presented to elucidate the impact of convergent versus divergent co-transmission, to separate regulation of co-transmitters and to show the distinct influence on the same microcircuits of different neurons with shared co-transmitters.

  • Work from the stomatogastric system is also used to provide insight regarding the imperfect match between the influence of apparently equivalent, small-molecule–neuropeptide co-transmitting neurons on the same microcircuits in different species.

Abstract

Colocalization of small-molecule and neuropeptide transmitters is common throughout the nervous system of all animals. The resulting co-transmission, which provides conjoint ionotropic ('classical') and metabotropic ('modulatory') actions, includes neuropeptide- specific aspects that are qualitatively different from those that result from metabotropic actions of small-molecule transmitter release. Here, we focus on the flexibility afforded to microcircuits by such co-transmission, using examples from various nervous systems. Insights from such studies indicate that co-transmission mediated even by a single neuron can configure microcircuit activity via an array of contributing mechanisms, operating on multiple timescales, to enhance both behavioural flexibility and robustness.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Co-transmission of small molecules and neuropeptides provides many degrees of freedom to microcircuit output.
Figure 2: The crab Cancer borealis stomatogastric nervous system.
Figure 3: The microcircuit response to peptidergic neuron activity is not necessarily mimicked by bath application of that neuropeptide.
Figure 4: Peptide co-transmitters can have complementary actions on microcircuit output.
Figure 5: The response of a microcircuit to co-transmission can be sculpted by feedback to the co-transmitting neuron.
Figure 6: The muscle stretch-sensitive GPR neuron causes a state-dependent prolongation of the gastric mill retractor phase by selectively inhibiting CabTRP Ia release from MCN1.

References

  1. 1

    Lingueglia, E., Champigny, G., Lazdunski, M. & Barbry, P. Cloning of the amiloride-sensitive FMRFamide peptide-gated sodium channel. Nature 378, 730–733 (1995).

    CAS  PubMed  Google Scholar 

  2. 2

    Durrnagel, S. et al. Three homologous subunits form a high affinity peptide-gated ion channel in Hydra. J. Biol. Chem. 285, 11958–11965 (2010).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Grunder, S. & Assmann, M. Peptide-gated ion channels and the simple nervous system of Hydra. J. Exp. Biol. 218, 551–561 (2015).

    PubMed  Google Scholar 

  4. 4

    Trudeau, L. E. et al. The multilingual nature of dopamine neurons. Prog. Brain Res. 211, 141–164 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Tritsch, N. X., Granger, A. J. & Sabatini, B. L. Mechanisms and functions of GABA co-release. Nat. Rev. Neurosci. 17, 139–145 (2016).

    CAS  PubMed  Google Scholar 

  6. 6

    Vaaga, C. E., Borisovska, M. & Westbrook, G. L. Dual-transmitter neurons: functional implications of co-release and co-transmission. Curr. Opin. Neurobiol. 29, 25–32 (2014).

    CAS  PubMed  Google Scholar 

  7. 7

    Kennedy, C. ATP as a cotransmitter in the autonomic nervous system. Auton. Neurosci. 191, 2–15 (2015).

    CAS  PubMed  Google Scholar 

  8. 8

    Barker, D. J., Root, D. H., Zhang, S. & Morales, M. Multiplexed neurochemical signaling by neurons of the ventral tegmental area. J. Chem. Neuroanat. 73, 33–42 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Granger, A. J., Mulder, N., Saunders, A. & Sabatini, B. L. Cotransmission of acetylcholine and GABA. Neuropharmacology 100, 40–46 (2016).

    CAS  PubMed  Google Scholar 

  10. 10

    Hnasko, T. S. & Edwards, R. H. Neurotransmitter corelease: mechanism and physiological role. Annu. Rev. Physiol. 74, 225–243 (2012).

    CAS  PubMed  Google Scholar 

  11. 11

    Nusbaum, M. P., Blitz, D. M., Swensen, A. M., Wood, D. & Marder, E. The roles of co-transmission in neural network modulation. Trends Neurosci. 24, 146–154 (2001).

    CAS  PubMed  Google Scholar 

  12. 12

    Sámano, C., Cifuentes, F. & Morales, M. A. Neurotransmitter segregation: functional and plastic implications. Prog. Neurobiol. 97, 277–287 (2012).

    PubMed  Google Scholar 

  13. 13

    Schöne, C. & Burdakov, D. Glutamate and GABA as rapid effectors of hypothalamic “peptidergic” neurons. Front. Behav. Neurosci. 6, 81 (2012).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Zhang, S. et al. Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons. Nat. Neurosci. 18, 386–392 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Jan, L. Y. & Jan, Y. N. Peptidergic transmission in sympathetic ganglia of the frog. J. Physiol. 327, 219–246 (1982). This seminal paper was among the first to determine that neuronally released peptides are transmitters, are co-released with a small-molecule transmitter (thereby establishing the concept of co-transmission) and can influence target neurons at a distance (that is, with no direct synaptic contacts).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Sigvardt, K. A., Rothman, B. S., Brown, R. O. & Mayeri, E. The bag cells of Aplysia as a multitransmitter system: identification of alpha bag cell peptide as a second neurotransmitter. J. Neurosci. 6, 803–813 (1986).

    CAS  PubMed  Google Scholar 

  17. 17

    Kupfermann, I. Functional studies of cotransmission. Physiol. Rev. 71, 683–732 (1991).

    CAS  PubMed  Google Scholar 

  18. 18

    Whim, M. D. & Lloyd, P. E. Frequency-dependent release of peptide cotransmitters from identified cholinergic motor neurons in Aplysia. Proc. Natl Acad. Sci. USA 86, 9034–9038 (1989).

    CAS  PubMed  Google Scholar 

  19. 19

    Whim, M. D. & Lloyd, P. E. Neuropeptide cotransmitters released from identified cholinergic motor neurons in Aplysia. J. Neurosci. 10, 3313–3322 (1990).

    CAS  PubMed  Google Scholar 

  20. 20

    Peng, Y.-Y. & Horn, J. P. Continuous repetitive stimuli are more effective than bursts for evoking LHRH release in bullfrog sympathetic ganglia. J. Neurosci. 11, 85–95 (1991).

    CAS  PubMed  Google Scholar 

  21. 21

    Vilim, F. S., Cropper, E. C., Price, D. A., Kupfermann, I. & Weiss, K. R. Release of peptide cotransmitters in Aplysia: regulation and functional implications. J. Neurosci. 16, 8105–8014 (1996).

    CAS  PubMed  Google Scholar 

  22. 22

    Vilim, F. S., Cropper, E. C., Price, D. A., Kupfermann, I. & Weiss, K. R. Peptide cotransmitter release from motorneuron B16 in Aplysia californica: costorage, corelease, and functional implications. J. Neurosci. 20, 2036–2042 (2000). This work reported that neuropeptide release can occur within the natural range of a neuron firing frequency, that co-released peptides with antagonist actions can be co-stored in the same dense-core vesicles (see also references 84 and 91) and that co-released peptides can have complementary actions on their shared target cells, even when their individual actions seem to be antagonistic.

    CAS  PubMed  Google Scholar 

  23. 23

    Vilim, F. S., Price, D. A., Lesser, W., Kupfermann, I. & Weiss, K. R. Costorage and corelease of modulatory peptide cotransmitters with partially antagonistic actions on the accessory radula closer muscle of Aplysia californica. J. Neurosci. 16, 8092–8104 (1996).

    CAS  PubMed  Google Scholar 

  24. 24

    Kirby, M. S. & Nusbaum, M. P. Peptide hormone modulation of a neuronally modulated motor circuit. J. Neurophysiol. 98, 3206–3220 (2007).

    CAS  PubMed  Google Scholar 

  25. 25

    Ludwig, M. & Leng, G. Dendritic peptide release and peptide-dependent behaviours. Nat. Rev. Neurosci. 7, 126–136 (2006).

    CAS  PubMed  Google Scholar 

  26. 26

    Whim, M. D. Near simultaneous release of classical and peptide cotransmitters from chromaffin cells. J. Neurosci. 26, 6637–6642 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Nusbaum, M. P. & Blitz, D. M. Neuropeptide modulation of microcircuits. Curr. Opin. Neurobiol. 22, 592–601 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Nässel, D. R. & Winther, A. M. Drosophila neuropeptides in regulation of physiology and behavior. Prog. Neurobiol. 92, 42–104 (2010).

    PubMed  Google Scholar 

  30. 30

    Nässel, D. R. Neuropeptide signaling near and far: how localized and timed is the action of neuropeptides in brain circuits? Invert. Neurosci. 9, 57–75 (2009).

    PubMed  Google Scholar 

  31. 31

    Taghert, P. H. & Nitabach, M. N. Peptide neuromodulation in invertebrate model systems. Neuron 76, 82–97 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ma, M., Szabo, T. M., Jia, C., Marder, E. & Li, L. Mass spectrometric characterization and physiological actions of novel crustacean C-type allatostatins. Peptides 30, 1660–1668 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Ma, M., Wang, J., Chen, R. & Li, L. Expanding the crustacean neuropeptidome using a multifaceted mass spectrometric approach. J. Proteome Res. 8, 2426–2437 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Winther, A. M., Siviter, R. J., Isaac, R. E., Predel, R. & Nässel, D. R. Neuronal expression of tachykinin-related peptides and gene transcript during postembryonic development of Drosophila. J. Comp. Neurol. 464, 180–196 (2003).

    CAS  PubMed  Google Scholar 

  35. 35

    Chen, R., Hui, L., Sturm, R. M. & Li, L. Three dimensional mapping of neuropeptides and lipids in crustacean brain by mass spectral imaging. J. Am. Soc. Mass Spectrom. 20, 1068–1077 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Dickinson, P. S. et al. Molecular, mass spectral, and physiological analyses of orcokinins and orcokinin precursor-related peptides in the lobster Homarus americanus and the crayfish Procambarus clarkii. Peptides 30, 297–317 (2009).

    CAS  PubMed  Google Scholar 

  37. 37

    Stemmler, E. A., Peguero, B., Bruns, E. A., Dickinson, P. S. & Christie, A. E. Identification, physiological actions, and distribution of TPSGFLGMRamide: a novel tachykinin-related peptide from the midgut and stomatogastric nervous system of Cancer crabs. J. Neurochem. 101, 1351–1366 (2007).

    CAS  PubMed  Google Scholar 

  38. 38

    Szabo, T. M. et al. Distribution and physiological effects of B-type allatostatins (myoinhibitory peptides, MIPs) in the stomatogastric nervous system of the crab Cancer borealis. J. Comp. Neurol. 519, 2658–2676 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Hui, L. et al. Discovery and functional study of a novel crustacean tachykinin neuropeptide. ACS Chem. Neurosci. 2, 711–722 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Dickinson, P. S. et al. Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system. J. Exp. Biol. 218, 2905–2917 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41

    Skiebe, P. & Schneider, H. Allatostatin peptides in the crab stomatogastric nervous system: inhibition of the pyloric motor pattern and distribution of allatostatin-like immunoreactivity. J. Exp. Biol. 194, 195–208 (1994).

    CAS  PubMed  Google Scholar 

  42. 42

    Nusbaum, M. P. & Marder, E. A neuronal role for a crustacean red pigment concentrating hormone-like peptide: neuromodulation of the pyloric rhythm in the crab, Cancer borealis. J. Exp. Biol. 135, 165–181 (1988).

    CAS  Google Scholar 

  43. 43

    Dickinson, P. S., Sreekrishnan, A., Kwiatkowski, M. A. & Christie, A. E. Distinct or shared actions of peptide family isoforms: I. Peptide-specific actions of pyrokinins in the lobster cardiac neuromuscular system. J. Exp. Biol. 218, 2892–2904 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Poels, J. et al. Pharmacology of stomoxytachykinin receptor depends on second messenger system. Peptides 26, 109–114 (2005).

    CAS  PubMed  Google Scholar 

  45. 45

    Poels, J. et al. Functional comparison of two evolutionary conserved insect neurokinin-like receptors. Peptides 28, 103–108 (2007).

    CAS  PubMed  Google Scholar 

  46. 46

    Poels, J. et al. Characterization and distribution of NKD, a receptor for Drosophila tachykinin-related peptide 6. Peptides 30, 545–556 (2009).

    CAS  PubMed  Google Scholar 

  47. 47

    Poels, J. et al. Myoinhibiting peptides are the ancestral ligands of the promiscuous Drosophila sex peptide receptor. Cell. Mol. Life Sci. 67, 3511–3522 (2010).

    CAS  PubMed  Google Scholar 

  48. 48

    Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).

    CAS  Google Scholar 

  49. 49

    Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).

    CAS  Google Scholar 

  50. 50

    Kombian, S. B., Mouginot, D. & Pittman, Q. J. Dendritically released peptides act as retrograde modulators of afferent excitation in the supraoptic nucleus in vitro. Neuron 19, 903–912 (1997).

    CAS  PubMed  Google Scholar 

  51. 51

    Isaac, R. E., Bland, N. D. & Shirras, A. D. Neuropeptidases and the metabolic inactivation of insect neuropeptides. Gen. Comp. Endocrinol. 162, 8–17 (2009).

    CAS  PubMed  Google Scholar 

  52. 52

    Nusbaum, M. P. Regulating peptidergic modulation of rhythmically active neural circuits. Brain Behav. Evol. 60, 378–387 (2002).

    PubMed  Google Scholar 

  53. 53

    Duzzi, B. et al. [des-Arg1]-proctolin: a novel NEP-like enzyme inhibitor identified in Tityus serrulatus venom. Peptides 80, 18–24 (2016).

    CAS  PubMed  Google Scholar 

  54. 54

    Chalasani, S. H. et al. Neuropeptide feedback modifies odor-evoked dynamics in Caenorhabditis elegans olfactory neurons. Nat. Neurosci. 13, 615–621 (2010). This work established that divergent co-transmission can both elicit (via fast synaptic transmission) a complex behaviour and regulate its duration (via slow, peptidergic transmission), the latter via a peptidergic negative feedback loop.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Mills, H. et al. Opiates modulate noxious chemical nociception through a complex monoaminergic/peptidergic cascade. J. Neurosci. 36, 5498–5508 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Leinwand, S. G. & Chalasani, S. H. Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat. Neurosci. 16, 1461–1467 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Harris, G. et al. The monoaminergic modulation of sensory-mediated aversive responses in Caenorhabditis elegans requires glutamatergic/peptidergic cotransmission. J. Neurosci. 30, 7889–7899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Hapiak, V. et al. Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans. J. Neurosci. 33, 14107–14116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    DeLong, N. D., Beenhakker, M. P. & Nusbaum, M. P. Presynaptic inhibition selectively weakens peptidergic cotransmission in a small motor system. J. Neurophysiol. 102, 3492–3504 (2009). This paper demonstrated that neuropeptide co-release (with GABA) from an identified modulatory projection neuron is selectively inhibited (by an identified sensory feedback pathway, acting via its own divergent co-transmitter action), altering the motor pattern generated by the target microcircuit.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Iremonger, K. J., Kuzmiski, J. B., Baimoukhametova, D. V. & Bains, J. S. Dual regulation of anterograde and retrograde transmission by endocannabinoids. J. Neurosci. 31, 12011–12020 (2011). This study revealed the complexity of co-transmission by showing that, in the hypothalamus, dendritic release of eCB can regulate, via its actions on the presynaptic neuron, release of its retrograde peptide co-transmitters (VP and DYN).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ignell, R. et al. Presynaptic peptidergic modulation of olfactory receptor neurons in Drosophila. Proc. Natl Acad. Sci. USA 106, 13070–13075 (2009).

    CAS  PubMed  Google Scholar 

  62. 62

    Barnstedt, O. et al. Memory-relevant mushroom body output synapses are cholinergic. Neuron 89, 1237–1247 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Root, C. M., Ko, K. I., Jafari, A. & Wang, J. W. Presynaptic facilitation by neuropeptide signaling mediates odor-driven food search. Cell 145, 133–144 (2011). This study showed that, during a particular behavioural state (starvation), a neuropeptide is released, binds to autoreceptors on identified olfactory neuron terminals and strengthens the co-release of that peptide and its small-molecule transmitter, thus driving increased food search behaviour.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Wang, J. W. Presynaptic modulation of early olfactory processing in Drosophila. Dev. Neurobiol. 72, 87–99 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kahsai, L., Kapan, N., Dircksen, H., Winther, A. M. & Nässel, D. R. Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides. PLoS ONE 5, e11480 (2010).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Kapan, N., Lushchak, O. V., Luo, J. & Nässel, D. R. Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin. Cell. Mol. Life Sci. 69, 4051–4066 (2012).

    CAS  PubMed  Google Scholar 

  67. 67

    Choi, C. et al. Autoreceptor control of peptide/neurotransmitter corelease from PDF neurons determines allocation of circadian activity in Drosophila. Cell Rep. 2, 332–344 (2012). This study demonstrated that a neuropeptide that is released and binds to autoreceptors on circadian clock neurons facilitates its own release and that of its small-molecule co-transmitter, in this case shifting more of the fly's circadian-regulated activity from evening to morning.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Kahsai, L., Kapan, N., Dircksen, H., Winther, A. M. & Nassel, D. R. Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides. PLoS ONE 5, e11480 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Pulst, S. M., Rothman, B. S. & Mayeri, E. Presence of immunoreactive alpha-bag cell peptide[1-8] in bag cell neurons of Aplysia suggests novel carboxypeptidase processing of neuropeptides. Neuropeptides 10, 249–259 (1987).

    CAS  PubMed  Google Scholar 

  70. 70

    Koh, H. Y., Vilim, F. S., Jing, J. & Weiss, K. R. Two neuropeptides colocalized in a command-like neuron use distinct mechanisms to enhance its fast synaptic connection. J. Neurophysiol. 90, 2074–2079 (2003).

    CAS  PubMed  Google Scholar 

  71. 71

    Koh, H. Y. & Weiss, K. R. Activity-dependent peptidergic modulation of the plateau-generating neuron B64 in the feeding network of Aplysia. J. Neurophysiol. 97, 1862–1867 (2007).

    CAS  PubMed  Google Scholar 

  72. 72

    Friedman, A. K. & Weiss, K. R. Repetition priming of motoneuronal activity in a small motor network: intercellular and intracellular signaling. J. Neurosci. 30, 8906–8919 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Sun, Q. Q., Baraban, S. C., Prince, D. A. & Huguenard, J. R. Target-specific neuropeptide Y-ergic synaptic inhibition and its network consequences within the mammalian thalamus. J. Neurosci. 23, 9639–9649 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Ptak, K. et al. Raphe neurons stimulate respiratory circuit activity by multiple mechanisms via endogenously released serotonin and substance P. J. Neurosci. 29, 3720–3737 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Jego, S. et al. Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus. Nat. Neurosci. 16, 1637–1643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Chee, M. J., Arrigoni, E. & Maratos-Flier, E. Melanin-concentrating hormone neurons release glutamate for feedforward inhibition of the lateral septum. J. Neurosci. 35, 3644–3651 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Qiu, J. et al. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. eLife 5, e16246 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Brown, C. H., Scott, V., Ludwig, M., Leng, G. & Bourque, C. W. Somatodendritic dynorphin release: orchestrating activity patterns of vasopressin neurons. Biochem. Soc. Trans. 35, 1236–1242 (2007).

    CAS  PubMed  Google Scholar 

  80. 80

    Israel, J. M., Poulain, D. A. & Oliet, S. H. Oxytocin-induced postinhibitory rebound firing facilitates bursting activity in oxytocin neurons. J. Neurosci. 28, 385–394 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Oliet, S. H., Baimoukhametova, D. V., Piet, R. & Bains, J. S. Retrograde regulation of GABA transmission by the tonic release of oxytocin and endocannabinoids governs postsynaptic firing. J. Neurosci. 27, 1325–1333 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Sabatier, N. et al. Alpha-melanocyte-stimulating hormone stimulates oxytocin release from the dendrites of hypothalamic neurons while inhibiting oxytocin release from their terminals in the neurohypophysis. J. Neurosci. 23, 10351–10358 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Sabatier, N. α-Melanocyte-stimulating hormone and oxytocin: a peptide signalling cascade in the hypothalamus. J. Neuroendocrinol. 18, 703–710 (2006).

    CAS  PubMed  Google Scholar 

  84. 84

    Whitnall, M. H., Gainer, H., Cox, B. M. & Molineaux, C. J. Dynorphin-A-(1–8) is contained within vasopressin neurosecretory vesicles in rat pituitary. Science 222, 1137–1139 (1983).

    CAS  PubMed  Google Scholar 

  85. 85

    Shuster, S. J., Riedl, M., Li, X., Vulchanova, L. & Elde, R. Stimulus-dependent translocation of κ opioid receptors to the plasma membrane. J. Neurosci. 19, 2658–2664 (1999).

    CAS  PubMed  Google Scholar 

  86. 86

    Hurbin, A., Orcel, H., Alonso, G., Moos, F. & Rabie, A. The vasopressin receptors colocalize with vasopressin in the magnocellular neurons of the rat supraoptic nucleus and are modulated by water balance. Endocrinology 143, 456–466 (2002).

    CAS  PubMed  Google Scholar 

  87. 87

    Wang, L. & Armstrong, W. E. Tonic regulation of GABAergic synaptic activity on vasopressin neurones by cannabinoids. J. Neuroendocrinol. 24, 664–673 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Iremonger, K. J. & Bains, J. S. Retrograde opioid signaling regulates glutamatergic transmission in the hypothalamus. J. Neurosci. 29, 7349–7358 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Apergis-Schoute, J. et al. Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J. Neurosci. 35, 5435–5441 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Li, Y. & van den Pol, A. N. Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. J. Neurosci. 26, 13037–13047 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Muschamp, J. W. et al. Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc. Natl Acad. Sci. USA 111, E1648–E1655 (2014).

    CAS  PubMed  Google Scholar 

  92. 92

    Li, X., Marchant, N. J. & Shaham, Y. Opposing roles of cotransmission of dynorphin and hypocretin on reward and motivation. Proc. Natl Acad. Sci. USA 111, 5765–5766 (2014).

    CAS  PubMed  Google Scholar 

  93. 93

    Schöne, C., Apergis-Schoute, J., Sakurai, T., Adamantidis, A. & Burdakov, D. Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep. 7, 697–704 (2014).

    PubMed  PubMed Central  Google Scholar 

  94. 94

    Cape, S. S., Rehm, K. J., Ma, M., Marder, E. & Li, L. Mass spectral comparison of the neuropeptide complement of the stomatogastric ganglion and brain in the adult and embryonic lobster, Homarus americanus. J. Neurochem. 105, 690–702 (2008).

    CAS  PubMed  Google Scholar 

  95. 95

    Rehm, K. J., Deeg, K. E. & Marder, E. Developmental regulation of neuromodulator function in the stomatogastric ganglion of the lobster, Homarus americanus. J. Neurosci. 28, 9828–9839 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Sandvik, G. K., Hodne, K., Haug, T. M., Okubo, K. & Weltzien, F. A. RFamide peptides in early vertebrate development. Front. Endocrinol. (Lausanne) 5, 203 (2014).

    Google Scholar 

  97. 97

    Sillar, K. T., Combes, D. & Simmers, J. Neuromodulation in developing motor microcircuits. Curr. Opin. Neurobiol. 29, 73–81 (2014).

    CAS  PubMed  Google Scholar 

  98. 98

    Dulcis, D., Jamshidi, P., Leutgeb, S. & Spitzer, N. C. Neurotransmitter switching in the adult brain regulates behavior. Science 340, 449–453 (2013). This paper established that environmental conditions (short versus long photoperiods) can trigger a switch in the balance of co-transmitters (dopamine and somatostatin) and their receptors in rodent hypothalamic neurons, altering behaviours associated with these neurons.

    CAS  PubMed  Google Scholar 

  99. 99

    Spitzer, N. C. Neurotransmitter switching? No surprise. Neuron 86, 1131–1144 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Marder, E., Hooper, S. L. & Siwicki, K. K. Modulatory action and distribution of the neuropeptide proctolin in the crustacean stomatogastric nervous system. J. Comp. Neurol. 243, 454–467 (1986).

    CAS  PubMed  Google Scholar 

  101. 101

    Coleman, M. J., Nusbaum, M. P., Cournil, I. & Claiborne, B. J. Distribution of modulatory inputs to the stomatogastric ganglion of the crab, Cancer borealis. J. Comp. Neurol. 325, 581–594 (1992).

    CAS  PubMed  Google Scholar 

  102. 102

    Nusbaum, M. P. & Marder, E. A modulatory proctolin-containing neuron (MPN). I. Identification and characterization. J. Neurosci. 9, 1591–1599 (1989).

    CAS  PubMed  Google Scholar 

  103. 103

    Nusbaum, M. P. & Marder, E. A modulatory proctolin-containing neuron (MPN). II. State-dependent modulation of rhythmic motor activity. J. Neurosci. 9, 1600–1607 (1989).

    CAS  PubMed  Google Scholar 

  104. 104

    Coleman, M. J. & Nusbaum, M. P. Functional consequences of compartmentalization of synaptic input. J. Neurosci. 14, 6544–6552 (1994).

    CAS  PubMed  Google Scholar 

  105. 105

    Blitz, D. M. et al. Different proctolin neurons elicit distinct motor patterns from a multifunctional neuronal network. J. Neurosci. 19, 5449–5463 (1999). This study established that different identified neurons containing the same peptide co-transmitter and influencing the same microcircuits can elicit different motor patterns from these circuits.

    CAS  PubMed  Google Scholar 

  106. 106

    Christie, A. E., Baldwin, D. H., Marder, E. & Graubard, K. Organization of the stomatogastric neuropil of the crab, Cancer borealis, as revealed by modulator immunocytochemistry. Cell Tissue Res. 288, 135–148 (1997).

    CAS  PubMed  Google Scholar 

  107. 107

    Nusbaum, M. P., Weimann, J. M., Golowasch, J. & Marder, E. Presynaptic control of modulatory fibers by their neural network targets. J. Neurosci. 12, 2706–2714 (1992).

    CAS  PubMed  Google Scholar 

  108. 108

    Swensen, A. M. et al. GABA and responses to GABA in the stomatogastric ganglion of the crab Cancer borealis. J. Exp. Biol. 203, 2075–2092 (2000).

    CAS  PubMed  Google Scholar 

  109. 109

    Hooper, S. L. & Marder, E. Modulation of the lobster pyloric rhythm by the peptide proctolin. J. Neurosci. 7, 2097–2112 (1987).

    CAS  PubMed  Google Scholar 

  110. 110

    Marder, E. & Bucher, D. Understanding circuit dynamics using the stomatogastric nervous system of lobsters and crabs. Annu. Rev. Physiol. 69, 291–316 (2007).

    CAS  Google Scholar 

  111. 111

    Marder, E. Neuromodulation of neuronal circuits: back to the future. Neuron 76, 1–11 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Fénelon, V. S., Kilman, V., Meyrand, P. & Marder, E. Sequential developmental acquisition of neuromodulatory inputs to a central pattern-generating network. J. Comp. Neurol. 408, 335–351 (1999).

    PubMed  Google Scholar 

  113. 113

    Thirumalai, V. & Marder, E. Colocalized neuropeptides activate a central pattern generator by acting on different circuit targets. J. Neurosci. 22, 1874–1882 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Wood, D. E., Stein, W. & Nusbaum, M. P. Projection neurons with shared cotransmitters elicit different motor patterns from the same neuronal circuit. J. Neurosci. 20, 8943–8953 (2000). This paper showed that two different identified projection neurons use the same two co-transmitters (GABA and proctolin) to elicit different motor patterns from the same microcircuit.

    CAS  PubMed  Google Scholar 

  115. 115

    Wood, D. E. & Nusbaum, M. P. Extracellular peptidase activity tunes motor pattern modulation. J. Neurosci. 22, 4185–4195 (2002). This paper showed that the same extracellular peptidase activity differentially influences how different identified projection neurons using the same neuropeptide co-transmitter modulate the same microcircuit.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Swensen, A. M. & Marder, E. Modulators with convergent cellular actions elicit distinct circuit outputs. J. Neurosci. 21, 4050–4058 (2001).

    CAS  PubMed  Google Scholar 

  117. 117

    Stein, W., DeLong, N. D., Wood, D. E. & Nusbaum, M. P. Divergent co-transmitter actions underlie motor pattern activation by a modulatory projection neuron. Eur. J. Neurosci. 26, 1148–1165 (2007).

    PubMed  Google Scholar 

  118. 118

    Bartos, M. & Nusbaum, M. P. Intercircuit control of motor pattern modulation by presynaptic inhibition. J. Neurosci. 17, 2247–2256 (1997).

    CAS  PubMed  Google Scholar 

  119. 119

    Bartos, M., Manor, Y., Nadim, F., Marder, E. & Nusbaum, M. P. Coordination of fast and slow rhythmic neuronal circuits. J. Neurosci. 19, 6650–6660 (1999).

    CAS  PubMed  Google Scholar 

  120. 120

    Nadim, F., Manor, Y., Nusbaum, M. P. & Marder, E. Frequency regulation of a slow rhythm by a fast periodic input. J. Neurosci. 18, 5053–5067 (1998).

    CAS  PubMed  Google Scholar 

  121. 121

    Golowasch, J. & Marder, E. Proctolin activates an inward current whose voltage dependence is modified by extracellular Ca2+. J. Neurosci. 12, 810–817 (1992).

    CAS  PubMed  Google Scholar 

  122. 122

    Swensen, A. M. & Marder, E. Multiple peptides converge to activate the same voltage-dependent current in a central pattern-generating circuit. J. Neurosci. 20, 6752–6759 (2000).

    CAS  PubMed  Google Scholar 

  123. 123

    Garcia, V. J., Daur, N., Temporal, S., Schulz, D. J. & Bucher, D. Neuropeptide receptor transcript expression levels and magnitude of ionic current responses show cell type-specific differences in a small motor circuit. J. Neurosci. 35, 6786–6800 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Saleh, T. M., Kombian, S. B., Zidichouski, J. A. & Pittman, Q. J. Peptidergic modulation of synaptic transmission in the parabrachial nucleus in vitro: importance of degradative enzymes in regulating synaptic efficacy. J. Neurosci. 16, 6046–6055 (1996).

    CAS  PubMed  Google Scholar 

  125. 125

    Turner, A. J., Isaac, R. E. & Coates, D. The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. Bioessays 23, 261–269 (2001).

    CAS  PubMed  Google Scholar 

  126. 126

    Blitz, D. M. et al. A newly identified extrinsic input triggers a distinct gastric mill rhythm via activation of modulatory projection neurons. J. Exp. Biol. 211, 1000–1011 (2008).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Coleman, M. J., Konstant, P. H., Rothman, B. S. & Nusbaum, M. P. Neuropeptide degradation produces functional inactivation in the crustacean nervous system. J. Neurosci. 14, 6205–6216 (1994).

    CAS  PubMed  Google Scholar 

  128. 128

    Katz, P. S. & Harris-Warrick, R. M. Neuromodulation of the crab pyloric central pattern generator by serotonergic/cholinergic proprioceptive afferents. J. Neurosci. 10, 1495–1512 (1990).

    CAS  PubMed  Google Scholar 

  129. 129

    Katz, P. S. & Harris-Warrick, R. M. Recruitment of crab gastric mill neurons into the pyloric motor pattern by mechanosensory afferent stimulation. J. Neurophysiol. 65, 1442–1451 (1991).

    CAS  PubMed  Google Scholar 

  130. 130

    Blitz, D. M. & Nusbaum, M. P. Distinct functions for cotransmitters mediating motor pattern selection. J. Neurosci. 19, 6774–6783 (1999). This study demonstrated that a single projection neuron uses spatially segregated actions of different co-transmitters to regulate separate microcircuits.

    CAS  PubMed  Google Scholar 

  131. 131

    Christie, A. E. et al. Actions of a histaminergic/peptidergic projection neuron on rhythmic motor patterns in the stomatogastric nervous system of the crab Cancer borealis. J. Comp. Neurol. 469, 153–169 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Kwiatkowski, M. A. et al. Coordination of distinct but interacting rhythmic motor programs by a modulatory projection neuron using different co-transmitters in different ganglia. J. Exp. Biol. 216, 1827–1836 (2013).

    PubMed  PubMed Central  Google Scholar 

  133. 133

    Ostroumov, A. et al. Stress increases ethanol self-administration via a shift toward excitatory GABA signaling in the ventral tegmental area. Neuron 92, 493–504 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Coleman, M. J., Meyrand, P. & Nusbaum, M. P. A switch between two modes of synaptic transmission mediated by presynaptic inhibition. Nature 378, 502–505 (1995).

    CAS  PubMed  Google Scholar 

  135. 135

    Beenhakker, M. P., Blitz, D. M. & Nusbaum, M. P. Long-lasting activation of rhythmic neuronal activity by a novel mechanosensory system in the crustacean stomatogastric nervous system. J. Neurophysiol. 91, 78–91 (2004).

    PubMed  Google Scholar 

  136. 136

    Diehl, F., White, R. S., Stein, W. & Nusbaum, M. P. Motor circuit-specific burst patterns drive different muscle and behavior patterns. J. Neurosci. 33, 12013–12029 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Beenhakker, M. P. & Nusbaum, M. P. Mechanosensory activation of a motor circuit by coactivation of two projection neurons. J. Neurosci. 24, 6741–6750 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    DeLong, N. D., Kirby, M. S., Blitz, D. M. & Nusbaum, M. P. Parallel regulation of a modulator-activated current via distinct dynamics underlies comodulation of motor circuit output. J. Neurosci. 29, 12355–12367 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Marder, E., Manor, Y., Nadim, F., Bartos, M. & Nusbaum, M. P. in Neuronal Mechanisms for Generating Locomotory Activity (eds Kiehn, O., Harris-Warrick, R. M., Jordan, L. M., Hultborn, H. & Kudo, N.) 226–237 (Ann. NY Acad. Sci., 1998).

    Google Scholar 

  140. 140

    Blitz, D. M. & Nusbaum, M. P. Motor pattern selection via inhibition of parallel pathways. J. Neurosci. 17, 4965–4975 (1997).

    CAS  PubMed  Google Scholar 

  141. 141

    Beenhakker, M. P., DeLong, N. D., Saideman, S. R., Nadim, F. & Nusbaum, M. P. Proprioceptor regulation of motor circuit activity by presynaptic inhibition of a modulatory projection neuron. J. Neurosci. 25, 8794–8806 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    DeLong, N. D. & Nusbaum, M. P. Hormonal modulation of sensorimotor integration. J. Neurosci. 30, 2418–2427 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Katz, P. S., Eigg, M. H. & Harris-Warrick, R. M. Serotonergic/cholinergic muscle receptor cells in the crab stomatogastric nervous system. I. Identification and characterization of the gastropyloric receptor cells. J. Neurophysiol. 62, 558–570 (1989).

    CAS  PubMed  Google Scholar 

  144. 144

    Birmingham, J. T., Szuts, Z., Abbott, L. F. & Marder, E. Encoding of muscle movement on two time scales by a sensory neuron that switches between spiking and burst modes. J. Neurophysiol. 82, 2786–2797 (1999).

    CAS  PubMed  Google Scholar 

  145. 145

    Beltz, B. et al. Serotonergic innervation and modulation of the stomatogastric ganglion of three decapod crustaceans (Panulirus interruptus, Homarus americanus and Cancer irroratus). J. Exp. Biol. 109, 35–54 (1984).

    CAS  PubMed  Google Scholar 

  146. 146

    Katz, P. S. & Harris-Warrick, R. M. Serotonergic/cholinergic muscle receptor cells in the crab stomatogastric nervous system. II. Rapid nicotinic and prolonged modulatory effects on neurons in the stomatogastric ganglion. J. Neurophysiol. 62, 571–581 (1989).

    CAS  PubMed  Google Scholar 

  147. 147

    Beenhakker, M. P., Kirby, M. S. & Nusbaum, M. P. Mechanosensory gating of proprioceptor input to modulatory projection neurons. J. Neurosci. 27, 14308–14316 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Meyrand, P., Faumont, S., Simmers, J., Christie, A. E. & Nusbaum, M. P. Species-specific modulation of pattern-generating circuits. Eur. J. Neurosci. 12, 2585–2596 (2000). This study showed that likely-equivalent projection neurons in different species share a co-transmitter phenotype (small-molecule plus peptide co-transmitters) but exhibit some distinct actions on their shared target microcircuits.

    CAS  PubMed  Google Scholar 

  149. 149

    Bucher, D., Taylor, A. L. & Marder, E. Central pattern generating neurons simultaneously express fast and slow rhythmic activities in the stomatogastric ganglion. J. Neurophysiol. 95, 3617–3632 (2006).

    PubMed  Google Scholar 

  150. 150

    Cournil, I., Meyrand, P. & Moulins, M. Identification of all GABA-immunoreactive neurons projecting to the lobster stomatogastric ganglion. J. Neurocytol. 19, 478–493 (1990).

    CAS  PubMed  Google Scholar 

  151. 151

    Marder, E. & Eisen, J. S. Electrically coupled pacemaker neurons respond differently to the same physiological inputs and neurotransmitters. J. Neurophysiol. 51, 1362–1374 (1984).

    CAS  PubMed  Google Scholar 

  152. 152

    Russell, D. F. & Hartline, D. K. A multiaction synapse evoking both EPSPs and enhancement of endogenous bursting. Brain Res. 223, 19–38 (1981).

    CAS  PubMed  Google Scholar 

  153. 153

    Sigvardt, K. A. & Mulloney, B. Properties of synapses made by IVN command-interneurones in the stomatogastric ganglion of the spiny lobster Panulirus interruptus. J. Exp. Biol. 97, 153–168 (1982).

    CAS  PubMed  Google Scholar 

  154. 154

    Claiborne, B. J. & Selverston, A. I. Histamine as a neurotransmitter in the stomatogastric nervous system of the spiny lobster. J. Neurosci. 4, 708–721 (1984).

    CAS  PubMed  Google Scholar 

  155. 155

    Bargmann, C. I. Beyond the connectome: how neuromodulators shape neural circuits. Bioessays 34, 458–465 (2012).

    CAS  Google Scholar 

  156. 156

    Bargmann, C. I. & Marder, E. From the connectome to brain function. Nat. Methods 10, 483–490 (2013).

    CAS  Google Scholar 

  157. 157

    Saideman, S. R. et al. Modulation of rhythmic motor activity by pyrokinin peptides. J. Neurophysiol. 97, 579–595 (2007).

    CAS  PubMed  Google Scholar 

  158. 158

    Nusbaum, M. P. & Beenhakker, M. P. A small systems approach to motor pattern generation. Nature 417, 343–350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    White, R. S. & Nusbaum, M. P. The same core rhythm generator underlies different rhythmic motor patterns. J. Neurosci. 31, 11484–11494 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Research in the authors' laboratories is funded by the US National Institutes of Health (NIH) grant NS-29436 (MPN), NSF grant IOS-1153417 (D.M.B.) and NIH grant NS17813 (E.M.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael P. Nusbaum.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Biogenic amines

Amine-containing neurotransmitters (dopamine, histamine, 5-hydroxytryptamine (vertebrates and invertebrates), noradrenaline (vertebrates) and octopamine (invertebrates)) that commonly, but not exclusively, act via G protein- coupled receptors to evoke metabotropic responses.

Stomatogastric ganglion

(STG). A small, well-defined ganglion in the decapod crustacean (for example, crabs and lobsters) stomatogastric nervous system containing 25–30 neurons (depending on species), nearly all of which contribute to one or both microcircuits (gastric mill circuit (chewing), pyloric circuit (pumping and filtering of chewed food)) located therein.

Postsynaptic convergence (of co-transmitters)

Multiple neurotransmitters released from the same neuron that bind to their respective receptors on the same postsynaptic neuron to regulate neuronal activity.

Presynaptic convergence (of co-transmitters)

Multiple neurotransmitters released from the same neuron that bind to their respective receptors on the same presynaptic terminal (or terminals) to regulate neurotransmitter release from said terminal (or terminals).

Retraction

Defines the phase of chewing when the teeth move apart; during the crab or lobster gastric mill rhythm, retraction defines the phase of neuronal activity in the sole interneuron (Int1) and the motor neurons (for example, DG neuron) that drive contraction of the 'retractor' muscles, which cause the teeth to move away from midline in the intact animal.

Protraction

Defines the phase of chewing when the teeth come together; during the crab or lobster gastric mill rhythm, protraction defines the phase of neuronal activity in the motor neurons (for example, LG neuron) that drive contraction of the 'protractor' muscles, which cause the teeth to come together at the midline in the intact animal.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nusbaum, M., Blitz, D. & Marder, E. Functional consequences of neuropeptide and small-molecule co-transmission. Nat Rev Neurosci 18, 389–403 (2017). https://doi.org/10.1038/nrn.2017.56

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing