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Journal of Pediatric Neurology 2024; 22(01): 001-007
DOI: 10.1055/s-0042-1758471
Review Article

Embryology and Clinical Development of the Human Olfactory System

Harvey B. Sarnat 
1   Department of Paediatrics, University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute (Owerko Centre), Calgary, Alberta, Canada
2   Department of Pathology and Laboratory Medicine (Neuropathology), University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute (Owerko Centre), Calgary, Alberta, Canada
3   Department of Clinical Neurosciences, University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute (Owerko Centre), Calgary, Alberta, Canada
,
Laura Flores-Sarnat
1   Department of Paediatrics, University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute (Owerko Centre), Calgary, Alberta, Canada
3   Department of Clinical Neurosciences, University of Calgary Cumming School of Medicine and Alberta Children's Hospital Research Institute (Owerko Centre), Calgary, Alberta, Canada
› Author Affiliations Funding This research received funding from Alberta Children's Hospital Research Institute, Grant #60–28450, Project 10027949.
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Abstract

The olfactory system is unique as a special sensory system in its developmental neuroanatomy and function. Neonatal olfactory reflexes can be detected in the fetus from 30 weeks gestation and can be tested in term and preterm neonates and older children. Most efferent axons from the olfactory bulb terminate in the anterior olfactory nucleus within the olfactory tract, with secondary projections to the amygdala, hypothalamus, hippocampus, and entorhinal cortex (parahippocampal gyrus), with tertiary projections also to the insula and other cortical regions. The olfactory bulb and tract incorporate an intrinsic thalamic equivalent. The olfactory bulb may be primary in generating olfactory auras in some cases of temporal lobe epilepsy. Developmental malformations may involve the olfactory bulb and tract, isolated or as part of complex cerebral malformations and genetic syndromes. Primary neural tumors may arise in the olfactory bulb or nerve. Impaired olfaction occurs in neonatal hypoxic/ischemic and some metabolic encephalopathies. Loss of sense of smell are early symptoms in some neurodegenerative diseases and in some viral respiratory diseases including coronavirus disease 2019. Testing cranial nerve I is easy and reliable at all ages, and is recommended in selected neonates with suspected brain malformations or encephalopathy.

Keywords

olfactory development - auras - malformations - encephalopathies

Ethics Committee Approval

This study was approved by the Conjoint Health Research Ethics Committee of the University of Calgary and Alberta Health Services.




Publication History

Received: 24 July 2022

Accepted: 29 September 2022

Article published online:
30 March 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Sarnat HB, Flores-Sarnat L. Survey on olfactory testing by pediatric neurologists. Is the olfactory nerve a true cranial nerve?. J Child Neurol 2020; 35 (05) 317-321
    CrossrefPubMedGoogle Scholar
  • 2 Sarnat HB. Olfactory reflexes in the newborn infant. J Pediatr 1978; 92 (04) 624-626
    CrossrefPubMedGoogle Scholar
  • 3 Sarnat HB, Flores-Sarnat L, Wei XC. Olfactory development. Part 1. Functional, from fetal perception to adult wine-tasting. J Child Neurol 2017; 32 (06) 566-578
    CrossrefPubMedGoogle Scholar
  • 4 Marlier L, Gaugler C, Astruc D, Messer J. The olfactory sensitivity of the premature newborn. Arch Pediatr 2007; 14 (01) 45-53
    PubMedGoogle Scholar
  • 5 Schaal B, Marlier L, Soussignan R. Human foetuses learn odours from their pregnant mother's diet. Chem Senses 2000; 25 (06) 729-737
    CrossrefPubMedGoogle Scholar
  • 6 Hepper P. Human fetal olfactory learning. Int J Prenatal Perinatal Psychol 1995; 2: 147
    PubMedGoogle Scholar
  • 7 Mennella JA, Johnson A, Beauchamp GK. Garlic ingestion by pregnant women alters the odor of amniotic fluid. Chem Senses 1995; 20 (02) 207-209
    CrossrefPubMedGoogle Scholar
  • 8 Sarnat HB, Flores-Sarnat L, Fajardo C, Leijser LM, Wusthoff C, Mohammad K. Sarnat grading scale for neonatal encephalopathy after 45 years: an update proposal. Pediatr Neurol 2020; 113: 75-79
    CrossrefPubMedGoogle Scholar
  • 9 Shepherd GM. Perception without a thalamus how does olfaction do it?. Neuron 2005; 46 (02) 166-168
    CrossrefPubMedGoogle Scholar
  • 10 Sarnat HB, Yu W. Maturation and dysgenesis of the human olfactory bulb. Brain Pathol 2016; 26 (03) 301-318
    CrossrefPubMedGoogle Scholar
  • 11 Sarnat HB, Flores-Sarnat L. Olfactory development. Part 2. Developmental neuroanatomy and neuropathology. J Child Neurol 2017; 32: 579-592
    CrossrefPubMedGoogle Scholar
  • 12 Parent A. Carpenter's Human Neuroanatomy. 9th ed. Baltimore: Williams & Wilkins; 1996: 748-757
    Google Scholar
  • 13 McTavish TS, Migliore M, Shepherd GM, Hines ML. Mitral cell spike synchrony modulated by dendrodendritic synapse location. Front Comput Neurosci 2012; 6: 3
    CrossrefPubMedGoogle Scholar
  • 14 Crosby EC, Humphrey T. Studies of the vertebrate telencephalon. II. The nuclear pattern of the anterior olfactory nucleus, tuberculum olfactorium and amygdaloid complex in adult man. J Comp Neurol 1939; 73: 309-352
    PubMedGoogle Scholar
  • 15 Ashwell KWS, Waite PME. Development of the peripheral nervous system. In: Paxinos G, Mai JK, eds. The Human Nervous System. 2nd ed. Amsterdam: Elsevier/Academic Press; 2004: 95-110
    Google Scholar
  • 16 Golgi C. Sulli fina struttura dei bulbi olfattorii. Riv Sper Freniat Reggio Emilia 1875; 1: 66-78
    PubMedGoogle Scholar
  • 17 Ramón y Cajal S de. La corteza olfativa del cerebro. Trab d Laborat d Investig Biol 1901;1.
    Google Scholar
  • 18 Vidaki M, Tivodar S, Doulgeraki K. et al. Rac1-dependent cell cycle exit of MGE precursors and GABAergic interneuron migration to the cortex. Cereb Cortex 2012; 22 (03) 680-692
    CrossrefPubMedGoogle Scholar
  • 19 Radonjić NV, Ayoub AE, Memi F. et al. Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche. Cell Rep 2014; 9 (06) 2139-2151
    CrossrefPubMedGoogle Scholar
  • 20 Rousselot P, Lois C, Alvarez-Buylla A. Embryonic (PSA) N-CAM reveals chains of migrating neuroblasts between the lateral ventricle and the olfactory bulb of adult mice. J Comp Neurol 1995; 351 (01) 51-61
    CrossrefPubMedGoogle Scholar
  • 21 Lois C, García-Verdugo JM, Alvarez-Buylla A. Chain migration of neuronal precursors. Science 1996; 271 (5251): 978-981
    CrossrefPubMedGoogle Scholar
  • 22 Jiménez D, López-Mascaraque LM, Valverde F, De Carlos JA. Tangential migration in neocortical development. Dev Biol 2002; 244 (01) 155-169
    CrossrefPubMedGoogle Scholar
  • 23 Anderson S, Mione M, Yun K, Rubenstein JLR. Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis. Cereb Cortex 1999; 9 (06) 646-654
    CrossrefPubMedGoogle Scholar
  • 24 Ragancokova D, Rocca E, Oonk AMM. et al. TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction. J Clin Invest 2014; 124 (03) 1214-1227
    CrossrefPubMedGoogle Scholar
  • 25 Yun K, Garel S, Fischman S, Rubenstein JL. Patterning of the lateral ganglionic eminence by the Gsh1 and Gsh2 homeobox genes regulates striatal and olfactory bulb histogenesis and the growth of axons through the basal ganglia. J Comp Neurol 2003; 461 (02) 151-165
    CrossrefPubMedGoogle Scholar
  • 26 Girard SD, Devéze A, Nivet E, Gepner B, Roman FS, Féron F. Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp 2011; 54 (54) 2762
    CrossrefPubMedGoogle Scholar
  • 27 Merkle FT, Fuentealba LC, Sanders TA, Magno L, Kessaris N, Alvarez-Buylla A. Adult neural stem cells in distinct microdomains generate previously unknown interneuron types. Nat Neurosci 2014; 17 (02) 207-214
    CrossrefPubMedGoogle Scholar
  • 28 Liem KF, Bemas WE, Walker Jr WF, Grande L. Functional Anatomy of the Vertebrates: An Evolutionary Perspective. 3 rd ed. Belmont, California: Thomas Learning Press; 2001: 398-400
    Google Scholar
  • 29 Humphrey T. The development of the olfactory and the secondary olfactory formations in human embryos and fetuses. J Comp Neurol 1940; 74: 431-438
    CrossrefPubMedGoogle Scholar
  • 30 Kratskin IL, Belluzi O. Anatomy and neurochemistry of the olfactory bulb. In: Doty RL, ed. Handbook of Olfaction and Gustation 2022; New York: Marcel Dekker; 139-164
    Google Scholar
  • 31 García-Ojeda E, Alonso JR, Briñón JG. et al. Calretinin immunoreactivity in the anterior olfactory nucleus of the rat. Brain Res 1998; 789 (01) 101-110
    CrossrefPubMedGoogle Scholar
  • 32 Sarnat HB. Transitory and vestigial structures of the developing human nervous system. Pediatr Neurol 2021; 123: 86-101
    CrossrefPubMedGoogle Scholar
  • 33 Brunjes PC, Illig KR, Meyer EA. A field guide to the anterior olfactory nucleus (cortex). Brain Res Brain Res Rev 2005; 50 (02) 305-335
    CrossrefPubMedGoogle Scholar
  • 34 Crosby EC, Humphrey T, Lauer EW. Correlative Anatomy of the Nervous System. New York: Macmillan; 1962: 412-433
    Google Scholar
  • 35 Stettler DD, Axel R. Representations of odor in the piriform cortex. Neuron 2009; 63 (06) 854-864
    CrossrefPubMedGoogle Scholar
  • 36 Miura K, Mainen ZF, Uchida N. Odor representations in olfactory cortex: distributed rate coding and decorrelated population activity. Neuron 2012; 74 (06) 1087-1098
    CrossrefPubMedGoogle Scholar
  • 37 Bolding KA, Franks KM. Recurrent cortical circuits implement concentration-invariant odor coding. Science 2018; 361 (6407): anat6904
    CrossrefPubMedGoogle Scholar
  • 38 Schoonover CE, Ohashi SN, Axel R, Fink AJP. Representational drift in primary olfactory cortex. Nature 2021; 594 (7864): 541-546
    CrossrefPubMedGoogle Scholar
  • 39 Poo C, Agarwal G, Bonacchi N, Mainen ZF. Spatial maps in piriform cortex during olfactory navigation. Nature 2022; 601 (7894): 595-599
    CrossrefPubMedGoogle Scholar
  • 40 Abellán A, Desfilis E, Medina L. The olfactory amygdala in amniotes: an evo-devo approach. Anat Rec (Hoboken) 2013; 296 (09) 1317-1332
    CrossrefPubMedGoogle Scholar
  • 41 Canto CB, Wouterlood FG, Witter MP. What does the anatomical organization of the entorhinal cortex tell us?. Neural Plast 2008; 2008: 381243
    CrossrefPubMedGoogle Scholar
  • 42 Naumann RK, Preston-Ferrer P, Brecht M, Burgalossi A. Structural modularity and grid activity in the medial entorhinal cortex. J Neurophysiol 2018; 119 (06) 2129-2144
    CrossrefPubMedGoogle Scholar
  • 43 Takehara-Nishiuchi K. Entorhinal cortex and consolidated memory. Neurosci Res 2014; 84: 27-33
    CrossrefPubMedGoogle Scholar
  • 44 García AD, Buffalo EA. Anatomy and function of the primate entorhinal cortex. Annu Rev Vis Sci 2020; 6: 411-432
    CrossrefPubMedGoogle Scholar
  • 45 Igarashi KM. The entorhinal map of space. Brain Res 2016; 1637: 177-187
    CrossrefPubMedGoogle Scholar
  • 46 Julian JB, Keinath AT, Frazzetta G, Epstein RA. Human entorhinal cortex represents visual space using a boundary-anchored grid. Nat Neurosci 2018; 21 (02) 191-194
    CrossrefPubMedGoogle Scholar
  • 47 Ginosar G, Aljadeff J, Burak Y, Sompolinsky H, Las L, Ulanovsky N. Locally ordered representation of 3D space in the entorhinal cortex. Nature 2021; 596 (7872): 404-409
    CrossrefPubMedGoogle Scholar
  • 48 Nilssen ES, Doan TP, Nigro MJ, Ohara S, Witter MP. Neurons and networks in the entorhinal cortex: a reappraisal of the lateral and medial entorhinal subdivisions mediating parallel cortical pathways. Hippocampus 2019; 29 (12) 1238-1254
    CrossrefPubMedGoogle Scholar
  • 49 Bellmund JL, Deuker L, Doeller CF. Mapping sequence structure in the human lateral entorhinal cortex. eLife 2019; 8: e45333
    CrossrefPubMedGoogle Scholar
  • 50 Kobro-Flatmoen A, Witter MP. Neuronal chemo-architecture of the entorhinal cortex: a comparative review. Eur J Neurosci 2019; 50 (10) 3627-3662
    CrossrefPubMedGoogle Scholar
  • 51 Lee JY, Jun H, Soma S. et al. Dopamine facilitates associative memory encoding in the entorhinal cortex. Nature 2021; 598 (7880): 321-326
    CrossrefPubMedGoogle Scholar
  • 52 Schmidt H, Gour A, Straehle J, Boergens KM, Brecht M, Helmstaedter M. Axonal synapse sorting in medial entorhinal cortex. Nature 2017; 549 (7673): 469-475
    CrossrefPubMedGoogle Scholar
  • 53 Mazzola L, Royet J-P, Catenoix H, Montavont A, Isnard J, Mauguière F. Gustatory and olfactory responses to stimulation of the human insula. Ann Neurol 2017; 82 (03) 360-370
    CrossrefPubMedGoogle Scholar
  • 54 Barbado MV, Briñón JG, Weruaga E. et al. Changes in immunoreactivity to calcium-binding proteins in the anterior olfactory nucleus of the rat after neonatal olfactory deprivation. Exp Neurol 2002; 177 (01) 133-150
    CrossrefPubMedGoogle Scholar
  • 55 Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown; 1954
    CrossrefGoogle Scholar
  • 56 Sarnat HB, Flores-Sarnat L. Might the olfactory bulb be an origin of olfactory auras in focal epilepsy?. Epileptic Disord 2016; 18 (04) 344-355
    CrossrefPubMedGoogle Scholar
  • 57 Fabbri VP, Riefolo M, Lazzarotto T. et al. COVID-19 and the Brain: The Neuropathological Italian Experience on 33 Adult Autopsies. Biomolecules 2022; 12 (05) 629
    CrossrefPubMedGoogle Scholar
  • 58 Wei G, Gu J, Gu Z. et al. Olfactory dysfunction in patients with coronavirus disease 2019: a review. Front Neurol 2022; 12: 783249
    CrossrefPubMedGoogle Scholar
  • 59 Di Stadio A, Brenner MJ, De Luca P. et al. Olfactory dysfunction, headache, and mental clouding in patients with long-COVID-19: what is the link between cognition and olfaction? A cross-sectional study. Brain Sci 2022; 12 (02) 154
    CrossrefPubMedGoogle Scholar
  • 60 Marshall M. COVID and smell loss: answers begin to emerge. Nature 2022; 606 (7915): 631-632
    CrossrefPubMedGoogle Scholar
  • 61 Shabhaz MA, De Bernardi F, Alatalo A. et al. Mechanistic understanding of the olfactory neuroepithelium involvement leading to short-term anosmia in COVID-19 using the Adverse Outcome Pathway framework. Cells 2022; 11 (19) 3027
    CrossrefPubMedGoogle Scholar
  • 62 Uemura N, Ueda J, Yoshihara T. et al. α-synuclein spread from olfactory bulb causes hyposmia, anxiety and memory loss in BAC-SNCA mice. Mov Disord 2021; 36 (09) 2036-2047
    CrossrefPubMedGoogle Scholar
  • 63 Dalton AJ, Seltzer GB, Adlin MS, Wisniewski HM. Association between Alzheimer's disease and Down's syndrome: clinical observations. In: Berg JM, Holland AJ, Karlinsky H, eds. Alzheimer's Disease and Down's Syndrome. London: Oxford University Press; 1992: 1-17
    Google Scholar
  • 64 Wong OGW, Cheung CLY, Ip PPC, Ngan HYS, Cheung ANY. Amyloid precursor protein overexpression is Down syndrome trophoblast reduces cell invasiveness and interferes with syncytialization. Am J Pathol 2018; 188 (10) 2307-2317
    CrossrefPubMedGoogle Scholar
  • 65 Robain O, Floquet C, Heldt N, Rozenberg F. Hemimegalencephaly: a clinicopathological study of four cases. Neuropathol Appl Neurobiol 1988; 14 (02) 125-135
    CrossrefPubMedGoogle Scholar
  • 66 Aleo S, Cinnante C, Avignone S. et al. Olfactory malformations in Mendelian disorders of the epigenetic machinery. Front Cell Dev Biol 2020; 8: 710
    CrossrefPubMedGoogle Scholar
  • 67 Ciurea AV, Iencean SM, Rizea RE, Brehar FM. Olfactory groove meningiomas: a retrospective study on 59 surgical cases. Neurosurg Rev 2012; 35 (02) 195-202 , discussion 202
    CrossrefPubMedGoogle Scholar
  • 68 Mori T, Onimaru R, Onodera S. et al. Olfactory neuroblastoma: the long-term outcome and late toxicity of multimodal therapy including radiotherapy based on treatment planning using computed tomography. Radiat Oncol 2015; 10: 88
    CrossrefPubMedGoogle Scholar
  • 69 Chen P, Wang W, Liu R. et al. Olfactory sensory experience regulates gliomagenesis via neuronal IGF1. Nature 2022; 606 (7914): 550-556
    CrossrefPubMedGoogle Scholar
  • 70 Fabbri VP, Papa V, Agati R. et al. Olfactory nerve schwannoma: how anatomy can help to solve an intriguing scientific puzzle. Int J Environ Res Public Health 2021;•••. Doi: 103390/xxxxx
    PubMedGoogle Scholar