Abstract
In numerous mammalian species, the nose harbors several compartments populated by chemosensory cells. Among them, the Grueneberg ganglion (GG) located in the anterior nasal region comprises sensory neurons activated by given substances. In rodents, in which the GG has been best studied, these chemical cues mainly include heterocyclic compounds released by predators or by conspecifics. Since some of these substances evoke fear- or stress-associated responses, the GG is considered as a detector for alerting semiochemicals. In fact, certain behavioral and physiological reactions to alarm pheromones and predator-secreted kairomones are attenuated in the absence of a functional GG. Intriguingly, GG neurons are also stimulated by cool temperatures. Moreover, ambient temperatures modulate olfactory responsiveness in the GG, indicating that cross-talks exist between the transduction pathways mediating chemo- and thermosensory signaling in this organ. In this context, exploring the relevant molecular cascades has demonstrated that some chemosensory transduction elements are also crucial for thermosensory signaling in the GG. Finally, for further processing of sensory information, axons of GG neurons project to the olfactory bulb of the brain where they innervate distinct glomerular structures belonging to the enigmatic necklace glomeruli. In this review, the stimuli activating GG neurons as well as the underlying transduction pathways are summarized. Because these stimuli do not exclusively activate GG neurons but also other sensory cells, the biological relevance of the GG is discussed, with a special focus on the role of the GG in detecting alarm signals.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00441-020-03380-w/MediaObjects/441_2020_3380_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00441-020-03380-w/MediaObjects/441_2020_3380_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00441-020-03380-w/MediaObjects/441_2020_3380_Fig3_HTML.png)
Similar content being viewed by others
Abbreviations
- 2,3-DMP:
-
2,3-Dimethylpyrazine
- 2-EP:
-
2-Ethylpyrazine
- 2-PT:
-
2-Propylthietane
- cGMP:
-
Cyclic guanosine monophosphate
- CNG:
-
Cyclic nucleotide-gated
- CNGA3:
-
Cyclic nucleotide-gated channel A3
- GC-G:
-
Guanylyl cyclase subtype G
- GFP:
-
Green fluorescent protein
- GG:
-
Grueneberg ganglion
- GPCR(s):
-
G protein-coupled receptor(s)
- HEK:
-
Human embryonic kidney
- MOE:
-
Main olfactory epithelium
- OB:
-
Olfactory bulb
- OMP:
-
Olfactory marker protein
- PDE:
-
Phosphodiesterase
- PDE2A:
-
Phosphodiesterase 2A
- PTU:
-
6-Propyl-2-thiouracil
- SBT:
-
2-S-butyl-4,5-dihydrothiazole
- STFP:
-
Social transmission of food preference
- TAAR(s):
-
Trace amine-associated receptor(s)
- TAS2R/T2R:
-
Bitter taste receptor
- TMT:
-
2,5-Dihydro-2,4,5-trimethylthiazoline
- VNO:
-
Vomeronasal organ
References
Adler E, Hoon MA, Mueller KL, Chandrashekar J, Ryba NJ, Zuker CS (2000) A novel family of mammalian taste receptors. Cell 100:693–702
Akiyoshi S, Ishii T, Bai Z, Mombaerts P (2018) Subpopulations of vomeronasal sensory neurons with coordinated coexpression of type 2 vomeronasal receptor genes are differentially dependent on Vmn2r1. Eur J Neurosci 47:887–900
Allin JT, Banks EM (1971) Effects of temperature on ultrasound production by infant albino rats. Dev Psychobiol 4:149–156
Arakawa H, Kelliher KR, Zufall F, Munger SD (2013) The receptor guanylyl cyclase type D (GC-D) ligand uroguanylin promotes the acquisition of food preferences in mice. Chem Senses 38:391–397
Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–208
Bean NJ, Galef BG, Mason JR (1988) The effect of carbon disulphide on food consumption by house mice. J Wildl Manage 52:502–507
Behrens M, Foerster S, Staehler F, Raguse JD, Meyerhof W (2007) Gustatory expression pattern of the human TAS2R bitter receptor gene family reveals a heterogenous population of bitter responsive taste receptor cells. J Neurosci 27:12630–12640
Blumberg MS, Efimova IV, Alberts JR (1992) Ultrasonic vocalizations by rat pups: the primary importance of ambient temperature and the thermal significance of contact comfort. Dev Psychobiol 25:229–250
Bozza TC, Mombaerts P (2001) Olfactory coding: revealing intrinsic representations of odors. Curr Biol 11:R687-690
Brechbühl J, de Vallière A, Wood D, Nenniger Tosato M, Broillet MC (2020) The Grueneberg ganglion controls odor-driven food choices in mice under threat. Commun Biol 3:533
Brechbühl J, Klaey M, Broillet MC (2008) Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 321:1092–1095
Brechbühl J, Klaey M, Moine F, Bovay E, Hurni N, Nenniger-Tosato M, Broillet MC (2014) Morphological and physiological species-dependent characteristics of the rodent Grueneberg ganglion. Front Neuroanat 8:87
Brechbühl J, Moine F, Broillet MC (2013b) Mouse Grueneberg ganglion neurons share molecular and functional features with C. elegans amphid neurons. Front Behav Neurosci 7:193
Brechbühl J, Moine F, Klaey M, Nenniger-Tosato M, Hurni N, Sporkert F, Giroud C, Broillet MC (2013a) Mouse alarm pheromone shares structural similarity with predator scents. Proc Natl Acad Sci U S A 110:4762–4767
Brechbühl J, Moine F, Tosato MN, Sporkert F, Broillet MC (2015) Identification of pyridine analogs as new predator-derived kairomones. Front Neurosci 9:253
Brunet LJ, Gold GH, Ngai J (1996) General anosmia caused by a targeted disruption of the mouse olfactory cyclic nucleotide-gated cation channel. Neuron 17:681–693
Buck LB (1996) Information coding in the vertebrate olfactory system. Annu Rev Neurosci 19:517–544
Buck LB (2000) The molecular architecture of odor and pheromone sensing in mammals. Cell 100:611–618
Bumbalo R, Lieber M, Lehmann E, Wolf I, Breer H, Fleischer J (2017b) Attenuated chemosensory responsiveness of the Grueneberg ganglion in mouse pups at warm temperatures. Neuroscience 366:149–161
Bumbalo R, Lieber M, Schroeder L, Polat Y, Breer H, Fleischer J (2017a) Grueneberg glomeruli in the olfactory bulb are activated by odorants and cool temperature. Cell Mol Neurobiol 37:729–742
Chao YC, Chen CC, Lin YC, Breer H, Fleischer J, Yang RB (2015) Receptor guanylyl cyclase-G is a novel thermosensory protein activated by cool temperatures. EMBO J 34:294–306
Chao YC, Fleischer J, Yang RB (2018) Guanylyl cyclase-G is an alarm pheromone receptor in mice. EMBO J 37:39–49
Chehrehasa F, Jacques A, St John JA, Ekberg JAK (2018) The Grueneberg olfactory organ neuroepithelium recovers after injury. Brain Res 1688:65–72
Cockerham RE, Leinders-Zufall T, Munger SD, Zufall F (2009) Functional analysis of the guanylyl cyclase type D signaling system in the olfactory epithelium. Ann N Y Acad Sci 1170:173–176
Dai G, Peng C, Liu C, Varnum MD (2013) Two structural components in CNGA3 support regulation of cone CNG channels by phosphoinositides. J Gen Physiol 141:413–430
Debiec J, Sullivan RM (2014) Intergenerational transmission of emotional trauma through amygdala-dependent mother-to-infant transfer of specific fear. Proc Natl Acad Sci U S A 111:12222–12227
DeMaria S, Berke AP, Van Name E, Heravian A, Ferreira T, Ngai J (2013) Role of a ubiquitously expressed receptor in the vertebrate olfactory system. J Neurosci 33:15235–15247
Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A (2007) TRPM8 is required for cold sensation in mice. Neuron 54:371–378
Duda T, Sharma RK (2008) ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer. Biochem Biophys Res Commun 367:440–445
Firestein S (2001) How the olfactory system makes sense of scents. Nature 413:211–218
Fleischer J (2014) The Grueneberg ganglion: a cool chemodetector. Chemosense 15:3–19
Fleischer J, Breer H (2010) The Grueneberg ganglion: a novel sensory system in the nose. Histol Histopathol 25:909–915
Fleischer J, Hass N, Schwarzenbacher K, Besser S, Breer H (2006a) A novel population of neuronal cells expressing the olfactory marker protein (OMP) in the anterior/dorsal region of the nasal cavity. Histochem Cell Biol 125:337–349
Fleischer J, Mamasuew K, Breer H (2009) Expression of cGMP signaling elements in the Grueneberg ganglion. Histochem Cell Biol 131:75–88
Fleischer J, Schwarzenbacher K, Besser S, Hass N, Breer H (2006b) Olfactory receptors and signalling elements in the Grueneberg ganglion. J Neurochem 98:543–554
Fleischer J, Schwarzenbacher K, Breer H (2007) Expression of trace amine-associated receptors in the Grueneberg ganglion. Chem Senses 32:623–631
Fuss SH, Omura M, Mombaerts P (2005) The Grueneberg ganglion of the mouse projects axons to glomeruli in the olfactory bulb. Eur J Neurosci 22:2649–2654
Galef BG (2012) A case study in behavioral analysis, synthesis and attention to detail: social learning of food preferences. Behav Brain Res 231:266–271
Galef BG, Mason JR, Preti G, Bean NJ (1988) Carbon disulfide: a semiochemical mediating socially-induced diet choice in rats. Physiol Behav 42:119–124
Gattermann R, Johnston RE, Yigit N, Fritzsche P, Larimer S, Ozkurt S, Neumann K, Song Z, Colak E, Johnston J, McPhee ME (2008) Golden hamsters are nocturnal in captivity but diurnal in nature. Biol Lett 4:253–255
Grüneberg H (1973) A ganglion probably belonging to the N. terminalis system in the nasal mucosa of the mouse. Z Anat Entwicklungsgesch 140:39–52
Hanke W, Mamasuew K, Biel M, Yang RB, Fleischer J (2013) Odorant-evoked electrical responses in Grueneberg ganglion neurons rely on cGMP-associated signaling proteins. Neurosci Lett 539:38–42
Jemiolo B, Andreolini F, **e TM, Wiesler D, Novotny M (1989) Puberty-affecting synthetic analogs of urinary chemosignals in the house mouse, Mus domesticus. Physiol Behav 46:293–298
Juilfs DM, Fülle HJ, Zhao AZ, Houslay MD, Garbers DL, Beavo JA (1997) A subset of olfactory neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc Natl Acad Sci U S A 94:3388–3395
Kaupp UB, Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824
Kelliher KR, Munger SD (2015) Chemostimuli for guanylyl cyclase-D-expressing olfactory sensory neurons promote the acquisition of preferences for foods adulterated with the rodenticide warfarin. Front Neurosci 9:262
Kobayakawa K, Kobayakawa R, Matsumoto H, Oka Y, Imai T, Ikawa M, Okabe M, Ikeda T, Itohara S, Kikusui T, Mori K, Sakano H (2007) Innate versus learned odour processing in the mouse olfactory bulb. Nature 450:503–508
Koos DS, Fraser SE (2005) The Grueneberg ganglion projects to the olfactory bulb. NeuroReport 16:1929–1932
Kuhn M (2016) Molecular physiology of membrane guanylyl cyclase receptors. Physiol Rev 96:751–804
Leinders-Zufall T, Cockerham RE, Michalakis S, Biel M, Garbers DL, Reed RR, Zufall F, Munger SD (2007) Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium. Proc Natl Acad Sci U S A 104:14507–14512
Liberles SD (2015) Trace amine-associated receptors: ligands, neural circuits, and behaviors. Curr Opin Neurobiol 34:1–7
Liberles SD, Buck LB (2006) A second class of chemosensory receptors in the olfactory epithelium. Nature 442:645–650
Liu CY, Fraser SE, Koos DS (2009) Grueneberg ganglion olfactory subsystem employs a cGMP signaling pathway. J Comp Neurol 516:36–48
Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52:375–414
Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honoré E (2000) TREK-1 is a heat-activated background K(+) channel. EMBO J 19:2483–2491
Mamasuew K, Breer H, Fleischer J (2008) Grueneberg ganglion neurons respond to cool ambient temperatures. Eur J Neurosci 28:1775–1785
Mamasuew K, Hofmann N, Breer H, Fleischer J (2011a) Grueneberg ganglion neurons are activated by a defined set of odorants. Chem Senses 36:271–282
Mamasuew K, Hofmann N, Kretzschmann V, Biel M, Yang RB, Breer H, Fleischer J (2011b) Chemo- and thermosensory responsiveness of Grueneberg ganglion neurons relies on cyclic guanosine monophosphate signaling elements. Neurosignals 19:198–209
Mamasuew K, Michalakis S, Breer H, Biel M, Fleischer J (2010) The cyclic nucleotide-gated ion channel CNGA3 contributes to coolness-induced responses of Grueneberg ganglion neurons. Cell Mol Life Sci 67:1859–1869
Martini S, Silvotti L, Shirazi A, Ryba NJ, Tirindelli R (2001) Co-expression of putative pheromone receptors in the sensory neurons of the vomeronasal organ. J Neurosci 21:843–848
Matsuo T, Rossier DA, Kan C, Rodriguez I (2012) The wiring of Grueneberg ganglion axons is dependent on neuropilin 1. Development 139:2783–2791
Menco BP (1997) Ultrastructural aspects of olfactory signaling. Chem Senses 22:295–311
Menco BP, Cunningham AM, Qasba P, Levy N, Reed RR (1997) Putative odour receptors localize in cilia of olfactory receptor cells in rat and mouse: a freeze-substitution ultrastructural study. J Neurocytol 26:691–706
Meyer MR, Angele A, Kremmer E, Kaupp UB, Muller F (2000) A cGMP-signaling pathway in a subset of olfactory sensory neurons. Proc Natl Acad Sci U S A 97:10595–10600
Moine F, Brechbühl J, Nenniger Tosato M, Beaumann M, Broillet MC (2018) Alarm pheromone and kairomone detection via bitter taste receptors in the mouse Grueneberg ganglion. BMC Biol 16:12
Mombaerts P (2004a) Genes and ligands for odorant, vomeronasal and taste receptors. Nat Rev Neurosci 5:263–278
Mombaerts P (2004b) Odorant receptor gene choice in olfactory sensory neurons: the one receptor-one neuron hypothesis revisited. Curr Opin Neurobiol 14:31–36
Mori K, Nagao H, Yoshihara Y (1999) The olfactory bulb: coding and processing of odor molecule information. Science 286:711–715
Munger SD, Leinders-Zufall T, McDougall LM, Cockerham RE, Schmid A, Wandernoth P, Wennemuth G, Biel M, Zufall F, Kelliher KR (2010) An olfactory subsystem that detects carbon disulfide and mediates food-related social learning. Curr Biol 20:1438–1444
Okon EE (1971) The temperature relations of vocalization in infant Golden hamsters and Wistar rats. J Zool 164:227–237
Osada K, Kurihara K, Izumi H, Kashiwayanagi M (2013) Pyrazine analogues are active components of wolf urine that induce avoidance and freezing behaviours in mice. PLoS ONE 8:e61753
Oswalt GL, Meier GW (1975) Olfactory, thermal, and tactual influences on infantile ultrasonic vocalization in rats. Dev Psychobiol 8:129–135
Pérez-Gómez A, Bleymehl K, Stein B, Pyrski M, Birnbaumer L, Munger SD, Leinders-Zufall T, Zufall F, Chamero P (2015) Innate predator odor aversion driven by parallel olfactory subsystems that converge in the ventromedial hypothalamus. Curr Biol 25:1340–1346
Roppolo D, Ribaud V, Jungo VP, Lüscher C, Rodriguez I (2006) Projection of the Grüneberg ganglion to the mouse olfactory bulb. Eur J Neurosci 23:2887–2894
Schmid A, Pyrski M, Biel M, Leinders-Zufall T, Zufall F (2010) Grueneberg ganglion neurons are finely tuned cold sensors. J Neurosci 30:7563–7568
Sievert T, Laska M (2016) Behavioral responses of CD-1 mice to six predator odor components. Chem Senses 41:399–406
Stebe S, Schellig K, Lesage F, Breer H, Fleischer J (2014) The thermosensitive potassium channel TREK-1 contributes to coolness-evoked responses of Grueneberg ganglion neurons. Cell Mol Neurobiol 34:113–122
Storan MJ, Key B (2006) Septal organ of Grüneberg is part of the olfactory system. J Comp Neurol 494:834–844
Strotmann J, Levai O, Fleischer J, Schwarzenbacher K, Breer H (2004) Olfactory receptor proteins in axonal processes of chemosensory neurons. J Neurosci 24:7754–7761
Szentgyörgyi H, Kapusta J, Marchlewska-Koj A (2008) Ultrasonic calls of bank vole pups isolated and exposed to cold or to nest odor. Physiol Behav 93:296–303
Tachibana T, Fujiwara N, Nawa T (1990) The ultrastructure of the ganglionated nerve plexus in the nasal vestibular mucosa of the musk shrew (Suncus murinus, insectivora). Arch Histol Cytol 53:147–156
Thompson DK, Garbers DL (1995) Dominant negative mutations of the guanylyl cyclase-A receptor. Extracellular domain deletion and catalytic domain point mutations. J Biol Chem 270:425–430
Vernet-Maury E, Polak EH, Demael A (1984) Structure-activity relationship of stress-inducing odorants in the rat. J Chem Ecol 10:1007–1018
Wallace KJ, Rosen JB (2000) Predator odor as an unconditioned fear stimulus in rats: elicitation of freezing by trimethylthiazoline, a component of fox feces. Behav Neurosci 114:912–922
Walz A, Feinstein P, Khan M, Mombaerts P (2007) Axonal wiring of guanylate cyclase-D-expressing olfactory neurons is dependent on neuropilin 2 and semaphorin 3F. Development 134:4063–4072
Wilson EM, Chinkers M (1995) Identification of sequences mediating guanylyl cyclase dimerization. Biochemistry 34:4696–4701
Wong ST, Trinh K, Hacker B, Chan GC, Lowe G, Gaggar A, **a Z, Gold GH, Storm DR (2000) Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27:487–497
Yamamoto Y, Hatakeyama T, Taniguchi K (2009) Immunohistochemical colocalization of TREK-1, TREK-2 and TRAAK with TRP channels in the trigeminal ganglion cells. Neurosci Lett 454:129–133
Zhang JX, Soini HA, Bruce KE, Wiesler D, Woodley SK, Baum MJ, Novotny MV (2005) Putative chemosignals of the ferret (Mustela furo) associated with individual and gender recognition. Chem Senses 30:727–737
Zheng J, Zagotta WN (2004) Stoichiometry and assembly of olfactory cyclic nucleotide-gated channels. Neuron 42:411–421
Zou DJ, Chesler A, Firestein S (2009) How the olfactory bulb got its glomeruli: a just so story? Nat Rev Neurosci 10:611–618
Acknowledgments
The author is indebted to Heinz Breer and Jürgen Krieger for generous support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares that there is no conflict of interest.
Ethical approval
This review does not contain any previously unpublished studies with human participants or animals.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Fleischer, J. The Grueneberg ganglion: signal transduction and coding in an olfactory and thermosensory organ involved in the detection of alarm pheromones and predator-secreted kairomones. Cell Tissue Res 383, 535–548 (2021). https://doi.org/10.1007/s00441-020-03380-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-020-03380-w