Convergence of Olfactory Inputs within the Central Nervous System of a Cartilaginous and a Bony Fish: An Anatomical Indicator of Olfactory Sensitivity.

The volume of the olfactory bulbs (OBs) relative to the brain has been used previously as a proxy for olfactory capabilities in many vertebrate taxa, including fishes. Although this gross approach has predictive power, a more accurate assessment of the number of afferent olfactory inputs and the convergence of this information at the level of the telencephalon is critical to our understanding of the role of olfaction in the behaviour of fishes. In this study, we used transmission electron microscopy to assess the number of first-order axons within the olfactory nerve (ON) and the number of second-order axons in the olfactory peduncle (OP) in established model species within cartilaginous (brownbanded bamboo shark, Chiloscyllium punctatum [CP]) and bony (common goldfish, Carassius auratus [CA]) fishes. The total number of axons varied from a mean of 18.12 ± 7.50 million in the ON to a mean of 0.38 ± 0.21 million in the OP of CP, versus 0.48 ± 0.16 million in the ON and 0.09 ± 0.02 million in the OP of CA. This resulted in a convergence ratio of approximately 50:1 and 5:1, respectively, for these two species. Based on astroglial ensheathing, axon type (unmyelinated [UM] and myelinated [M]) and axon size, we found no differentiated tracts in the OP of CP, whereas a lateral and a medial tract (both of which could be subdivided into two bundles or areas) were identified for CA, as previously described. Linear regression analyses revealed significant differences not only in axon density between species and locations (nerves and peduncles), but also in axon type and axon diameter (p < 0.05). However, UM axon diameter was larger in the OPs than in the nerve in both species (p = 0.005), with no significant differences in UM axon diameter in the ON (p = 0.06) between species. This study provides an in-depth analysis of the neuroanatomical organisation of the ascending olfactory pathway in two fish taxa and a quantitative anatomical comparison of the summation of olfactory information. Our results support the assertion that relative OB volume is a good indicator of the level of olfactory input and thereby a proxy for olfactory capabilities.

Synaptic distribution of individually labeled mitral cells in the external plexiform layer of the mouse olfactory bulb.

Mitral cells are the major projection neurons of the olfactory bulb. They receive olfactory inputs, regulate information, and project their axons to the olfactory cortex. To understand output regulation of mitral cells better, we established a method to visualize individual projection neurons and quantitatively examined their synaptic distribution. Individual mitral cells were labeled by viral injection, reconstructed three dimensionally with light microscopy, and serial sectioned for electron microscopy. Synaptic distributions were analyzed in electron microscopically reconstructed cell bodies, two regions of secondary dendrites (near the somata and ∼200 µm from the somata), and primary dendrites. The ratio of presynaptic sites (60%) and reciprocal synapses (60% presynaptic and 80% postsynaptic sites) were similar in each region. Characteristically, primary dendrite synapses were distributed mainly within the inner half of the external plexiform layer (EPL). For comparison, tufted cells were also examined, and the synaptic distribution in two secondary dendrite regions, which corresponded with mitral cells, was analyzed. The results showed that the ratio of reciprocal synapses (80% presynaptic and 90% postsynaptic sites) was greater than in mitral cells. The distribution of symmetrical synapses was also analyzed with synaptic and neuronal markers, such as parvalbumin, vesicular gamma-aminobutyric acid transporter, and gephyrin. Parvalbumin-expressing neurons tended to form synapses on secondary dendrites near the somata and were more uniformly distributed on primary dendrites of mitral cells. These results indicate that local mitral cell synaptic circuits are formed in accordance with their functional roles and restricted to the inner half of the EPL. J. Comp. Neurol. 525:1633-1648, 2017. © 2016 Wiley Periodicals, Inc.

Spatial distribution of synapses on tyrosine hydroxylase-expressing juxtaglomerular cells in the mouse olfactory glomerulus.

Olfactory sensory axons converge in specific glomeruli where they form excitatory synapses onto dendrites of mitral/tufted (M/T) and juxtaglomerular (JG) cells, including periglomerular (PG), external tufted (ET), and superficial-short axon cells. JG cells consist of heterogeneous subpopulations with different neurochemical, physiological, and morphological properties. Among JG cells, previous electron microscopic (EM) studies have shown that the majority of synaptic inputs to tyrosine hydroxylase (TH)-immunoreactive neurons were asymmetrical synapses from olfactory nerve (ON) terminals. However, recent physiological results revealed that 70% of dopaminergic/γ-aminobutyric acid (GABA)ergic neurons received polysynaptic inputs via ET cells, whereas the remaining 30% received monosynaptic ON inputs. To understand the discrepancies between EM and physiological data, we used serial EM analysis combined with confocal laser scanning microscope images to examine the spatial distribution of synapses on dendrites using mice expressing enhanced green fluorescent protein under the control of the TH promoter. The majority of synaptic inputs to TH-expressing JG cells were from ON terminals, and they preferentially targeted distal dendrites from the soma. On the other hand, the numbers of non-ON inputs were fewer and targeted proximal dendrites. Furthermore, individual TH-expressing JG cells formed serial synapses, such as M/T→TH→another presumed M/T or ON→TH→presumed M/T, but not reciprocal synapses. Serotonergic fibers also associated with somatic regions of TH neurons, displaying non-ON profiles. Thus, fewer proximal non-ON synapses provide more effective inputs than large numbers of distal ON synapses and may occur on the physiologically characterized population of dopaminergic-GABAergic neurons (70%) that receive their most effective inputs indirectly via an ON→ET→TH circuit. J. Comp. Neurol. 525:1059-1074, 2017. © 2017 Wiley Periodicals, Inc.

Ultrastructural analysis of olfactory ensheathing cells derived from olfactory bulb and nerve of neonatal and juvenile rats.

Olfactory nerve derived and olfactory bulb derived olfactory ensheathing cells (OECs) have the ability to promote axonal regeneration and remyelination, both of which are essential in a successful cell transplant. Thus, morphological identification of OECs is a key aspect to develop an applicable cell therapy for injuries to the nervous system. However, there is no clear definition regarding which developmental stage or anatomical origin of OECs is more adequate for neural repair. In the present study, an ultrastructural comparison was made between OECs recovered from primary cultures of olfactory nerve and bulb in two developmental stages. The most notorious difference between cells obtained from olfactory nerve and bulb was the presence of indented nuclei in bulb derived OECs, suggesting a greater ability for possible chemotaxis. In neonatal OECs abundant mitochondria, lipid vacuoles, and smooth endoplasmic reticulum were detected, suggesting an active lipid metabolism, probably involved in synthesis of myelin. Our results suggest that neonatal OECs obtained from olfactory bulb have microscopic properties that could make them more suitable for neural repair.

Transcriptional profiling predicts overwhelming homology of Schwann cells, olfactory ensheathing cells, and Schwann cell-like glia.

Schwann cells (SCs), olfactory ensheathing cells (OECs), and central nervous system Schwann cell-like glia (SG) represent a group of nerve growth factor receptor p75 (NGFR)-positive cells, originating from different tissues. Because of their pro-regenerative capacities, these cells are subjects in experimental transplantation-based therapies of spinal cord trauma. The objective of this study was to compare the transcriptomes of uninfected and canine distemper virus-infected OECs, SCs, SG and fibroblasts (FBs) derived from four beagle dogs and cultured under identical conditions in vitro, employing canine genome 2.0 arrays (Affymetrix). Here, we observed a complete lack of transcriptional differerences between OECs and SG, a high similarity of OECs/SG to SCs, and a marked difference of SCs and OECs/SG towards FBs. Differentially expressed genes possibly involved in the maintenance of cell type-specific identity included an up-regulation of HOXD8 and HOXC4 in SCs, and an up-regulation of CNTNAP2 and EFEMP1 in OECs/SG. We identified cell type-specific biomarkers employing supervised clustering with a K-nearest-neighbors algorithm and correlation-based feature selection. Thereby AQP1 and SCRG1 were predicted to be the most powerful biomarkers distinguishing SCs from OECs/SG. Immunofluorescence confirmed a higher expression of SCRG1 in OECs and SG, and conversely a higher expression of AQP1 in SCs in vitro. Furthermore, canine and murine olfactory nerves showed SCRG1-positive, AQP1-negative OECs and/or axons, whereas sciatic nerves displayed multifocal non-myelinated, AQP1-positive, SCRG1-negative cells. Conclusively, OECs/SG are suggested to be a uniform cell type differing only in the tissue of origin and highly related to SCs.

Histological and ultrastructural characteristics of the primordial vomeronasal organ in lungfish.

Many vertebrates have two anatomically distinct olfactory organs--the olfactory epithelium and the vomeronasal organ--to detect chemicals such as general odorants and pheromones in their environment. The vomeronasal organ is not present in fish but is present in vertebrates of a higher order than amphibians. Among all extant fishes, the lungfish is considered to be genetically and phylogenetically closest to tetrapods. In this study, we examined the olfactory organs of African lungfish, Protopterus annectens, by lectin histochemistry, immunohistochemistry, and transmission electron microscopy. Two types of sensory epithelia were identified in the olfactory organ--the olfactory epithelium covering the surface of lamellae and the sensory epithelium lining the recesses both at the base of lamellae and in the wall of the nasal sac--and designated here as the lamellar olfactory epithelium and the recess epithelium, respectively. Based on analysis of G-protein expression and ultrastructure, the lamellar olfactory epithelium resembled the olfactory epithelium of ordinary teleosts and the recess epithelium resembled the vomeronasal organ of tetrapods. Furthermore, lectin histochemistry demonstrated that the axons from the recess epithelium converge and project to the ventrolateral part of the olfactory bulb, suggesting that lungfish possess a region homologous to the accessory olfactory bulb of tetrapods. Based on these results, it seems appropriate to refer to the recess epithelium as "a primordium of the vomeronasal organ." This study may provide important clues to elucidate how the vomeronasal organ emerged during the evolution of vertebrates.

Ultrastructural and histochemical properties of the olfactory system in the japanese jungle crow, Corvus macrorhynchos.

Although it has been commonly believed that birds are more dependent on the vision and audition than the olfaction, recent studies indicate that the olfaction of birds is related to the reproductive, homing, and predatory behaviors. In an attempt to reveal the dependence on the olfactory system in crows, we examined the olfactory system of the Japanese jungle crow (Corvus macrorhynchos) by histological, ultrastructural, and lectin histochemical methods. The olfactory epithelium (OE) of the crow occupied remarkably a small area of the nasal cavity (NC) and had the histological and ultrastructural features like other birds. The olfactory bulb (OB) of the crow was remarkably small and did not possess the olfactory ventricle. The left and right halves of the OB were fused in many cases. In the lectin histochemistry, soybean agglutinin (SBA) and Vicia villosa agglutinin (VVA) stained a small number of the receptor cells (RCs) in the OE and the olfactory nerve layer (ONL) and glomerular layer (GL) on the dorsocaudal region of the OB. Phaseolus vulgaris agglutinin-E (PHA-E) stained several RCs in the OE and the ONL and GL on the ventral region of the OB. These results suggest that 1) the crow has less-developed olfactory system than other birds, and 2) the dedicated olfactory receptor cells project their axons to the specific regions of the OB in the crow.

[How is the sense of smell connected? Cellular and molecular mechanisms guiding the development of the synaptic connections from the nose to the cortex (I)]. / ¿Cómo se conecta la olfacción? Mecanismos celulares y moleculares que dirigen el desarrollo de las conexiones sinápticas desde la nariz a la corteza (I).

The physiological particularities that occur during the development of the olfactory system make it one of the most fascinating parts of the central nervous system and one of models that has been most widely studied in order to understand the mechanisms related with axonal growth and guidance towards the right targets. A variety of mechanisms are known, some mediated by contact (laminins, cell adhesion molecules, ephrins, etc.) and others that are secreted (semaphorins, slits, growth factors, etc.), to play diverse roles in establishing the synaptic interactions among the olfactory epithelium, the olfactory bulb and the olfactory cortex. In relation to this, other specific mechanisms for this system have also been proposed, including the incredible family of close to 1000 different olfactory receptors. In recent years, different reviews have focused on the partial elements of this system, especially on the mechanisms involved in the formation of the olfactory nerve. However, no detailed review of those related with the development of the connections between the different olfactory structures (epithelium, bulb and cortex) has been put forward to date. In this first part of the review, we address this topic from the following perspective: the different cellular and molecular mechanisms that guide the formation of the olfactory nerve and the lateral olfactory tract.

Synaptic connectivity of serotonergic axons in the olfactory glomeruli of the rat olfactory bulb.

Although the major mode of transmission for serotonin in the brain is volume transmission, previous anatomical studies have demonstrated that serotonergic axons do form synaptic contacts. The olfactory glomeruli of the olfactory bulb of mammals receive a strong serotonergic innervation from the dorsal and medial raphe nuclei. In the present report, we investigate the synaptic connectivity of these serotonergic axons in the glomerular neuropil of the rat olfactory bulb. Our study shows that serotonergic axons form asymmetrical synaptic contacts on dendrites within the glomerular neuropil. Analyzing the neurochemical nature of the synaptic targets, we have found that 55% of the synapses were on GABA-immunopositive profiles and 45% on GABA-immunonegative profiles. These data indicate that barely half of the contacts were found in GABA-immunonegative profiles and half of the synapses in GABA-positive dendrites belonging to type 1 periglomerular cells. Synaptic contacts from serotonergic axons on dendrites of principal cells cannot be excluded, since some of the GABA-immunonegative postsynaptic profiles contacted by serotonergic axons had the typical ultrastructural features of bulbar principal cell dendrites. Altogether, our results suggest a complex action of the serotonergic system in the modulation of the bulbar circuitry.

Immunoelectron microscopic analysis of the distribution of tyrosine kinase receptor B in olfactory axons.

To determine the morphological basis for the neurotrophic effects of brain-derived neurotrophic factor (BDNF) in the primary olfactory pathway (POP), tyrosine kinase receptor B (TrkB), a membrane-bound receptor for BDNF, was identified and localized in axons of olfactory receptor cells (ORC) of neonatal rat olfactory mucosa using immuno-histochemical and -cytochemical techniques. Initially, the immunospecificity of an anti-TrkB antibody that had been used as a specific antibody for full-length TrkB was confirmed in the olfactory mucosa. Then, a combination of a reduced osmium-LR-White and post-embedding immunogold technique was applied to ORC axons in the lamina propria just beneath the olfactory epithelium. Immunogold particles, which indicate TrkB immunoreactivity, were noted either in close association with the plasma membranes of ORC axons, and designated plasma-lemmal (PL), or within their cytoplasm, and designated cytoplasmic (CP). Most PL particles were seen in the CP portion of the axonal plasma membranes, suggesting that the anti-TrkB antibody binds to the membrane-inserted TrkB that acts as a functional receptor. Some CP particles were on vesicular structures. Quantitative analysis demonstrated that the ratio of CP to PL particles was 7:3, and this ratio was constant between animals examined (n = 5). Because membrane proteins are wrapped in vesicles and transported within the axonal cytoplasm and inserted into the plasma membrane to function there, the present study suggests that TrkB is transported within the cytoplasm of ORC axons and is positioned as a functional receptor for BDNF in their membranes.

Activation of postsynaptic GABAB receptors modulates the bursting pattern and synaptic activity of olfactory bulb juxtaglomerular neurons.

Olfactory bulb glomeruli are formed by a network of three major types of neurons collectively called juxtaglomerular (JG) cells, which include external tufted (ET), periglomerular (PG), and short axon (SA) cells. There is solid evidence that gamma-aminobutyric acid (GABA) released from PG neurons presynaptically inhibits glutamate release from olfactory nerve terminals via activation of GABA(B) receptors (GABA(B)-Rs). However, it is still unclear whether ET cells have GABA(B)-Rs. We have investigated whether ET cells have functional postsynaptic GABA(B)-Rs using extracellular and whole cell recordings in olfactory bulb slices. In the presence of fast synaptic blockers (CNQX, APV, and gabazine), the GABA(B)-R agonist baclofen either completely inhibited the bursting or reduced the bursting frequency and increased the burst duration and the number of spikes/burst in ET cells. In the presence of fast synaptic blockers and tetrodotoxin, baclofen induced an outward current in ET cells, suggesting a direct postsynaptic effect. Baclofen reduced the frequency and amplitude of spontaneous EPSCs in PG and SA cells. In the presence of sodium and potassium channel blockers, baclofen reduced the frequency of miniature EPSCs, which were inhibited by the calcium channel blocker cadmium. All baclofen effects were reversed by application of the GABA(B)-R antagonist CGP55845. We suggest that activation of GABA(B)-Rs directly inhibits ET cell bursting and decreases excitatory dendrodendritic transmission from ET to PG and SA cells. Thus the postsynaptic GABA(B)-Rs on ET cells may play an important role in shaping the activation pattern of the glomeruli during olfactory coding.

Chemical properties of type 1 and type 2 periglomerular cells in the mouse olfactory bulb are different from those in the rat olfactory bulb.

We analyzed the cellular composition of the juxtaglomerular region in the main olfactory bulb of C57B/6J strain mice, focusing on 1) the compartmental organization of the glomerulus and the presence of type 1 and 2 periglomerular cells, 2) the colocalization relationships among the 4 major chemically identified groups of periglomerular cells, glutamic acid decarboxylase (GAD)/gamma-aminobutyric acid (GABA), tyrosine hydroxylase, calretinin and calbindin D28k positive periglomerular cells, and 3) the chemical properties of the nitric oxide synthase (NOS)-positive juxtaglomerular cells. We confirmed the compartmental organization of the glomerulus and the presence of both type 1 and 2 periglomerular cells in the mice. Similar to rat periglomerular cells, the tyrosine hydroxylase-positive cells were type 1 and GAD/GABA-positive. On the other hand, both the calbindin D28k-positive and calretinin-positive cells were type 2 periglomerular cells, but in contrast to those in rats, which are GAD/GABA-negative, all of the calbindin D28k-positive periglomerular cells and 65% of the calretinin-positive periglomerular cells were GAD/GABA-positive. The GAD/GABA-positive cells thus included both type 1 and type 2 periglomerular cells. Juxtaglomerular NOS-positive cells have been proposed as a subgroup of type 1 periglomerular cells that are separate from the calretinin-positive and calbindin D28k-positive cells in rats. However, in the mice, about 70% of the NOS-positive cells were calretinin-positive, and 50% of the calretinin-positive cells were NOS-positive. We herein reveal the significant species differences in the chemical properties of periglomerular cells and suggest that the cellular organization of the mouse main olfactory bulb cannot be extrapolated from that of rats.

The olfactory route for cerebrospinal fluid drainage into the peripheral lymphatic system.

Drainage of the cerebrospinal fluid through the olfactory nerves into the nasal lymphatics has been suggested repeatedly. To investigate precisely the morphology of this pathway, India ink was injected into the subarachnoidal space of the rat brain, and samples including the olfactory bulbs, olfactory tracts and the nasal mucosa were observed by light and electron microscopy. Under the dissecting microscope, ink particles were found within the subarachnoid space and along the olfactory nerves. At the nasal mucosa, a lymphatic network stained in black was identified near the olfactory nerves, which finally emptied into the superficial and deep cervical lymph nodes. Light microscopically, ink particles were found in the subarachnoid space, partially distributed around the olfactory nerves and within the lymphatic vessels. By electron microscopy, the subarachnoid space often formed a pocket-like space in the entrance of the fila olfactoria. The olfactory nerves were partially surrounded by ink particles within the space between perineurial cells and epineurial fibroblasts. At the nasal mucosa, the lymphatics were frequently located close to the nerves. These results indicate that the cerebrospinal fluid drains from the subarachnoid space along the olfactory nerves to the nasal lymphatics, which in turn, empties into the cervical lymph nodes. This anatomical communication, thus, allows the central nervous system to connect with the lymphatic system. The presence of this route may play an important role in the movement of antigens from the subarachnoidal space to the extracranial lymphatic vessels, resulting in inducement of an immune response of the central nervous system.

Abnormalities of axon growth in human olfactory mucosa.

OBJECTIVES/HYPOTHESIS: Random biopsies of the human adult olfactory mucosa often demonstrate degenerative changes in the olfactory epithelium (OE) in both dysosmic and normosmic patients and, consequently, have limited diagnostic usefulness. However, detailed analysis of the subepithelial tissue with specific attention to the fascicles of the olfactory nerve and abnormalities of axonal growth may improve the correlation of histopathology with sensory function. STUDY DESIGN: Retrospective review of human OE biopsies. METHODS: Mucosal biopsies from the olfactory area obtained from 27 subjects were examined by light and electron microscopy, with particular attention to the olfactory nerve fascicles; results were correlated with clinical status. Immunohistochemical analysis was used to characterize the extent of axonal depletion, relative maturity of the parent population, and aberrant axonal growth. RESULTS: As expected, there are areas of respiratory metaplasia and neuronal depletion in normosmic as well as dysosmic patients. The degree of axon degeneration within the fascicles correlates better with individual olfactory status. Immature neurons predominate, and re-entrant neuromas develop in patients with olfactory loss caused by disconnection from the olfactory bulb. Individuals with olfactory loss caused by epithelial damage as with chronic rhinosinusitis display evidence of nerve fascicle degeneration and intraepithelial neuromas. CONCLUSION: The status of olfactory axons provides useful information on the overall condition of the olfactory periphery and improves the diagnostic usefulness of mucosal biopsies. In addition to an assessment of the epithelium per se, the fascicles of the olfactory nerve need to be characterized for a complete analysis of the olfactory mucosa.

Characterization of somatostatin- and cholecystokinin-immunoreactive periglomerular cells in the rat olfactory bulb.

Periglomerular cells (PG) are interneurons of the olfactory bulb (OB) that modulate the first synaptic relay of the olfactory information from the olfactory nerve to the dendrites of the bulbar principal cells. Previous investigations have pointed to the heterogeneity of these interneurons and have demonstrated the presence of two different types of PG. In the rat OB, type 1 PG receive synaptic contacts from the olfactory axons and are gamma-aminobutyric acid (GABA)-ergic, whereas type 2 PG do not receive synaptic contacts from the olfactory axons and are GABA immunonegative. In this study, we analyze and characterize neurochemically a group of PG that has not been previously classified either as type 1 or type 2. These PG are immunoreactive for the neuropeptides somatostatin (SOM) or cholecystokinin (CCK). By using double immunocytochemistry, we demonstrate that neither the SOM- nor the CCK-immunoreactive PG contain GABA immunoreactivity, which is a neurochemical feature of type 1 PG. Moreover, they do not contain the calcium-binding proteins calbindin D-28k and calretinin, which are neurochemical markers of the type 2 PG. Electron microscopy demonstrates that the dendrites of the SOM- and CCK-containing PG are distributed in the synaptic and sensory subcompartments of the glomerular neuropil and receive synaptic contacts from the olfactory axons. Therefore, they should be included in the type 1 group rather than in the type 2. Altogether, these data indicate that the SOM- and the CCK-containing PG may constitute a group of GABA-immunonegative type 1 PG that has not been previously described. These results further extend the high degree of complexity of the glomerular circuitry.

synaptic organization of the glomerulus in the main olfactory bulb: compartments of the glomerulus and heterogeneity of the periglomerular cells.

According to the combinatorial receptor and glomerular codes for odors, the fine tuning of the output level from each glomerulus is assumed to be important for information processing in the olfactory system, which may be regulated by numerous elements, such as olfactory nerves (ONs), periglomerular (PG) cells, centrifugal nerves and even various interneurons, such as granule cells, making synapses outside the glomeruli. Recently, structural and physiological analyses at the cellular level started to reveal that the neuronal organization of the olfactory bulb may be more complex than previously thought. In the present paper, we describe the following six points of the structural organization of the glomerulus, revealed by confocal laser scanning microscopy and electron microscopy analyses of rats, mice and other mammals: (i) the chemical heterogeneity of PG cells; (ii) compartmental organization of the glomerulus, with each glomerulus consisting of two compartments, the ON zone and the non-ON zone; (iii) the heterogeneity of PG cells in terms of their structural and synaptic features, whereby type 1 PG cells send their intraglomerular dendrites into both the ON and non-ON zones and type 2 PG cells send their intraglomerular dendrites only into the non-ON zone, thus receiving either few synapses from the ON terminals, if present, or none at all; (iv) the spatial relationship of mitral/tufted cell dendritic processes with ON terminals and PG cell dendrites; (v) complex neuronal interactions via chemical synapses and gap junctions in the glomerulus; and (vi) comparative aspects of the organization of the main olfactory bulb.

Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres.

The ensheathing cells of the olfactory nerves are arranged end-to-end to form a continuous channel enclosing the olfactory axons from their origin in the olfactory mucosa to their termination in the olfactory bulb. On their outer surface, the olfactory ensheathing cell channels have a basal lamina and an outer encirclement of olfactory nerve fibroblasts. We present an anatomical model of the ensheathing arrangements for the entire transit of the olfactory axons from the horizontal basal cells of the mucosa through the nerves to the superficial astrocytes of the bulb. We used intracranial section of the olfactory nerves to induce a rapid retrograde loss of olfactory neurons and degeneration of their axons, followed by replacement of the neurons from stem cells in the mucosa and growth of the newly formed axons along the olfactory nerves. The olfactory ensheathing cells survive and play a vital role in this process. Unlike Schwann cells in damaged peripheral nerve, the olfactory ensheathing cells neither divide nor migrate. They are actively phagocytic for removal of the degenerating axons, and provide continuous stable open channels along which adventitious cells such as erythrocytes and macrophages can travel, and along which the newly formed axons can regenerate. We suggest that the persistence of these open channels is an important element in the effectiveness of the regeneration. These properties, which the olfactory ensheathing cells exert in collaboration with olfactory nerve fibroblasts, may also be involved in the reparative effects of these cells when transplanted into lesions of the spinal cord.

Defining the role of olfactory ensheathing cells in facilitating axon remyelination following damage to the spinal cord.

Olfactory ensheathing cells (OECs) are unique cells that are responsible for the successful regeneration of olfactory axons throughout the life of adult mammals. More than a decade of research has shown that implantation of OECs may be a promising therapy for damage to the nervous system, including spinal cord injury. Based on this research, several clinical trials worldwide have been initiated that use autologous transplantation of olfactory tissue containing OECs into the damaged spinal cord of humans. However, research from several laboratories has challenged the widely held belief that OECs are directly responsible for myelinating axons and promoting axon regeneration. The purpose of this review is to provide a working hypothesis that integrates several current ideas regarding the mechanisms of the beneficial effects of OECs. Specifically, OECs promote axon regeneration and functional recovery indirectly by augmenting the endogenous capacity of host Schwann cells to invade the damaged spinal cord. Together with Schwann cells, OECs create a 3-dimensional matrix that provides a permissive microenvironment for successful axon regeneration in the adult mammalian central nervous system.

Olfactory ensheathing cells: their role in central nervous system repair.

The olfactory system is an unusual tissue in that it can support neurogenesis throughout life; permitting the in-growth and synapse formation of olfactory receptor axons into the central nervous system (CNS) environment of the olfactory bulb. It is thought that this unusual property is in part due to the olfactory glial cells, termed olfactory ensheathing cells (OECs), but also due to neuronal stem cells. These glial cells originate from the olfactory placode and possess many properties in common with the glial cells from the peripheral nervous system (PNS), Schwann cells. Recent data has suggested that olfactory ensheathing cells are a distinct glial cell type and possess properties, which might make them more suitable for transplant-mediated repair of central nervous system injury models. This paper reviews the biological properties of these cells and illustrates their use in central nervous system repair.