Anosmia in COVID-19 Associated with Injury to the Olfactory Bulbs Evident on MRI.

Patients with coronavirus disease 2019 (COVID-19) may have symptoms of anosmia or partial loss of the sense of smell, often accompanied by changes in taste. We report 5 cases (3 with anosmia) of adult patients with COVID-19 in whom injury to the olfactory bulbs was interpreted as microbleeding or abnormal enhancement on MR imaging. The patients had persistent headache (n = 4) or motor deficits (n = 1). This olfactory bulb injury may be the mechanism by which the Severe Acute Respiratory Syndrome coronavirus 2 causes olfactory dysfunction.

Acute N-Acetylcysteine Administration Ameliorates Loss of Olfactory Neurons Following Experimental Injury In Vivo.

The olfactory epithelium (OE) is the peripheral organ for the sense of smell, housing primary sensory neurons that project axons from the nose to the brain. Due to the presence of a basal stem cell niche, the adult mammalian OE is a dynamic tissue capable of replacing neurons following their loss. Nonetheless, certain conditions, such as blunt head trauma, can result in persistent olfactory loss, thought to be due to shearing of olfactory nerve filaments at the skull base, degeneration, and failures in proper regeneration/reinnervation. The identification of new treatment strategies aimed at preventing degeneration of olfactory neurons is, therefore, needed. In considering potential therapies, we have focused on N-acetylcysteine (NAC), a glutathione substrate shown to be neuroprotective, with a record of safe clinical use. Here, we have tested the use of NAC in an animal model of olfactory degeneration. Administered acutely, we found that NAC (100 mg/kg, twice daily) resulted in a reduction of olfactory neuronal loss from the OE of the nose following surgical ablation of the olfactory bulb. At 1 week postlesion, we identified 54 ± 8.1 mature neurons per 0.5 mm epithelium in NAC-treated animals vs. 28 ± 4.2 in vehicle-treated controls (P = 0.02). Furthermore, in an olfactory cell culture model, we have identified significant alterations in the expression of several genes involved in oxidative stress pathways following NAC exposure. Our results provide evidence supporting the potential therapeutic utility for NAC acutely following head trauma-induced olfactory loss. Anat Rec, 303:626-633, 2020. © 2019 American Association for Anatomy.

The Olfactory System of Zebrafish as a Model for the Study of Neurotoxicity and Injury: Implications for Neuroplasticity and Disease.

The olfactory system, composed of the olfactory organs and the olfactory bulb, allows organisms to interact with their environment and through the detection of odor signals. Olfaction mediates behaviors pivotal for survival, such as feeding, mating, social behavior, and danger assessment. The olfactory organs are directly exposed to the milieu, and thus are particularly vulnerable to damage by environmental pollutants and toxicants, such as heavy metals, pesticides, and surfactants, among others. Given the widespread occurrence of olfactory toxicants, there is a pressing need to understand the effects of these harmful compounds on olfactory function. Zebrafish (Danio rerio) is a valuable model for studying human physiology, disease, and toxicity. Additionally, the anatomical components of the zebrafish olfactory system are similar to those of other vertebrates, and they present a remarkable degree of regeneration and neuroplasticity, making it an ideal model for the study of regeneration, reorganization and repair mechanisms following olfactory toxicant exposure. In this review, we focus on (1) the anatomical, morphological, and functional organization of the olfactory system of zebrafish; (2) the adverse effects of olfactory toxicants and injury to the olfactory organ; and (3) remodeling and repair neuroplasticity mechanisms following injury and degeneration by olfactory toxicant exposure.

Mysterious effects of olfactory pathway lesions on intestinal immunodeficiency targeting Peyer's patches: The first experimental study.

BACKGROUND: Although olfaction has been considered as important neuroimmunomodulatory foundation, there is no satisfying analytical information between neurohistomorphological features olfactory networks and intestinal immune system hardwares. We studied if the olfactory bulb lesions (OBL) may rely on histopathological features of intestinal lymphatic Peyer's patches in an animal model. METHODS: Thirty-two rats were grouped as control (Group I, n = 8), SHAM (Group II, n = 7) and OBL (Group III, n = 17) respectively; and followed eight weeks and animals were decapitated. The olfactory bulbs and intestines were extracted. Specimens stained with hematoxylin/eosin and GFAP methods and analyzed Stereologically to evaluate volume loss of olfactory bulbs and Peyer's patches volumes (PV) of intestines per cubic millimeter and compared with each other's statistically. RESULTS: The mean olfactory bulbs volumes were estimated as 3.65 ±â€¯0.32/mm3 in group I, 3.12 ±â€¯0.20/mm3 in group II and 2.21 ±â€¯0.15/mm3 in group III (p < 0.0005 Group III vs. I and II). The mean of PV were estimated as; (9 ±â€¯2) × 106 µm3/cm3 in Group-I, (12 ±â€¯3) × 106 µm3/cm3 in Group-II; and (23 ±â€¯4) × 106 µm3/cm3 in group-III (p < 0.005 Group II vs. I, p < 0.0005 Group III vs. I-II). CONCLUSIONS: OBL could rely on intestinal immunodeficiency causing by olfaction loss induced denervation injury of Peyer's patches.

Bax inhibitor-1 overexpression in prelimbic cortex protects rats against depression-like behavior induced by olfactory bulbectomy and reduces apoptotic and inflammatory signals.

BACKGROUND AND PURPOSE: Depression is a mental disorder characterized by a pervasive low mood and loss of pleasure or interest in usual activities, and often results in the impairment of learning and memory. Bax inhibitor-1 (BI-1) has been reported to be involved in the pathological mechanisms for neurodegenerative disorders including depression. Here, we aimed to investigate the role of BI-1 in regulating depression-like behavior induced by olfactory bulbectomy (OB) in rats and the possible mechanism. METHODS: Adeno-associated virus vectors expressing BI-1 (AAV-BI-1) were bilaterally microinjected into the prelimbic cortex (PFC-PL) to establish a BI-1 overexpression model in the PFC-PL of rats. TUNEL staining was used to evaluate the cellular apoptosis rate in the PFC-PL. Western blot analysis was performed to examine the expressions of apoptotic and inflammatory signals. RESULTS: BI-1 overexpression significantly attenuated the OB-induced behavioral abnormalities, including the decreased hyperactivity in the open field, decreased immobility time in the forced swimming test, as well as the increased sucrose consumption. BI-1 overexpression significantly inhibited cellular apoptosis in the PFC-PL of OB rats. The expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-6, B-cell lymphoma (Bcl)-2 associated X protein (Bax), and caspase-3 in the PFC-PL of OB rats were significantly increased as compared with the sham rats, but the Bcl-2 and IL-10 expressions were decreased, whereas BI-1 overexpression significantly suppressed the changes of these proteins in the PFC-PL of OB rats. CONCLUSION: These results indicated that BI-1 may play an anti-depression function with concurrent regulation of apoptotic and inflammatory signals.

Exploring of the Unpredicted Effects of Olfactory Network Injuries on Mammary Gland Degeneration: A Preliminary Experimental Study.

Purpose of the study: Hypofunctioning breasts are typically considered a dysfunction of higher brain centers that regulate hormonal feedback, and olfactory information has been proposed as a triggering factor for lactation in the maternal body. However, there are no substantive studies regarding whether olfaction disorders and/or loss of olfactory sense may result in breast gland atrophy by causing diminished olfactory stimulation. To fill this gap in the literature, we studied the histologic features of breast glands as a sample model in animals that had undergone an olfactory bulb lesion (OBL). Materials and methods: This study was conducted on 22 rats. Six, eight, and six of them were used as control, SHAM, and OBL groups, respectively. After 10 weeks, the animals were decapitated. Olfactory bulbs and breast glands were stained with Hematoxylin-eosin and tunnel dye. Specimens were analyzed stereologically to evaluate the loss in volume of the olfactory bulbs, total breast follicle volume (TBFV) and Meissner's corpuscles per cubic centimeter, and these two senior metrics were compared with each other statistically. Results: Olfactory bulb volume loss and breast gland atrophy were both detected in study group. Mean TBFV and OB volumes were measured as: (296 ± 89) × 106 µm3/cm3 and 4.43 ± 0.98 mm3 in control (Group I); (264 ± 63) × 106 µm3/cm3 and 3.86 ± 0.81 mm3 in SHAM (Group II) and (194 ± 52) × 106 µm3/cm3 and 1.52 ± 0.36 mm3 in OBL group (Group III). It was noted that the TBFV was significantly diminished, with apoptotic degradation in the olfactory bulbs and breast glands of OBL-applied animals (p < 0.001). Conclusion: It seems that diminished milk secretion is attributable to the degradation of breast glands that results from olfaction loss in OBL animals.

Dopaminergic Lesion in the Olfactory Bulb Restores Olfaction and Induces Depressive-Like Behaviors in a 6-OHDA Model of Parkinson's Disease.

Olfactory impairments and depressive behavior are commonly reported by individuals with Parkinson's disease (PD) being observed before motor symptoms. The mechanisms underlying these clinical manifestations are not fully elucidated. However, the imbalance in dopaminergic neurotransmission seems to play an important role in this context. In patients and animal models of PD, an increase in the dopaminergic interneurons of the glomerular layer in olfactory bulb (OB-gl) is observed, which may contribute to the olfactory impairment. In addition, neuronal imbalance in OB is related to depressive symptoms, as demonstrated by chemical olfactory bulbectomy. In view of that, we hypothesized that a reduction in the number or density of dopaminergic neurons present in OB could promote an olfactory improvement and, in contrast, would accentuate the depressive-like behaviors in the 6-hydroxydopamine (6-OHDA) model of PD. Therefore, we performed single or double injections of 6-OHDA within the substantia nigra pars compacta (SNpc) and/or in the OB-gl. We observed that, after 7 days, the group with nigral lesion exhibited olfactory impairment, as well as the group with the lesion in the OB-gl. However, the combination of the lesions prevented the occurrence of hyposmia. In relation to depressive-like behaviors, we observed that the SNpc injury promoted depressive-like behavior, being accentuated after a double injury. Our results demonstrated the importance of the dopaminergic neurons of the OB-gl in different non-motor features of PD, since the selective reduction of these periglomerular neurons was able to induce olfactory impairment and depressive-like behaviors.

Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice.

Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IκB-α, p-NF-κB p65, TNF-α, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels.

Enhanced Homing Technique of Mesenchymal Stem Cells Using Iron Oxide Nanoparticles by Magnetic Attraction in Olfactory-Injured Mouse Models.

Intranasal delivery of mesenchymal stem cells (MSCs) to the olfactory bulb is a promising approach for treating olfactory injury. Additionally, using the homing phenomenon of MSCs may be clinically applicable for developing therapeutic cell carriers. Herein, using superparamagnetic iron oxide nanoparticles (SPIONs) and a permanent magnet, we demonstrated an enhanced homing effect in an olfactory model. Superparamagnetic iron oxide nanoparticles with rhodamine B (IRBs) had a diameter of 5.22 ± 0.9 nm and ζ-potential of +15.2 ± 0.3 mV. IRB concentration of 15 µg/mL was injected with SPIONs into MSCs, as cell viability significantly decreased when 20 μg/mL was used (p ≤ 0.005) compared to in controls. The cells exhibited magnetic attraction in vitro. SPIONs also stimulated CXCR4 (C-X-C chemokine receptor type 4) expression and CXCR4-SDF-1 (Stromal cell-derived factor 1) signaling in MSCs. After injecting magnetized MSCs, these cells were detected in the damaged olfactory bulb one week after injury on one side, and there was a significant increase compared to when non-magnetized MSCs were injected. Our results suggest that SPIONs-labeled MSCs migrated to injured olfactory tissue through guidance with a permanent magnet, resulting in better homing effects of MSCs in vivo, and that iron oxide nanoparticles can be used for internalization, various biological applications, and regenerative studies.

Acetyl-l-carnitine enhances myelination of regenerated fibers of the lateral olfactory tract.

It is well known that acetyl-l-carnitine (ALC) has various neuroprotective effects against neurodegenerative diseases. In addition, it has been reported that ALC facilitates myelination of regenerated axons after peripheral nerve injuries. We previously reported that spontaneous regeneration of the lateral olfactory tract (LOT), the main fiber tract of the central olfactory system, consistently occurred in newborn rats and a majority of these regenerated fibers were unmyelinated in neonatally LOT-transected young adult rats. To investigate the effects of ALC treatment on myelination in LOT, neonatal rats were treated with ALC after LOT transection. Immunohistochemistry for myelin basic protein showed more positive areas in ALC-treated rats than in control rats. Moreover, the number of myelinated axons of regenerated fibers was assessed using electron microscopy and was found to be statistically higher in ALC-treated rats compared to control rats. The study revealed that ALC accelerates myelination of regenerated fibers in neonatally LOT-injured young adult rats.

[Olfactory bulb volume in patients with posttraumatic olfactory dysfunction].

Objective: To analyze the correlation between olfactory bulb(OB) volume and olfactory function in patients with posttraumatic olfactory dysfunction. Methods: Forty patients with posttraumatic olfactory dysfunction were compared with forty controls in terms of olfactory function T&T testing, OB volume assessed with magnetic resonance imaging (MRI). SPSS 17.0 software was used to analyze the data. Results: T&T olfactory testing revealed that patients with posttraumatic olfactory dysfunction had higher scores than controls(3.47±0.63 vs.1.39±0.19, t=4.317, P<0.05). Both men and women with posttraumatic olfactory dysfunction were affected by the same extent of olfactory loss(3.52±0.66 vs.3.43±0.61, t=0.896, P>0.05). Both men and women as controls were affected by the same extent of olfactory loss(1.41±0.20 vs.1.38±0.17, t=1.073, P>0.05). OB volume of left side in patients with posttraumatic olfactory dysfunction were (36.15±3.16)mm(3,) right side were (39.28±3.76)mm(3,) average OB volume were (37.55±3.42)mm(3;) OB volume of left side in controls were (81.74±5.87)mm(3,) right side were (83.58±6.13)mm(3,) average OB volume were (82.59±5.99)mm(3;) OB volumes were lower in patients with posttraumatic olfactory dysfunction as compared with controls(t value were 4.815, 4.837 and 4.825, all P<0.01). Average olfactory discriminate threshold was negatively correlated with average OB volume in posttraumatic olfactory dysfunction and controls(r value was-0.582, -0.564, both P<0.05). Average olfactory discriminate threshold was positively correlated with impairment degree in patients with posttraumatic olfactory dysfunction(r value was 0.472, P<0.05), average OB volume was negatively correlated with impairment degree in patients with posttraumatic olfactory dysfunction(r value was -0.397, P<0.05) Conclusions: The OB volumes are lower in patients with posttraumatic olfactory dysfunction as compared with controls. The OB volume is correlated with olfactory function. Impairment degree in patients with posttraumatic olfactory dysfunction is accordance with olfactory function lowering degree. Megnetic resonance imaging can be used as a supplementary diagnostic tool for patients with posttraumatic olfactory dysfunction.

Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.

Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus.

Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice.

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-ß (Aß) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aß binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aß binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.

Analysis of anti-depressant potential of curcumin against depression induced male albino wistar rats.

The present study investigated the antidepressant potential of curcumin in olfactory bulbectomy and forced swimming test models of depression in male albino rats under chronic treatment. The experimental animals were divided into four groups, and curcumin was administered for 45 days. Our results showed that the curcumin significantly reduced olfactory bulbectomy-induced behavioral abnormalities including deficits in step-down passive avoidance, increased activity in the open area and immobility time. Chronic administration of curcumin significantly reversed levels of 3, 4-dihydroxyphenylacetic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the hippocampus region of male albino rats. Also, curcumin normalizes the levels of dopamine, noradrenaline, and 5-hydroxyindoleacetic acid in the frontal cortex of rats. Taking all these results together, it may suggest that curcumin is potent compound acting against the depression in the male albino rats.

Sistema olfatorio y nariz en el nuevo baremo médico / Olfactory system and nose in the new medical scale

Los traumatismos nasales son los más frecuentes en los accidentes de tráfico con afectación facial. En el baremo, recogido en la Ley 35/2015 de Reforma del Sistema para la Valoración de los Daños y Perjuicios causados a las personas en accidentes de circulación, la clasificación y la valoración de las secuelas debido a estos traumatismos presentan ligeras modificaciones con relación al baremo anterior, así como la puntuación otorgada a cada una de ellas. Dentro de las secuelas, la desviación del tabique nasal es la más frecuente. La sinusitis debida a alteración en el drenaje de los senos paranasales y las alteraciones en el sentido del olfato por traumatismos de la lámina cribosa del etmoides y lesiones neurológicas tienen menor incidencia, siendo bastante infrecuente la pérdida parcial o total de la nariz (AU)

Nasal traumas are the most frequent in road traffic accidents with facial involvement. In the scale, contained in Law 35/2015 for the modification of the system for the assessment of damages caused to people involved in traffic accidents, the classification and sequels assessment due to these traumas presents slight differences in relation to the preceding scale as well as the score given to each of them. Among the sequels, the nasal septum deviation is the most frequent. Sinusitis due to the alteration in the paranasal sinus drainage and smell disorders owing to trauma of the cribiform plate of the ethmoid bone and neurological injuries have lower incidence, partial or complete nose loss is quite rare (AU)

Ghrelin effects expression of several genes associated with depression-like behavior.

Ghrelin (Ghr) is an orexigenic peptide that is being investigated for its potential role in development of anxiety-like behavior and modulation of depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. Olfactory bulbectomy is an animal model useful to study of depression and Ghr could be an alternative therapeutic tool in depression therapy. We studied the effects of intracerebroventricular (i.c.v.) Ghr administration on the expression of hypothalamic genes related to depression and mood (delta opioid receptor (DOR), mu opioid receptor (MOR) and kappa opioid receptor (KOR), lutropin-choriogonadotropic hormone receptor (LHCGR), serotonin transporter (SERT), interleukin 1 beta (IL-1b), vasopressin (AVP) and corticotrophin releasing hormone (CRH)) in OB animals, as well as changes in plasma levels of AVP, CRH and adenocorticotropic hormone (ACTH). We found that acute Ghr 0.3 nmol/µl administration increases gene expression of DOR, SERT and LHCGR in OB mice and decreased expression of IL-1b, suggesting that these genes could be involved in the antidepressant-like effects of Ghr. In addition, OB animals exhibit high AVP gene expression and elevated plasma concentrations of AVP and ACTH and acute Ghr 0.3 nmol/µl administration reduces AVP gene expression and the concentration of these hormones, suggesting that peptide-effects on depressive-like behavior could be mediated at least in part via AVP. In conclusion, this study provides new evidence about genes, receptors and hormones involved in the antidepressant mechanism/s induced by Ghr in OB animals.

Olfactory ensheathing cells are the main phagocytic cells that remove axon debris during early development of the olfactory system.

During development of the primary olfactory system, axon targeting is inaccurate and axons inappropriately project within the target layer or overproject into the deeper layers of the olfactory bulb. As a consequence there is considerable apoptosis of primary olfactory neurons during embryonic and postnatal development and axons of the degraded neurons need to be removed. Olfactory ensheathing cells (OECs) are the glia of the primary olfactory nerve and are known to phagocytose axon debris in the adult and postnatal animal. However, it is unclear when phagocytosis by OECs first commences. We investigated the onset of phagocytosis by OECs in the developing mouse olfactory system by utilizing two transgenic reporter lines: OMP-ZsGreen mice which express bright green fluorescent protein in primary olfactory neurons, and S100ß-DsRed mice which express red fluorescent protein in OECs. In crosses of these mice, the fate of the degraded axon debris is easily visualized. We found evidence of axon degradation at embryonic day (E)13.5. Phagocytosis of the primary olfactory axon debris by OECs was first detected at E14.5. Phagocytosis of axon debris continued into the postnatal animal during the period when there was extensive mistargeting of olfactory axons. Macrophages were often present in close proximity to OECs but they contributed only a minor role to clearing the axon debris, even after widespread degeneration of olfactory neurons by unilateral bulbectomy and methimazole treatment. These results demonstrate that from early in embryonic development OECs are the primary phagocytic cells of the primary olfactory nerve.

Using the olfactory system as an in vivo model to study traumatic brain injury and repair.

Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75(NTR), ß-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration.

An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression.

The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal µ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

A novel method using intranasal delivery of EdU demonstrates that accessory olfactory ensheathing cells respond to injury by proliferation.

Olfactory ensheathing cells (OECs) play an important role in the continuous regeneration of the primary olfactory nervous system throughout life and for regeneration of olfactory neurons after injury. While it is known that several individual OEC subpopulations with distinct properties exist in different anatomical locations, it remains unclear how these different subpopulations respond to a major injury. We have examined the proliferation of OECs from one distinct location, the peripheral accessory olfactory nervous system, following large-scale injury (bulbectomy) in mice. We used crosses of two transgenic reporter mouse lines, S100ß-DsRed and OMP-ZsGreen, to visualise OECs, and main/accessory olfactory neurons, respectively. We surgically removed one olfactory bulb including the accessory olfactory bulb to induce degeneration, and found that accessory OECs in the nerve bundles that terminate in the accessory olfactory bulb responded by increased proliferation with a peak occurring 2 days after the injury. To label proliferating cells we used the thymidine analogue ethynyl deoxyuridine (EdU) using intranasal delivery instead of intraperitoneal injection. We compared and quantified the number of proliferating cells at different regions at one and four days after EdU labelling by the two different methods and found that intranasal delivery method was as effective as intraperitoneal injection. We demonstrated that accessory OECs actively respond to widespread degeneration of accessory olfactory axons by proliferating. These results have important implications for selecting the source of OECs for neural regeneration therapies and show that intranasal delivery of EdU is an efficient and reliable method for assessing proliferation of olfactory glia.