Skip to main content
Log in

Local corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

Neuropeptides play important physiological functions during distinct behaviors such as arousal, learning, memory, and reproduction. However, the role of local, extrahypothalamic neuropeptide signaling in shaping synapse formation and neuronal plasticity in the brain is not well understood. Here, we characterize the spatiotemporal expression profile of the neuropeptide corticotropin-releasing hormone (CRH) and its receptor CRHR1 in the mouse OB throughout development. We found that CRH-expressing interneurons are present in the external plexiform layer, that its cognate receptor is expressed by granule cells, and show that both CRH and CRHR1 expression enriches in the postnatal period when olfaction becomes important towards olfactory-related behaviors. Further, we provide electrophysiological evidence that CRHR1-expressing granule cells functionally respond to CRH ligand, and that the physiological circuitry of CRHR1 knockout mice is abnormal, leading to impaired olfactory behaviors. Together, these data suggest a physiologically relevant role for local CRH signaling towards shaping the neuronal circuitry within the mouse OB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Abraham NM, Egger V, Shimshek DR, Renden R, Fukunaga I, Sprengel R, Seeburg PH, Klugmann M, Margrie TW, Schaefer AT et al (2010) Synaptic inhibition in the olfactory bulb accelerates odor discrimination in mice. Neuron 65:399–411

    Article  CAS  PubMed  Google Scholar 

  • Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569

    Article  CAS  PubMed  Google Scholar 

  • Alvarez-Buylla A, Garcia-Verdugo JM (2002) Neurogenesis in adult subventricular zone. J Neurosci 22:629–634

    CAS  PubMed  Google Scholar 

  • Arenkiel BR, Hasegawa H, Yi JJ, Larsen RS, Wallace ML, Philpot BD, Wang F, Ehlers MD (2011) Activity-induced remodeling of olfactory bulb microcircuits revealed by monosynaptic tracing. PLoS One 6:e29423

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557

    Article  CAS  PubMed  Google Scholar 

  • Batista-Brito R, Close J, Machold R, Fishell G (2008) The distinct temporal origins of olfactory bulb interneuron subtypes. J Neurosci 28:3966–3975

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bayatti N, Zschocke J, Behl C (2003) Brain region-specific neuroprotective action and signaling of corticotropin-releasing hormone in primary neurons. Endocrinology 144:4051–4060

    Article  CAS  PubMed  Google Scholar 

  • Belnoue L, Grosjean N, Abrous DN, Koehl M (2011) A critical time window for the recruitment of bulbar newborn neurons by olfactory discrimination learning. J Neurosci 31:1010–1016

    Article  CAS  PubMed  Google Scholar 

  • Berger H, Heinrich N, Wietfeld D, Bienert M, Beyermann M (2006) Evidence that corticotropin-releasing factor receptor type 1 couples to Gs- and Gi-proteins through different conformations of its J-domain. Br J Pharmacol 149:942–947

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Blank T, Nijholt I, Grammatopoulos DK, Randeva HS, Hillhouse EW, Spiess J (2003) Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning. J Neurosci 23:700–707

    CAS  PubMed  Google Scholar 

  • Breton-Provencher V, Lemasson M, Peralta MR 3rd, Saghatelyan A (2009) Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors. J Neurosci 29:15245–15257

    Article  CAS  PubMed  Google Scholar 

  • Chaves VE, Tilelli CQ, Brito NA, Brito MN (2013) Role of oxytocin in energy metabolism. Peptides 45:9–14

    Article  CAS  PubMed  Google Scholar 

  • Chen WR, Xiong W, Shepherd GM (2000) Analysis of relations between NMDA receptors and GABA release at olfactory bulb reciprocal synapses. Neuron 25:625–633

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen Y, Bender RA, Brunson KL, Pomper JK, Grigoriadis DE, Wurst W, Baram TZ (2004) Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proc Natl Acad Sci USA 101:15782–15787

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen J, Evans AN, Liu Y, Honda M, Saavedra JM, Aguilera G (2012) Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. J Neuroendocrinol 24:1055–1064

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eyre MD, Antal M, Nusser Z (2008) Distinct deep short-axon cell subtypes of the main olfactory bulb provide novel intrabulbar and extrabulbar GABAergic connections. J Neurosci 28:8217–8229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gheusi G, Cremer H, McLean H, Chazal G, Vincent JD, Lledo PM (2000) Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc Natl Acad Sci USA 97:1823–1828

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gheusi G, Lepousez G, Lledo PM (2013) Adult-born neurons in the olfactory bulb: integration and functional consequences. Curr Top Behav Neurosci 2013(15):49–72

    Google Scholar 

  • Gracia-Llanes FJ, Crespo C, Blasco-Ibanez JM, Marques-Mari AI, Martinez-Guijarro FJ (2003) VIP-containing deep short-axon cells of the olfactory bulb innervate interneurons different from granule cells. Eur J Neurosci 18:1751–1763

    Article  PubMed  Google Scholar 

  • Hamilton KA, Heinbockel T, Ennis M, Szabo G, Erdelyi F, Hayar A (2005) Properties of external plexiform layer interneurons in mouse olfactory bulb slices. Neuroscience 133(3):819–829

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hanstein R, Lu A, Wurst W, Holsboer F, Deussing JM, Clement AB, Behl C (2008) Transgenic overexpression of corticotropin releasing hormone provides partial protection against neurodegeneration in an in vivo model of acute excitotoxic stress. Neuroscience 156:712–721

    Article  CAS  PubMed  Google Scholar 

  • Holzer P, Reichmann F, Farzi A (2012) Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides 46:261–274

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Huang L, Garcia I, Jen HI, Arenkiel BR (2013) Reciprocal connectivity between mitral cells and external plexiform layer interneurons in the mouse olfactory bulb. Front Neural Circuits 7:32

    Article  PubMed Central  PubMed  Google Scholar 

  • Inutsuka A, Yamanaka A (2013a) The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 4:18

    Google Scholar 

  • Inutsuka A, Yamanaka A (2013b) The regulation of sleep and wakefulness by the hypothalamic neuropeptide orexin/hypocretin. Nagoya J Med Sci 75:29–36

    PubMed Central  CAS  PubMed  Google Scholar 

  • Iovino M, Guastamacchia E, Giagulli VA, Licchelli B, Triggiani V (2012) Vasopressin secretion control: central neural pathways, neurotransmitters and effects of drugs. Curr Pharm Des 18:4714–4724

    Article  CAS  PubMed  Google Scholar 

  • Isaacson JS, Strowbridge BW (1998) Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20:749–761

    Article  CAS  PubMed  Google Scholar 

  • Jacquet BV, Muthusamy N, Sommerville LJ, Xiao G, Liang H, Zhang Y, Holtzman MJ, Ghashghaei HT (2011) Specification of a Foxj1-dependent lineage in the forebrain is required for embryonic-to-postnatal transition of neurogenesis in the olfactory bulb. J Neurosci 31(25):9368–9382

    Article  PubMed Central  PubMed  Google Scholar 

  • Justice NJ, Yuan ZF, Sawchenko PE, Vale W (2008) Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 511:479–496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kato HK, Gillet SN, Peters AJ, Isaacson JS, Komiyama T (2013) Parvalbumin-expressing interneurons linearly control olfactory bulb output. Neuron 80:1218–1231

    Article  CAS  PubMed  Google Scholar 

  • Kelsch W, Lin CW, Mosley CP, Lois C (2009) A critical period for activity-dependent synaptic development during olfactory bulb adult neurogenesis. J Neurosci 29:11852–11858

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kosaka T, Kosaka K (2008) Heterogeneity of parvalbumin-containing neurons in the mouse main olfactory bulb, with special reference to short-axon cells and betaIV-spectrin positive dendritic segments. Neurosci Res 60:56–72

    Article  CAS  PubMed  Google Scholar 

  • Lazarini F, Mouthon MA, Gheusi G, de Chaumont F, Olivo-Marin JC, Lamarque S, Abrous DN, Boussin FD, Lledo PM (2009) Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice. PLoS One 4:e7017

    Article  PubMed Central  PubMed  Google Scholar 

  • Le Magueresse C, Monyer H (2013) GABAergic interneurons shape the functional maturation of the cortex. Neuron 77:388–405

    Article  PubMed  Google Scholar 

  • Lepousez G, Csaba Z, Bernard V, Loudes C, Videau C, Lacombe J, Epelbaum J, Viollet C (2010a) Somatostatin interneurons delineate the inner part of the external plexiform layer in the mouse main olfactory bulb. J Comp Neurol 518:1976–1994

    Article  PubMed  Google Scholar 

  • Lepousez G, Mouret A, Loudes C, Epelbaum J, Viollet C (2010b) Somatostatin contributes to in vivo gamma oscillation modulation and odor discrimination in the olfactory bulb. J Neurosci 30:870–875

    Article  CAS  PubMed  Google Scholar 

  • Lledo PM, Saghatelyan A (2005) Integrating new neurons into the adult olfactory bulb: joining the network, life death decisions, and the effects of sensory experience. Trends Neurosci 28:248–254

    Article  CAS  PubMed  Google Scholar 

  • Lovenberg TW, Chalmers DT, Liu C, De Souza EB (1995) CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 136(9):4139–4142

    CAS  PubMed  Google Scholar 

  • Luo M, Katz LC (2001) Response correlation maps of neurons in the mammalian olfactory bulb. Neuron 32:1165–1179

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Hu H, Berrebi AS, Mathers PH, Agmon A (2006) Distinct subtypes of somatostatin-containing neocortical interneurons revealed in transgenic mice. J Neurosci 26:5069–5082

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ma S, Blasiak A, Olucha-Bordonau FE, Verberne AJ, Gundlach AL (2013) Heterogeneous responses of nucleus incertus neurons to corticotropin-releasing factor and coherent activity with hippocampal theta rhythm in the rat. J Physiol 591:3981

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maras PM, Baram TZ (2012) Sculpting the hippocampus from within: stress, spines, and CRH. Trends Neurosci 35:315–324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Merrill L, Girard B, Arms L, Guertin P, Vizzard MA (2013) Neuropeptide/receptor expression and plasticity in micturition pathways. Curr Pharm Des 19:4411–4422

    Article  CAS  PubMed  Google Scholar 

  • Ming GL, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  CAS  PubMed  Google Scholar 

  • Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70(4):687–702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mitsui S, Igarashi KM, Mori K, Yoshihara Y (2011) Genetic visualization of the secondary olfactory pathway in Tbx21 transgenic mice. Neural Syst Circuits 1(1):5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miyamichi K, Shlomai-Fuchs Y, Shu M, Weissbourd BC, Luo L, Mizrahi A (2013) Dissecting local circuits: parvalbumin interneurons underlie broad feedback control of olfactory bulb output. Neuron 80:1232–1245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moriceau S, Shionoya K, Jakubs K, Sullivan RM (2009) Early-life stress disrupts attachment learning: the role of amygdala corticosterone, locus ceruleus corticotropin releasing hormone, and olfactory bulb norepinephrine. J Neurosci 29(50):15745–15755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mouret A, Lepousez G, Gras J, Gabellec MM, Lledo PM (2009) Turnover of newborn olfactory bulb neurons optimizes olfaction. J Neurosci 29:12302–12314

    Article  CAS  PubMed  Google Scholar 

  • Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116:201–211

    CAS  PubMed  Google Scholar 

  • Muthusamy N, Vijayakumar A, Cheng JG, Ghashghaei HT (2014) A knock-in Foxj1CreERT2:GFP mouse for recombination in epithelial cells with motile cilia. Genesis 52:350–358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW (1993) Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor. Endocrinology 133:3058–3061

    CAS  PubMed  Google Scholar 

  • Perrin M, Donaldson C, Chen R, Blount A, Berggren T, Bilezikjian L, Sawchenko P, Vale W (1995) Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc Natl Acad Sci USA 92:2969–2973

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pressler RT, Strowbridge BW (2006) Blanes cells mediate persistent feedforward inhibition onto granule cells in the olfactory bulb. Neuron 49:889–904

    Article  CAS  PubMed  Google Scholar 

  • Ramirez-Sanchez M, Prieto I, Wangensteen R, Banegas I, Segarra AB, Villarejo AB, Vives F, Cobo J, de Gasparo M (2013) The renin-angiotensin system: new insight into old therapies. Curr Med Chem 20:1313–1322

    Article  CAS  PubMed  Google Scholar 

  • Rochefort C, Gheusi G, Vincent JD, Lledo PM (2002) Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci 22:2679–2689

    CAS  PubMed  Google Scholar 

  • Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ (2002) Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acac Sci USA 99:13908–13913

    Article  CAS  Google Scholar 

  • Rudy B, Fishell G, Lee S, Hjerling-Leffler J (2011) Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 71:45–61

    Article  PubMed Central  PubMed  Google Scholar 

  • Sakanaka M, Shibasaki T, Lederis K (1987) Corticotropin releasing factor-like immunoreactivity in the rat brain as revealed by modified cobalt-glucose-oxidase-diaminobenzidine method. J Comp Neurol 260:256–298

    Article  CAS  PubMed  Google Scholar 

  • Schmolesky MT, De Ruiter MM, De Zeeuw CI, Hansel C (2007) The neuropeptide corticotropin-releasing factor regulates excitatory transmission and plasticity at the climbing fibre-purkinje cell synapse. Eur J Neurosci 25(5):1460–1467

    Article  CAS  PubMed  Google Scholar 

  • Schoppa NE, Kinzie JM, Sahara Y, Segerson TP, Westbrook GL (1998) Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J Neurosci 18:6790–6802

    CAS  PubMed  Google Scholar 

  • Selever J, Kong JQ, Arenkiel BR (2011) A rapid approach to high-resolution fluorescence imaging in semi-thick brain slices. J Vis Exp

  • Sheng H, Xu Y, Chen Y, Zhang Y, Ni X (2012) Corticotropin-releasing hormone stimulates mitotic kinesin-like protein 1 expression via a PLC/PKC-dependent signaling pathway in hippocampal neurons. Mol Cell Endocrinol 362:157–164

    Article  CAS  PubMed  Google Scholar 

  • Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA et al (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102

    Article  CAS  PubMed  Google Scholar 

  • Snyder K, Wang WW, Han R, McFadden K, Valentino RJ (2012) Corticotropin-releasing factor in the norepinephrine nucleus, locus coeruleus, facilitates behavioral flexibility. Neuropsychopharmacology 37:520–530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Fu Y, Lu J, Lin Y et al (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71:995–1013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thiel G, Cibelli G (1999) Corticotropin-releasing factor and vasoactive intestinal polypeptide activate gene transcription through the cAMP signaling pathway in a catecholaminergic immortalized neuron. Neurochem Int 34:183–191

    Article  CAS  PubMed  Google Scholar 

  • Tobin VA, Hashimoto H, Wacker DW, Takayanagi Y, Langnaese K, Caquineau C, Noack J, Landgraf R, Onaka T, Leng G et al (2010) An intrinsic vasopressin system in the olfactory bulb is involved in social recognition. Nature 464:413–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397

    Article  CAS  PubMed  Google Scholar 

  • Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L, Bilezikjian L, Bloom F, Rivier J (1983) Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 39:245–270

    CAS  PubMed  Google Scholar 

  • Valentino RJ, Wehby RG (1988) Corticotropin-releasing factor: evidence for a neurotransmitter role in the locus coeruleus during hemodynamic stress. Neuroendocrinology 48:674–677

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Jeong HY, Tremblay R, Rudy B (2013) Neocortical somatostatin-expressing GABAergic interneurons disinhibit the thalamorecipient layer 4. Neuron 77:155–167

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yamaguchi M, Mori K (2005) Critical period for sensory experience-dependent survival of newly generated granule cells in the adult mouse olfactory bulb. Proc Natl Acad Sci USA 102:9697–9702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yaylaoglu MB, Titmus A, Visel A, Alvarez-Bolado G, Thaller C, Eichele G (2005) Comprehensive expression atlas of fibroblast growth factors and their receptors generated by a novel robotic in situ hybridization platform. Dev Dyn 234:371–386

    Article  CAS  PubMed  Google Scholar 

  • Zwanzger P, Domschke K, Bradwejn J (2012) Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin. Depress Anxiety 29:762–774

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Roy Sillitoe for critical comments on this manuscript. This work was supported through the McNair Medical Institute, and NINDS awards 1F31NS081805 to I.G. and 1R01NS078294 to B.R.A. The project described was supported in part by the RNA in situ Hybridization Core facility at Baylor College of Medicine, which is supported by a shared instrumentation Grant from the NIH (1S10OD016167) and the NIH IDDRC Grant 5P30HD024064 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Benjamin R. Arenkiel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garcia, I., Bhullar, P.K., Tepe, B. et al. Local corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb. Brain Struct Funct 221, 1–20 (2016). https://doi.org/10.1007/s00429-014-0888-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-014-0888-4

Keywords

Navigation