Olfactory Training Prevents Olfactory Dysfunction Induced by Bulbar Excitotoxic Lesions: Role of Neurogenesis and Dopaminergic Interneurons


Glutamatergic excitotoxicity is involved in pathologies affecting the central nervous system, including traumatic brain injury (TBI) and neurodegenerative diseases, such as Parkinson’s disease (PD), in which olfactory dysfunction is an early symptom. Interestingly, our group has recently shown that bilateral administration of the glutamate agonist, N-methyl-d-aspartate (NMDA) in the olfactory bulbs (OBs) induces an olfactory dysfunction 1 week after lesions. Although a wide range of treatments have been attempted, no standard therapy has been established to treat olfactory disorders. Increasing evidence suggests a beneficial effect of olfactory training (OT) in olfactory function. However, the mechanisms underlying OT effects remain unknown. We investigated the effects of OT on the olfactory dysfunction induced by excitotoxicity in bilateral OB NMDA–lesioned animals. We compared OT effects with the ones obtained with neuroprotective therapies (pramipexole and MK801). We studied the underlying mechanisms involved in OT effects investigating the changes in the subventricular zone (SVZ) neurogenesis and in the number of periglomerular dopaminergic interneurons. One week after lesion, NMDA decreased the number of correct trials in the olfactory discrimination tests in the non-trained group (p < 0.01). However, OT performed for 1 week after lesions prevented olfactory dysfunction (p < 0.01). Pramipexole did not prevent olfactory dysfunction, whereas MK801 treatment showed a partial recovery (p < 0.05). An increase in SVZ neurogenesis (p < 0.05) associated with an increase in OB dopaminergic interneurons (p < 0.05) was related to olfactory function prevention induced by OT. The present results suggest a role for dopaminergic OB interneurons underlying the beneficial effects of OT improving olfactory dysfunction in bilaterally OB NMDA–lesioned animals.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Mullol J, Alobid I, Mariño-Sánchez F, Ll Q, de Haro J, Bernal-Sprekelsen M, Valero A, Picado C et al (2012) Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: a population based survey (OLFACAT study). BMJ Open 2:e001256

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Boesveldt S, Postma EM, Boak D, Welge-Luessen A, Schöpf V, Mainland JD, Martens J, Ngai J et al (2017) Anosmia-a clinical review. Chem Senses 42:513–523

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Marin C, Vilas D, Langdon C, Alobid I, López-Chacón M, Haehner A, Hummel T, Mullol J (2018) Olfactory dysfunction in neurodegeneration diseases. Curr Allergy Asthma Rep 18:42

    Article  PubMed  Google Scholar 

  4. 4.

    Hummel T, Nordin S (2005) Olfactory disorders and their consequences for quality of life. Acta Otolaryngol 125:116–121

    Article  PubMed  Google Scholar 

  5. 5.

    Attems J, Wlaker L, Jellinger KA (2015) Olfaction and aging: a mini-review. Gerontology 61:485–490

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Doty RL (2018) Age-related deficits in taste and smell. Otolaryngol Clin N Am 51:815–825

    Article  Google Scholar 

  7. 7.

    Haehner A, Boesveldt S, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD et al (2009) Prevalence of smell loss in Parkinson’s disease-a multicenter study. Parkinsonism Relat Disord 15:490–494

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Doty RL (2017) Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrates? Lancet Neurol 16:478–488

    Article  PubMed  Google Scholar 

  9. 9.

    Langdon C, Guillemany JM, Valls M, Alobid I, Bartra J, Dávila I, Del Cuvillo A, Ferrer M et al (2016) Allergic rhinitis causes loss of smell in children. Pediatr Allergy Immunol 27:867–870

    Article  PubMed  Google Scholar 

  10. 10.

    Langdon C, Lehrer E, Berenguer J, Laxe S, Alobid I, Quintó L, Mariño-Sánchez F, Bernabeu M et al (2018) Olfactory training in posttraumatic smell impairment: mild improvement in threshold performances-results from a randomized controlled study. J Neurotrauma 35:2641–2652

    Article  PubMed  Google Scholar 

  11. 11.

    Hummel T, Whitcroft KL, Andrews P, Altundag A, Cinghi C, Costanzo RM, Damm M, Frasnelli J et al (2017) Position paper on olfactory dysfunction. Rhinol Suppl 54:1–30

    CAS  PubMed  Google Scholar 

  12. 12.

    Bowman GL (2017) Biomarkers for early detection of Parkinson’s disease: a scent of consistency with olfactory dysfunction. Neurology 89:1432–1434

    Article  PubMed  Google Scholar 

  13. 13.

    Woodward MR, Amrutkar CV, Ahah HC, Benedict RH, Rajakrishnan S, Doody RS, Yan L, Szigeti K (2017) Validation of olfactory deficit as a biomarker of Alzheimer disease. Neurol Clin Pract 7:5–14

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lee JH, Wei L, Deveau TC, Gu X, Yu SP (2016) Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse. Brain Struct Funct 221:3259–3273

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Marin C, Laxe S, Langdon C, Berenguer J, Lehrer E, Mariño-Sánchez F, Alobid I, Bernabeu M et al (2017) Olfactory function in an excitotoxic model for secondary neuronal degeneration: role of dopaminergic interneurons. Neuroscience 364:28–44

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Marin C, Langdon C, Alobid I, Fuentes M, Bonastre M, Mullol J (2019) Recovery of olfactory function after excitotoxic lesion of the olfactory bulbs is associated with increases in bulbar SIRT1 and SIRT4 expressions. Mol Neurobiol (in press)

  17. 17.

    Lethbridge R, Hou Q, Harley CW, Yuan Q (2012) Olfactory bulb glomerular NMDA receptors mediate olfactory nerve potentiation and odor preference learning in the neonate rat. PLoS One 7:e35024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tatti R, Bhaukaurally K, Gschwend O, Seal RP, Edwards RH, Rodriguez I, Carleton A (2014) A population of glomerular glutamatergic neurons controls sensory information transfer in the mouse olfactory bulb. Nat Commun 5:3791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Abramov AY, Duchen MR (2008) Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochim Biophys Acta 1777:953–964

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Jia N, Sun Q, Chen G (2016) SIRT-1-mediated deacetylation of PGC1a attributes to the protection of curcumin against glutamate excitotoxicity in cortical neurons. Biochem Biophys Res Commun 478:1376–1381

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Dorsett CR, McGuire JL, Niedzielko TL, DePasquale EA, Meller J, Floyd CL, McCullumsmith RE (2017) Traumatic brain injury induces alterations in cortical glutamate uptake without a reduction in glutamate transporter-1 protein expression. J Neurotrauma 34:220–234

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Stefani MA, Modkovski R, Hansel G, Zimmer ER, Kopczynski A, Muller AP, Stroguiski NR, Rodolphi MS et al (2017) Elevated glutamate and lactate predict brain death after severe head trauma. Ann Clin Transl Neurol 4:392–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57:1041–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    DeLong MR, Wichmann T (2015) Basal ganglia circuits as targets for neuromodulation in Parkinson’s disease. JAMA Neurol 72:1354–1360

    Article  PubMed  Google Scholar 

  25. 25.

    Gudziol V, Hummel T (2009) Effects of pentoxifylline on olfactory sensitivity: a postmarketing surveillance study. Arch Otolaryngol Head Neck Surg 135:291–295

    Article  PubMed  Google Scholar 

  26. 26.

    Gudziol V, Pietsch J, Witt M, Hummel T (2010) Theophylline induces changes in the electro-olfactogram of the mouse. Eur Arch Otorhinolaryngol 267:239–243

    Article  PubMed  Google Scholar 

  27. 27.

    Blomqvist EH, Lundblad L, Bergstedt H, Stjärne P (2003) Placebo-controlled, randomized, double-blind study evaluating the efficacy of fluticasone propionate nasal spray for the treatment of patients with hyposmia/anosmia. Acta Otolaryngol 123:862–868

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Konstantinidis I, Tsakiropoulou E, Bekiaridou P, Kazantzidou C, Constantinidis K (2013) Use of olfactory training in post-traumatic and postinfectious olfactory dysfunction. Laryngoscope 123:E85–E90

    Article  PubMed  Google Scholar 

  29. 29.

    Kollndorfer K, Fischmeister FP, Kowalczyk K, Hoche E, Mueller CA, Trattnig S, Schöpf V (2015) Olfactory training induces changes in regional functional connectivity in patients with long-term smell loss. Neuroimage Clin 9:401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Altunfag A, Cayonu M, Kayabasoglu G, Salihoglu M, Tekeli H, Saglam O, Hummel T (2015) Modified olfactory training in patients with postinfectious olfactory loss. Laryngoscope 125:1763–1766

    Article  Google Scholar 

  31. 31.

    Rösser N, Berger K, Vomhof P, Knecht S, Breitenstein C, Flöel A (2008) Lack of improvement in odor identification by levodopa in humans. Physiol Behav 93:1024–1029

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Escanilla O, Mandairon N, Linster C (2008) Odor-reward learning and enrichment have similar effects on odor perception. Physiol Behav 94:621–626

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Chapuis J, Wilson DA (2011) Bidirectional plasticity of cortical pattern recognition and behavioural sensory acuity. Nat Neurosci 15:155–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sorokowska A, Drechsler E, Karwowski M, Hummel T (2017) Effects of olfactory training: a meta-analysis. Rhinology 55:17–26

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Patel ZM (2017) The evidence for olfactory training in treating patients with olfactory loss. Curr Opin Otolaryngol Head Neck Surg 25:43–46

    Article  PubMed  Google Scholar 

  36. 36.

    Pekala K, Chandra RK, Turner JH (2016) Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. Int Forum Allergy Rhinol 6:299–307

    Article  PubMed  Google Scholar 

  37. 37.

    Mariño-Sánchez FS, Alobid I, Centellas S, Alberca C, Guilemany JM, Canals JM, De Haro J, Mullol J (2010) Smell training increases cognitive smell skills of wine tasters compared to the general healthy population. The WINECAT study. Rhinology 48:273–276

    Article  PubMed  Google Scholar 

  38. 38.

    Mörlein D, Meier-Dinkel L, Moritz J, Sharifi AR, Knorr C (2013) Learning to smell: repeated exposure increases sensitivity to adrostenone, a major component of boar taint. Meat Sci 94:425–431

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Hummel T, Rissom K, Reden J, Hähner A, Weidenbecher M, Hüttenbrink KB (2009) Effects of olfactory training in patients with olfactory loss. Laryngoscope 119:496–499

    Article  PubMed  Google Scholar 

  40. 40.

    Damm M, Pikart LK, Reimann H, Burkert S, Göktas O, Haxel B, Frey S, Charalampakis I et al (2014) Olfactory training is helpful in postinfectious olfactory loss: a randomized, controlled, multicenter study. Laryngoscope 124:826–831

    Article  PubMed  Google Scholar 

  41. 41.

    Haehner A, Tosch C, Wolz M, Klingelhoefer L, Fauser M, Storch A, Reichmann H, Hummel T (2013) Olfactory training in patients with Parkinson’s disease. PLoS One 8:e61680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Fleiner F, Lau L, Göktas Ö (2012) Active olfactory training for the treatment of smelling disorders. Ear Nose Throat 91:198–203

    Article  Google Scholar 

  43. 43.

    Motyl J, Przykaza L, Boguszewski PM, Kosson P, Strosznajder JB (2018) Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson’s disease by activation of sphingosine kinase 1 and Akt kinase. Neuropharmacology 135:139–150

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    De Miranda AS, Brant F, Vieira LB et al (2017) A neuroprotective effect of the glutamate receptor antagonist MK801 on long-term cognitive and behavioral outcomes secondary to experimental cerebral malaria. Mol Neurobiol 54:7063–7082

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Ardiles Y, de la Puente R, Toledo R, Isgor C, Guthrie K (2007) Response of olfactory axons to loss of synaptic targets in the adult mouse. Exp Neurol 207:275–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Liu H, Guthrie KM (2011) Neuronal replacement in the injured olfactory bulb. Exp Neurol 228:270–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  48. 48.

    Mandairon N, Peace S, Karnow A, Kim J, Ennis M, Linster C (2008) Noradrenergic modulation in the olfactory bulb influences spontaneous and reward-motivated discrimination, but not the formation of habituation memory. Eur J Neurosci 27:1210–1219

    Article  PubMed  Google Scholar 

  49. 49.

    Escanilla O, Yuhas C, Marzan D, Linster C (2009) Dopaminergic modulation of olfactory bulb processing affects odor discrimination learning in rats. Behav Neurosci 123:828–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Escanilla O, Arrellanos A, Karnow A, Ennis M, Linster C (2010) Noradrenergic modulation of behavioral odor detection and discrimination thresholds in the olfactory bulb. Eur J Neurosci 32:458–468

    Article  PubMed  Google Scholar 

  51. 51.

    Brushfield AM, Luu T, Callahan B, Giblert PE (2008) A comparison of discrimination and reversal learning for olfactory and visual stimuli in aged rats. Behav Neurosci 122:54–62

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Zou J, Pan YW, Wang Z, Chang SY, Wang W, Wang X, Tournier C, Storm DR et al (2012) Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioural discrimination between structurally similar odorants. J Neurosci 32:4118–4132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Mihalick SM, Langlois JC, Krienke JD, Dube WV (2000) An olfactory discrimination procedure for mice. J Exp Anal Behav 73:305–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Tillerson JL, Caudle WM, Parent JM, Gong C, Schallert T, Miller GW (2006) Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor. Behav Brain Res 172:97–105

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Prichard A, Panoz-Brown D, Bruce K, Galizio (2015) Emergent identity but not symmetry following successive olfactory discrimination training in rats. J Exp Anal Behav 104:133–145

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bruce K, Dyer K, Mathews M, Nealley C, Phasukkan T, Prichard A, Galizio M (2018) Successive odor matching- and non-matching-to-sample in rats: a reversal design. Behav Process 155:26–32

    Article  Google Scholar 

  57. 57.

    Tseng CS, Chou SJ, Hunag YS (2019) CPEB4-dependent neonate-born granule cells are required for olfactory discrimination. Front Behav Neurosci 13:5

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Mandairon N, Sacquet J, Garcia S, Ravel N, Jourdan F, Didier A (2006) Neurogenic correlates of an olfactory discrimination task in the adult olfactory bulb. Eur J Neurosci 24:3578–3588

    Article  PubMed  Google Scholar 

  59. 59.

    He J, Wei J, Rizak JD, Chen Y, Wang J, Hu X, Ma Y (2015) An odor detection system based on automatically trained mice by relative go no-go olfactory operant conditioning. Sci Rep 5:10019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Devore S, Lee J, Linster C (2013) Odor preferences shape discrimination learning in rats. Behav Neurosci 127:498–504

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Martoncikova M, Lievajova K, Orendacová J, Blasko J, Racekova E (2011) Odor enrichment influences neurogenesis in the rostral migratory stream of young rats. Acta Histochem 113:326–332

    Article  PubMed  Google Scholar 

  62. 62.

    Kesner RP, Gilbert PE, Barua LA (2002) The role of the hippocampus in memory for the temporal order of a sequence of odors. Behav Neurosci 116:286–290

    Article  PubMed  Google Scholar 

  63. 63.

    Pavlis M, Feretti C, Levy A, Gupta N, Linster C (2006) L-Dopa improves odor discrimination learning in rats. Physiol Behav 87:109–113

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    Hansson AC, Nixon K, Rimondini R, Damadzic R, Sommer WH, Eskay R, Crews FT, Heilig M (2010) Long-term suppression of forebrain neurogenesis and loss of neuronal progenitor cells following prolonged alcohol dependence in rats. Int J Neuropsychopharmacol 13:583–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Choi JH, Lee CH, Yoo KY, Kwon SH, Shin HC, Lee YL, Hwang IK, Lee IS et al (2010) Immunoreactivity and protein levels of olfactory marker protein and tyrosine hydroxylase are not changes in the dog main olfactory bulb and normal ageing. J Comp Pathol 142:147–156

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Patel DA, Booze RM, Mactutus CF (2012) Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain. Int J Dev Neurosci 30:1–9

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Sohrabji F, Peeples KW, Marroquin OA (2000) Local and cortical effects of olfactory bulb lesion on trophic support and cholinergic function and their modulation by estrogen. J Neurobiol 45:61–74

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Reichelt D, Radad K, Moldzio R, Rausch WD, Reichmann H, Gille G (2016) Comparable neuroprotective effects of pergolide and Pramipexole on ferrous sulfate-induced dopaminergic cell death in cell culture. CNS Neurol Disord Drug Targets 15:1325–1332

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Albrecht S, Buerger E (2009) Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole. Curr Med Res Opin 25:2977–2987

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez MF (2010) Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J Neuropsychiatr Clin Neurosci 22:8–18

    Article  CAS  Google Scholar 

  71. 71.

    Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurting HI (1992) Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 55:138–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ziemssen T, Reichmann H (2007) Non-motor dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 13:323–332

    Article  PubMed  Google Scholar 

  73. 73.

    Doty RL, Risser JM (1989) Influence of the D-2 dopamine receptor agonist quinpirole on the odor detection performance of rats before and after spiperone administration. Psychopharmacology 98:310–315

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Doty RL, Li C, Bagla R, Huang W, Pfeiffer C, Brosvic GM, Risser JM (1998) SKF-38393 enhances odor detection performance. Psychopharmacology 136:75–82

    Article  CAS  PubMed  Google Scholar 

  75. 75.

    McIntosh TK, Vink R, Soares H, Hayes R, Simon R (1989) Effects of the N-methyl-D-aspartate receptor blocker MK801 on neurologic function after experimental brain injury. J Neurotrauma 6:247–259

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, Xu L, Duan WH et al (2008) Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39:3042–3048

    Article  CAS  PubMed  Google Scholar 

  77. 77.

    Liu Y, Wing TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J et al (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846–2857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Jiménez A, Marin C, Bonastre M, Tolosa E (1999) Narrow beneficial effect of dextromethorphan on levodopa-induced motor response alterations in an experimental model of parkinsonism. Brain Res 839:190–193

    Article  PubMed  Google Scholar 

  79. 79.

    Birte-Antina E, Llona C, Antje H, Thomas H (2018) Olfactory training with older people. Int J Geriatr Psychiatry 33:212–220

    Article  PubMed  Google Scholar 

  80. 80.

    Jing RS, Twu CW, Liang KL (2017) The effect of olfactory training on the odor threshold in patients with traumatic anosmia. Am J Rhinol Allergy 31:317–322

    Article  Google Scholar 

  81. 81.

    Youngentob SL, Kent PF (1995) Enhancement of odorant-induced mucosal activity patterns in rats trained on an odorant identification task. Brain Res 670:82–88

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Oleszkiewicz A, Hanf S, Whitcroft KL, Haehner A, Hummel T (2018) Examination of olfactory training effectiveness in relation to its complexity and the cause of olfactory loss. Laryngoscope 128:1518–1522

    Article  PubMed  Google Scholar 

  83. 83.

    Knudsen K, Flensborg Damholdt M, Mouridsen K, Borghammer P (2015) Olfactory function in Parkinson’s disease-effects of training. Acta Neurol Scand 132:395–400

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    Hummel T, Stupka G, Haehner A, Poletti SC (2018) Olfactory training changes electrophysiological responses at the level of the olfactory epithelium. Rhinology 556:330–335

    Google Scholar 

  85. 85.

    Bonzano S, Bovetti S, Fasolo A, Peretto P, De Marchis S (2014) Odour enrichment increases adult-born dopaminergic neurons in the mouse olfactory bulb. Eur J Neurosci 40:3450–3457

    Article  PubMed  Google Scholar 

  86. 86.

    Lois C, Alvarez-Buylla A (1994) Long distance neuronal migration in the adult mammalian brain. Science 264:1145–1148

    Article  CAS  Google Scholar 

  87. 87.

    Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev 7:179–193

    Article  CAS  Google Scholar 

  88. 88.

    Lledo PM, Merkle FT, Alvarez-Buylla A (2008) Origin and function of olfactory bulb interneuron diversity. Trends Neurosci 31:392–400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Rey NL, Sacquet J, Veyrac A, Jourda F, Didier A (2012) Behavioral and cellular markers of olfactory aging and their response to enrichment. Neurobiol Aging 33:626

    PubMed  Google Scholar 

  90. 90.

    Huart C, Rombaux P, Hummel T (2019) Neural plasticity in developing and adult olfactory pathways-focus on the human olfactory bulb. J Bioenerg Biomembr (in press 51:77–87

    Article  CAS  PubMed  Google Scholar 

  91. 91.

    Bragado Alonso S, Reinert JK, Marichal N, Massalini S, beninger B, Kuner T, Calegari F (2019) An increase in neural stem cells and olfactory bulb adult neurogenesis improves discrimination of highly similar odorants. EMBO J 38:e98791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Bonzano S, Bovetti S, Gendusa C, Peretto P, De Marchis S (2016) Adult born olfactory bulb dopaminergic interneurons: molecular determinants and experience-dependent plasticity. Front Neurosci 10:1–8

    Article  Google Scholar 

  93. 93.

    Breton-Provencher V, Saghatelyan A (2012) Newborn neuron in the adult olfactory bulb: unique properties for specific odor behaviour. Behav Brain Res 227:480–489

    Article  PubMed  Google Scholar 

  94. 94.

    Belluzzi O, Benedusi M, Ackman J, LoTurco KK (2003) Electrophysiological differentiation of new neurons in the olfactory bulb. J Neurosci 23:10411–10418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Lledo PM, Valley M (2016) Adult olfactory bulb neurogenesis. Cold Spring Harb Perspect Biol 8:a018945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Zhang W, Sun C, Shao Y, Zhou Z, Hou Y, Li A (2019) Partial depletion of dopaminergic neurons in the substantia nigra impairs olfaction and alters neural activity in the olfactory bulb. Sci Rep 9:254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Rodrigues LS, Noseda ACD, Targa ADS, Aurich MF, Lima MMS (2019) Olfaction in female Wistar rats is influenced by dopaminergic periglomerular neurons after nigral and bulbar lesions. Behav Pharmacol 30:343-350

  98. 98.

    Lepousez G, Nissant A, Bryant AK, Gheusi G, Greer CA, Lledo PM (2014) Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons. Proc Natl Acad Sci U S A 111:13984–13989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Sawada M, Kaneko N, Inada H, Wake H, Kato Y, Yanagawa Y, Kobayashi K, Nemoto T et al (2011) Sensory input regulates spatial and subtype-specific patterns of neuronal turnover in the adult olfactory bulb. J Neurosci 31:11587–11596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Bastien-Dionne PO, David LS, Parent A, Saghatelyan A (2010) Role of sensory activity on chemospecific populations of interneurons in the adult olfactory bulb. J Comp Neurol 518:1847–1861

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Breton-Provencher V, Lemasson M, Peralta MR III, 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  PubMed Central  Google Scholar 

  102. 102.

    Pignatelli A, Belluzzi O (2017) Dopaminergic neurons in the main olfactory bulb: an overview from an electrophysiological perspective. Front Neuroanat 11:7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Philpot BD, Men D, McCarty R, Brunjes PC (1998) Activity-dependent regulation of dopamine content in the olfactory bulbs of naris-occluded rats. Neuroscience 85:969–977

    Article  CAS  PubMed  Google Scholar 

  104. 104.

    Baker H, Kawano T, Margolis FL, Joh TH (1983) Transneuronal regulation of tyrosine hydroxylase expression in olfactory bulb of mouse and rat. J Neurosci 3:69–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Kawano T, Margolis FL (1982) Transynaptic regulation of olfactory bulb catecholamines in mice and rats. J Neurochem 39:342–348

    Article  CAS  PubMed  Google Scholar 

Download references


This work was supported by a research grant (110610) from Fundació La Marató TV3.

Author information



Corresponding authors

Correspondence to Concepció Marin or Joaquim Mullol.

Ethics declarations

All experiments were carried out following the European (2010/63/UE) and Spanish (RD 53/2013) regulation for the care and use of laboratory animals and approved by the local Government (Generalitat de Catalunya). The Ethic’s Committee of our institution approved this study.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Marin, C., Laxe, S., Langdon, C. et al. Olfactory Training Prevents Olfactory Dysfunction Induced by Bulbar Excitotoxic Lesions: Role of Neurogenesis and Dopaminergic Interneurons. Mol Neurobiol 56, 8063–8075 (2019). https://doi.org/10.1007/s12035-019-1639-6

Download citation


  • Excitotoxicity
  • Olfaction
  • Olfactory training
  • Parkinson’s disease
  • Traumatic brain injury
  • Dopamine
  • Neurogenesis