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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., (© 2020 by American Journal of Neuroradiology.)

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., (© 2019 Wiley Periodicals, Inc.)

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) × 10 6 µm 3 /cm 3 and 4.43 ± 0.98 mm 3 in control (Group I); (264 ± 63) × 10 6 µm 3 /cm 3 and 3.86 ± 0.81 mm 3 in SHAM (Group II) and (194 ± 52) × 10 6 µm 3 /cm 3 and 1.52 ± 0.36 mm 3 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.

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.

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 ± 0.32/mm 3 in group I, 3.12 ± 0.20/mm 3 in group II and 2.21 ± 0.15/mm 3 in group III (p < 0.0005 Group III vs. I and II). The mean of PV were estimated as; (9 ± 2) × 10 6  µm 3 /cm 3 in Group-I, (12 ± 3) × 10 6  µm 3 /cm 3 in Group-II; and (23 ± 4) × 10 6  µm 3 /cm 3 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

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.

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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 &plusmn; 0.9 nm and &zeta;-potential of +15.2 &plusmn; 0.3 mV. IRB concentration of 15 &micro;g/mL was injected with SPIONs into MSCs, as cell viability significantly decreased when 20 &mu;g/mL was used ( p &le; 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.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.

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., (© 2016 S. Karger AG, Basel.)

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., (Copyright © 2016. Published by Elsevier B.V.)

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ 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 Aβ 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.

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 S100β-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., (© 2014 Wiley Periodicals, Inc.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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), β-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.

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.

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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Brain deterioration resulting from "protein folding" diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-β (Aβ) peptide and, in the case of 5XFAD mice, reduces Aβ plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed.

The microscopic organization of the piriform cortex (PC) was studied in normal and experimental material from adult albino rats. In rapid-Golgi specimens a set of collaterals from the lateral olfactory tract (i.e., sublayer Ia) to the neuropil of the Layer II (LII) was identified. Specimens from experimental animals that received electrolytic lesion of the main olfactory bulb three days before sacrificing, were further processed for pre-embedding immunocytochemistry to the enzyme glutamic acid decarboxylase 67 (GAD 67). This novel approach permitted a simultaneous visualization at electron microscopy of both synaptic degeneration and GAD67-immunoreactive (GAD-I) sites. Degenerating and GAD-I synapses were separately found in the neuropil of Layers I and II of the PC. Previously overlooked patches of neuropil were featured in sublayer Ia. These areas consisted of dendritic and axonal processes including four synaptic types. Tridimensional reconstructions from serial thin sections from LI revealed the external appearance of the varicose and tubular dendrites as well as the synaptic terminals therein. The putative source(s) of processes to the neuropil of sublayer Ia is discussed in the context of the internal circuitry of the PC and an alternative model is introduced., (Copyright © 2013 Wiley Periodicals, Inc.)

The removal of bilateral olfactory bulbs (OBs) can result in serious behavioral, neurochemical, neuroendocrine, and neuroimmune alterations in depressed patients. However, there is little information on how olfactory bulbectomy (OBX) leads to depression. Habenular nuclei and their connections are important in the regulation of psychomotor and psychosocial behaviors through afferent impulses of the olfactory system. Therefore, we investigated whether OB lesions lead to habenular degeneration. We used a sample of 50 rats (25 female and 25 male) for this study. Of these rats, five male and five female rats were taken as the control group. The remaining 40 rats (20 male and 20 female rats) constituted the study group, and frontal burr holes were performed at the OB level on these rats. OB cauterization was applied to 10 male and 10 female rats (n=10, 10; study group 1), mechanical OBX was applied to five male and five female rats (n=5, 5; study group 2), and no procedure was performed on the remaining 10 rats (n=5, 5). The psychomotor movements; pregnancy rates; and sexual, feeding, maternal, social, and grooming behaviors for both study groups were observed daily for 3 months. Their OBs, olfactory cortices, and habenular complexes were examined using stereological methods. All of the animals in the study groups, especially in the cauterization group, demonstrated anorexia, nutritional disorders, weight loss, psychomotor retardation, sexual aversion, decreased grooming behavior, and reduced social interaction similar to depression symptoms. As compared to the control group, the pregnancy rates, number of offspring per mother rat, and birth weights in the study groups were lower, whereas the number of stillbirths was higher. Gross anatomical examinations revealed that the OBs of all of the animals in the study groups were atrophied. Histopathological examinations detected prominent neuronal loss due to apoptosis in the habenular structures in the study groups. We detected a relationship between a decreased healthy neuronal density of the habenula and depressive symptomatology in rats with OBX. We suggest that olfaction disorders might cause neuropsychiatric disorders by affecting neuronal degeneration in habenular nuclei., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Secreted protein acidic rich in cysteine (SPARC) is a matricellular protein that modulates the activity of growth factors, cytokines, and extracellular matrix to play multiple roles in tissue development and repair, such as cellular adhesion, migration, and proliferation. Throughout the CNS, SPARC is highly localized in mature ramified microglia, but its role in microglia--in development or during response to disease or injury--is not understood. In the postnatal brain, immature amoeboid myeloid precursors only induce SPARC expression after they cease proliferation and migration, and transform into mature, ramified resting microglia. SPARC null/CX3CR1-GFP reporter mice reveal that SPARC regulates the distribution and branching of mature microglia, with significant differences between cortical gray and white matter in both controls and SPARC nulls. Following ischemic and excitotoxic lesion, reactive, hypertrophic microglia rapidly downregulate and release SPARC at the lesion, concomitant with reactive, hypertrophic perilesion astrocytes upregulating SPARC. After photothrombotic stroke in the forelimb sensorimotor cortex, SPARC nulls demonstrate enhanced microgliosis in and around the lesion site, which accompanies significantly enhanced functional recovery by 32 d after lesion. Microglia from SPARC nulls also intrinsically proliferate at a greater rate in vitro--an enhanced effect that can be rescued by the addition of exogenous SPARC. SPARC is thus a novel regulator of microglial proliferation and structure, and, in addition to regulating glioma progression, may play an important role in differently regulating the gray and white matter microglial responses to CNS lesion--and modulating behavioral recovery--after injury.

Introduction: Unconsciously detected chemicals may affect human behaviour (Kirk-Smith et al., 1983; Stern and McClintock, 1998; Zucco et al., 2009), likeability judgements (Li et al., 2007) and brain activity (Lorig et al., 1990; Sobel et al., 1999). No studies, however, have investigated blind smell - the hypothetical olfactory counterpart of blindsight (Weiskrantz et al., 1974)., Methods: In this report, free and cued olfactory identification of suprathreshold odorants varying in irritancy (i.e., low or no irritant odours versus irritant odours), and taste identification abilities, were examined in patient MB who had undergone surgery for a meningioma. Post-operative imaging revealed encephalomalacia in the left gyrus rectus, with ablation of the left olfactory bulb and damage to the right, subcortical abnormality on the left near the orbital cortex, and damage to a small section of the right gyrus rectus., Results: On free identification MB, while denying a capacity to smell the odours, still correctly identified some and detected others significantly above chance. In contrast, awareness always accompanied correct detections of irritant odours. Cued odour identification was at chance and no taste impairments were observed., Conclusions: We suggest, tentatively, that MB's unusual pattern of awareness when detecting and identifying odours relative to irritant odours may represent an example of 'blind smell'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The olfactory system is a useful model for studying central nervous system recovery from damage due to its neuroplasticity. We recently developed a novel method of deafferentation by repeated exposure of Triton X-100 to the olfactory organ of adult zebrafish. This long-term, reversible method of deafferentation allows both degeneration and regeneration to be observed in the olfactory bulb. The aim of the present study is to examine olfactory bulb innervation, glomerular patterns, and olfactory-mediated behavior with repeated Triton X-100 treatment and the potential for recovery following cessation of treatment. Olfactory bulbs of control, chronic-treated, and recovery animals were examined for the presence or absence of glomeruli that have been identified in the zebrafish glomerular map. Following chronic treatment, the number of glomeruli was dramatically reduced; however, partial innervation remained in the lateral region of the bulb. When animals were given time to recover, complete glomerular distribution returned. A behavioral assay was developed to determine if innervation remaining correlated with behavior of the fish. Chronic-treated fish did not respond to odorants involved with social behavior but continued to react to odorants that mediate feeding behavior. Following recovery, responses to odorants involved with social behavior returned. The morphological and behavioral effects of chronic Triton X-100 treatment in the olfactory system suggest there may be differential susceptibility or resistance to external damage in a subset of sensory neurons. The results of this study demonstrate the remarkable regenerative ability of the olfactory system following extensive and long-term injury., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cyclooxygenase-2 (COX-2) is thought to play a role in the pathogenesis of various neurodegenerative disorders. However, clinical trials with COX-2 inhibitors have yielded contradictory results. In the present study we investigated whether COX-2 plays a role in the behavioral and cognitive impairments seen in olfactory bulbectomized rats. These impairments arise from neurodegenerative processes. First, we determined the time course of the OBX-induced behavioral (hyperactivity) and cognitive changes (fear memory) and how these correlate with changes in COX-2 mRNA expression in hippocampus. This experiment showed that the major impairments in behavior and cognition developed between Days 3 and 14 after OBX surgery, which correlated with changes in mRNA levels of COX-2, which increased at Days 7 and 14 after surgery but not anymore at day 28. In a subsequent experiment, rats were treated, starting two days before surgery, with the COX-2 inhibitor celecoxib (10 mg/kg, dissolved in drinking water) for 4 weeks. OBX-induced hyperactivity in the open field was normalized after 2 weeks of celecoxib treatment, but not longer after 4 weeks. Celecoxib partly rescued fear learning and memory deficits without affecting spatial memory. The effects of celecoxib on fear memory lasted up to 1 week posttreatment, but disappeared thereafter. Our results show that COX-2 plays a limited role (both in magnitude and time) in the development of the OBX syndrome., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Conclusions: The olfactory and intranasal trigeminal systems are closely connected. With regard to intranasal trigeminal event-related potential (ERP), patients with olfactory dysfunction (OD) showed longer latency and lower amplitude, which indicated decreased trigeminal sensitivity. Different age, etiology, and olfactory status also affect trigeminal sensitivity differently., Objective: OD is a common symptom in the rhinology clinic. ERP is considered an important method to evaluate chemosensitivity. The aim of this study was to investigate changes of intranasal trigeminal sense in patients with postviral OD (PVOD) and post-traumatic OD (PTOD)., Methods: A total of 96 participants (30 healthy adults and 66 patients with OD) aged 20-65 years were investigated. The T&T olfactometer, the Sniffin' Sticks olfactory test, and trigeminal ERPs (tERPs) were used. We evaluated trigeminal sensitivity influenced by different factors (age, etiology, and olfactory status) in healthy subjects with normal olfactory function and in patients with PVOD and PTOD., Results: Patients with OD showed higher trigeminal thresholds than normal controls. Compared with controls, N1/P2 latencies of tERPs increased and amplitudes decreased in patients with OD. Older subjects showed longer latencies and lower amplitudes than young subjects in both controls and the OD group. Patients with PTOD exhibited worse psychophysical olfactory function and decreased trigeminal sensitivity.

In mammals, olfactory bulb granule cells (GCs) are generated throughout life in the subventricular zone. GABAergic inputs onto newborn neurons likely regulate their maturation, but the details of this process remain still elusive. Here, we investigated the differentiation, synaptic integration, and survival of adult-born GCs when their afferent GABAergic inputs are challenged by conditional gene targeting. Migrating GC precursors were targeted with Cre-eGFP-expressing lentiviral vectors in mice with a floxed gene encoding the GABA(A) receptor α2-subunit (i.e., Gabra2). Ablation of the α2-subunit did not affect GC survival but dramatically delayed their maturation. We found a reduction in postsynaptic α2-subunit and gephyrin clusters accompanied by a decrease in the frequency and amplitude of GABAergic postsynaptic currents beginning ∼14 d post-injection (dpi). In addition, mutant cells exhibited altered dendritic branching and spine density. Spine loss appeared with mislocation of glutamatergic synapses on dendritic shafts and a reduction of spontaneous glutamatergic postsynaptic currents, underscoring the relevance of afferent GABAergic transmission for a proper synaptic integration of newborn GCs. To test the role of GABAergic signaling during much early stages of GC maturation, we used a genetic strategy to selectively inactivate Gabra2 in precursor cells of the subventricular zone. In these mice, labeling of newborn GCs with eGFP lentiviruses revealed similar morphological alterations as seen on delayed Gabra2 inactivation in migrating neuroblasts, with reduced dendritic branching and spine density at 7 dpi. Collectively, these results emphasize the critical role of GABAergic synaptic signaling for structural maturation of adult-born GCs and formation of glutamatergic synapses.

Olfactory ensheathing cells (OECs) support the regeneration of olfactory sensory neurons throughout life, however, it remains unclear how OECs respond to a major injury. We have examined the proliferation and migration of OECs following unilateral bulbectomy in postnatal mice. S100ß-DsRed and OMP-ZsGreen transgenic mice were used to visualize OECs and olfactory neurons, respectively, and we used the thymidine analogue ethynyl deoxyuridine (EdU) to identify cells that were proliferating at the time of administration. Following unilateral bulbectomy, there was an initial phase of OEC proliferation throughout the olfactory pathway with a peak of proliferation occurring 2 to 7 days after the injury. A second phase of proliferation also occurred in which precursors localized within the olfactory mucosa divided to replenish the OEC population. We then tracked the positions of OECs that had proliferated and found that there was a progressive increase in OECs in the cavity for at least 12 to 16 days after injury which could not be accounted for solely by local proliferation of OECs within the cavity. These results suggest that OECs migrated from the peripheral olfactory nerve to populate the mass of cells that filled cavity left by bulbectomy. Our results demonstrate that following injury to the olfactory nervous system, the OEC population is replenished by migration of cells that arise from both local proliferation of OECs throughout the olfactory nerve pathway as well as from precursor cells in the olfactory mucosa., (Copyright © 2011 Wiley Periodicals, Inc.)

Permanent olfactory dysfunction can often arise after traumatic brain injury (TBI) and while one of the main causes is the immediate loss of neurons in the olfactory bulb (OB), the emergent neuroinflammatory environment following TBI may further promote OB deterioration. Therefore, we examined the effects of acute anti-inflammatory treatment with minocycline on post-TBI olfactory behavior and on OB surface. The mouse model of closed-head injury by mechanical percussion was applied to anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h, and 9 h (45 mg/kg) post-TBI. An olfactory avoidance test was run up to 12 weeks post-TBI. The mice were then sacrificed and their OB surface was measured. Our results demonstrated a post-TBI olfactory behavior deficit that was significant up to at least 12 weeks post-TBI. Additionally, substantial post-TBI OB atrophy was observed that was strongly correlated with the behavioral impairment. Minocycline was able to attenuate both the olfactory lesions and corresponding functional deficit in the short and long term. These results emphasize the potential role of minocycline as a promising neuroprotective agent for the treatment of TBI-related olfactory bulb lesions and deficits.

In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Depression, especially in the elderly, is associated with poor cognitive functioning. Exercise has received much attention in the treatment for depression and also dementia. Here we studied the effect of an enriched environment combined with voluntary exercise (EE/VE) on the olfactory bulbectomized (OBX) rat. The OBX rat is hyperactive in an open field, which is normalized by chronic antidepressant treatment, and suffers from learning and memory impairments. Neurotrophic factors are thought to be involved in the antidepressant action of EE/VE. Hyperactivity and cognitive functioning (both hippocampal dependent and independent tasks) were investigated before and after EE/VE. We quantified hippocampal mRNA levels of the neurotrophic factors BDNF, VGF and VEGF. VEGF receptor (FLK-1) inhibition was achieved by i.c.v administration of the antagonist SU5416 during the period of EE/VE. OBX almost completely blocked fear memory acquired either 48 h or 28 days before surgery. EE/EV normalized OBX-induced hyperactivity in open field, while having no effect on the decrease in hippocampal dependent learning and memory. VEGF mRNA levels in hippocampus were significantly increased both in OBX and control rats following EE/VE. OBX reduced BDNF mRNA levels, but EE did not reverse this. Inhibition of the FLK-1 receptor did not suppress EE/VE induced normalization of the hyperactivity of the OBX rat. The lack of effect of EE/VE on cognitive parameters, while normalizing hyperactivity, suggests different neuronal mechanisms underlying OBX-induced behavioral changes. Since EE/VE still normalizes the OBX-induced hyperactivity while the FLK-1 receptor was blocked, we assume that VEGF is not obligatory for the antidepressant effect of EE/VE. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Despite the evidence that exercise improves cognitive behavior in animal models, little is known about these beneficial effects in animal models of pathology. We examined the effects of activity wheel (AW) running on contextual fear conditioning (CFC) and locomotor/exploratory behavior in the olfactory bulbectomy (OBX) model of depression, which is characterized by hyperactivity and changes in cognitive function. Twenty-four hours after the conditioning session of the CFC protocol, the animals were tested for the conditioned response in a conditioned and a novel context to test for the effects of both AW and OBX on CFC, but also the context specificity of the effect. OBX reduced overall AW running behavior throughout the experiment, but increased locomotor/exploratory behavior during CFC, thus demonstrating a context-dependent effect. OBX animals, however, displayed normal CFC behavior that was context-specific, indicating that aversively conditioned memory is preserved in this model. AW running increased freezing behavior during the testing session of the CFC protocol in the control animals but only in the conditioned context, supporting the hypothesis that AW running improves cognitive function in a context-specific manner that does not generalize to an animal model of pathology. Blood corticosterone levels were increased in all animals at the conclusion of the testing sessions, but levels were higher in AW compared to sedentary groups indicating an effect of exercise on neuroendocrine function. Given the differential results of AW running on behavior and neuroendocrine function after OBX, further exploration of the beneficial effects of exercise in animal models of neuropathology is warranted., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Granule cells (GCs) in the mouse olfactory bulb (OB) continue to be generated in adulthood, with nearly half incorporated and the remainder eliminated. Here, we show that elimination of adult-born GCs is promoted during a short time window in the postprandial period. Under restricted feeding, the number of apoptotic GCs specifically increased within a few hours after the start of feeding. This enhanced GC apoptosis occurred in association with postprandial behaviors that included grooming, resting, and sleeping, and was particularly correlated with the length of postprandial sleep. Further, deprivation of olfactory sensory experience in the local OB area potentiated the extent of GC elimination in that area during the postprandial period. Sensory experience-dependent enhancement of GC elimination also occurred during postprandial period under natural feeding condition. These results suggest that extensive structural reorganization of bulbar circuitry occurs during the postprandial period, reflecting sensory experience during preceding waking period., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We previously reported an increase in matrix metalloproteinase-9 (MMP-9) levels in the olfactory bulb immediately after nerve transection; however, its role remains unknown. In this study, we determined the source of MMP-9 by monitoring the infiltration of inflammatory leukocytes in the olfactory bulb after nerve transection. We used myeloperoxidase to identify neutrophils and CD68 to identify macrophages at days 1, 7, and 10. MMP-9 colocalized with neutrophils at all three time points but was not contained in macrophages. This is the first study to demonstrate that MMP-9 is associated with early inflammatory response after olfactory injury, and provides insight into mechanisms underlying olfactory injury and recovery processes.

Damage to the olfactory bulb and tract is a frequently described complication of brain surgery in the frontal region, and it seems to be influenced by the surgical approaches. Eighty cerebral hemispheres and 5 formalin-fixed cadavers filled with colored latex were used. Parameters were directly measured, and after olfactory bulb and tract were mobilized with careful dissections, retraction of the frontal lobe was noted. The anterior border of the olfactory bulb is 22.21 (SD, 5.45) mm posterior to the frontomarginal sulcus, and arachnoidal dissection should be performed parallel to olfactory structures using sharp instruments to allow early visualization. Overall mobilization of the olfactory bulb and tract as 29.3 (SD, 6.4) mm in length is possible without disrupting the structures and enables a greater degree of the frontal-lobe elevation window up to 13.1 (SD, 3.2) mm. Using the morphometric data and anatomic knowledge may prevent unwanted anosmia complication during surgical approaches.

The adult forebrain subventricular zone contains neural stem cells that produce neurons destined for the olfactory bulb, where interneuron populations turnover throughout life. Forebrain injuries can stimulate production of these cells, and re-direct migrating precursors from the olfactory system to areas of damage, where their region-appropriate differentiation and long-term functional integration remain a matter for debate. Paradoxically, little is known about the ability of these progenitors to replace olfactory neurons lost to injury. Their innate capacity to generate bulb neurons may give them an advantage in this regard, and using injections of N-methyl-d-aspartate to kill mature olfactory bulb neurons, combined with bromodeoxyuridine labeling to monitor the fate of adult-born cells, we investigated the potential for injury-induced neurogenesis in this system. Widespread degeneration of bulb neurons did not affect the rate of cell proliferation in the subventricular zone, or cause neuroblasts to divert from their normal migratory route. However migration was slowed by the injury, leading to the accumulation and differentiation of neuroblasts as NeuN+ cells in the rostral migratory stream within 2 weeks of their birth. Despite this, a subset of new neurons successfully invaded the damaged bulb tissue, where they expressed neuronal markers including NeuN, calretinin, GABA, and tyrosine hydroxylase, with some surviving here for as long as 6 months. To test for functional integration of cells born post-injury, we also performed smaller NMDA lesions in restricted portions of the bulb granule cell layer and observed adult-born NeuN+ cells in these areas within 5 weeks, and BrdU+ cells that expressed the immediate-early gene c-fos following odor stimulation. These data suggest that the normal neurogenic capacity of the adult subventricular zone can be adapted to replace subsets of olfactory neurons lost to injury., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Several members of the fibroblast growth factor (FGF) family have been shown to be dysregulated in individuals with major depression, and treatment with antidepressants has been reported to increase FGF-2 mRNA levels in the forebrain., Methods: We have used the tail suspension test (TST), and olfactory bulbectomy (OBX), and FGF-2 deficient mice to investigate putative roles of FGF-2 as an antidepressant and mediator of antidepressive drug actions., Results: FGF-2 applied intraventricularly generated antidepressant-like effects in the TST. FGF-2, similar to the antidepressant amitriptyline, attenuated neuron demise in the piriform cortex and posterolateral cortical nucleus of the amygdala following OBX. Moreover, OBX induced reduction in hippocampal neurogenesis could be ameliorated by subsequent treatment with either amitriptyline or FGF-2. Furthermore, FGF-2 was effective in reversing depressive-like behavior induced by OBX, monitored in the locomotor activity and the passive avoidance test. In bulbectomized FGF-2 deficient mice, treatment with amitriptyline protected neurons, but failed to reverse behavioral alterations., Conclusions: Together, these results suggest that FGF-2 constitutes both a potential target for antidepressive treatments and an important growth factor in the cytokine network underlying the actions of antidepressive drugs. The results further suggest a requirement of endogenous FGF-2 for mediating behavioral, but not neuroprotective actions of amitriptyline.

Altered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomized (OB) and the Wistar-Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to sham-operated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and von Frey tests did not differ between WKY and Sprague-Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 min post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

It has been suggested by studies in animals and humans that substance P (SP) and its receptor neurokinin 1 (NK1R) play an important role in the pathology of depression. The pharmacological blockade or genetic deletion of the NK1 receptor, or the substance P coding gene tac1 led to a decreased emotionality and a reduction of depression-related behaviours in different animal models. In order to characterize molecular changes associated with reduced SP-NK1 signalling in animal models of depression, we assessed the regulation of the CRH system. First, tac1(-/-) animals and tac1(+/+) controls were subjected to bulbectomy, which induces physiological and behavioural changes that are relevant to depression. We demonstrate that tac1(-/-) animals, in contrast to tac1(+/+) controls, do not show anhedonia in the saccharine preference test after bulbectomy. Next, we studied expression levels of CRH, the receptors CRHR1 and CRHR2, and the binding protein CRHBP in the cortex and paraventricular nucleus using real-time RT-PCR. Our results show a strong induction of CRH, CRHBP and CRHR1 expression in the cortex of tac1(-/-), but not in tac1(+/+) animals. In the PVN, bulbectomized tac1(-/-) mice showed an elevated expression of CRHR1 and CRHR2. These results show that substance P/NKA is involved in modulating CRH signalling in an animal model of depression., ((c) 2010 Elsevier B.V. All rights reserved.)

The olfactory bulbectomized (OBX) rat model is an animal model of depression. The deregulation of the serotonergic (5-HT) system is implicated in the pathophysiology of depression. Buspirone is a partial agonist of 5-HT(1A) receptors and is used in the treatment of depression and anxiety. The aim of this study was to assess, in OBX rats and sham operated controls, the effect of chronic buspirone treatment on the densities of 5-HT(2A) and 5-HT(1B) receptors, as well as the 5-HT transporter (5-HTT), which are all important mediators of 5-HT transmission. Male Sprague-Dawley rats (180-240 g) were used. Two weeks following the surgeries, the rats were assigned into the saline or treatment groups, receiving either saline, or 10 or 20 mg/kg day of buspirone, for 2 weeks by subcutaneous mini pump. Following the treatment, the rats were sacrificed. The autoradiographic experiments were performed ex vivo using [(3)H]5-HT for the 5-HT(1B) receptors, [(3)H]-ketanserin for the 5-HT(2A) receptors, and [(3)H]-paroxetine for the 5-HTT binding. The receptors and 5-HTT densities were quantified in 38 brain regions as well as the pineal body. Chronic treatment with buspirone produced the following: 1) a decrease in the 5-HT(1B) densities, which was more pronounced in the Sham rats; 2) an increase in the 5-HT(2A) receptor densities, which was more pronounced in the Sham rats; and 3) an decrease in 5-HTT densities in both groups. The results indicate differential effects of chronic antidepressant treatment on the 5-HT system regulation in the OBX model of depression and normal rats., (Copyright 2010 Elsevier B.V. All rights reserved.)

In adults, the subventricular zone is known to contain undifferentiated neural progenitor cells that proliferate and generate the olfactory bulb (OB) interneurons throughout life. We earlier showed that trimethyltin (TMT) causes neuronal damage in the granular cell layer of the OB in adult mice. In the current study, we examined neurogenesis in the OB in adult mice after injury induced by acute treatment with TMT. On day 2 post-TMT treatment, enhanced incorporation of 5-bromo-2'-deoxyuridine (BrdU) was seen in the granular cell layer of the OB. Many of the BrdU-labeled cells were undifferentiated cells on day 2 post-treatment. On day 30 post-TMT treatment, BrdU-labeled neuronal cells were dramatically increased in number in the granular cell layer of the OB. However, TMT treatment was ineffective in affecting the migration of BrdU-labeled cells from the subventricular zone to the OB. The results of a neurosphere assay revealed that the number of neurospheres derived from the OB was significantly increased on day 2 post-TMT treatment. The neurosphere-forming neural progenitor cells derived from the OB of TMT-treated animals were capable of differentiating into neuronal cells as well as into astrocytes. Taken together, our data suggest that the OB has the ability to undergo enhanced neurogenesis following TMT-induced neuronal injury in adult mice., ((c) 2009 Wiley-Liss, Inc.)

Affective startle modulation is used to study emotional reactivity in humans, and blunted affective startle modulation has been reported in depressed patients. To determine whether blunted affective startle modulation is also a common feature in animal models for affective disorders, light-enhanced startle was studied in three models: inescapable foot shock (IFS), repeated restraint stress (RRS) and olfactory bulbectomy (OBX). In addition, prepulse inhibition was studied in these models. Light-enhanced startle was blunted following IFS and OBX and RRS decreased overall startle responding. Prepulse inhibition, however, was unaffected. These findings indicate that induction models for affective disorders may be associated with long term effects on affective startle modulation. The lack of changes in sensory motor gating suggests that these changes can be ascribed to alterations in emotional reactivity. In conclusion, our results indicate that the blunted affective startle modulation seen in animal models for affective disorders may be used to examine the mechanisms underlying altered emotional reactivity., (Copyright 2009 Elsevier B.V. All rights reserved.)

This is the first description of a population of Iba1- and annexin A3-immunopositive cells residing in the peripheral olfactory nerves of adult rats and adult cats. Based on their ramified appearance, positive immunostaining for the monocytic markers Iba1 and annexin A3, and reactivity to bulbectomy (in adult rats), these cells found within the olfactory nerve fascicles of both mammalian species meet several important criteria for their designation as microglia/macrophages. These Iba1-/annexin A3-immunopositive cells may be uniquely positioned to protect against the potential spread of dangerous environmental xenobiotics (such as viruses and toxins) into the brain, where such pathogens may contribute to the development of neurological diseases, such Alzheimer's and Parkinson's diseases.

Objective: This study investigated olfactory dysfunction after using a contralateral or ipsilateral pterional approach for anterior circulation aneurysms and related risk factors., Methods: This study included 189 patients who experienced an aneurysmal subarachnoid hemorrhage and in whom a pterional approach was used, including a contralateral pterional approach (12 patients), a pterional approach for an anterior communicating artery (AComA) aneurysm (70 patients), and an ipsilateral pterional approach for aneurysms of the anterior circulation, excluding the AComA (107 patients). In addition to questionnaires on olfactory function, Sniffin' Sticks tests were performed 12 to 38 months after the operation., Results: The incidence of olfactory dysfunction was high: 58% (7 of 12) with a contralateral pterional approach, 14% (10 of 70) with a pterional approach for an AComA aneurysm, and 4% (4 of 107) with an ipsilateral pterional approach for aneurysms of the anterior circulation, except for the AComA. In addition, patients 55 years and older had a higher incidence of olfactory dysfunction. Among the 12 patients in whom the contralateral pterional approach was used, 5 (42%) were anosmic and 2 (17%) were hyposmic. The incidence of olfactory dysfunction was also significantly higher at ages 55 years and older. The size and location of the contralateral aneurysm, if small (<1 cm) and located within a 3-cm lateral distance from the midline, were not found to influence the incidence., Conclusion: A higher incidence of olfactory dysfunction was found in those patients in whom a contralateral pterional approach and a pterional approach for an AComA aneurysm were used. Another major risk factor was an age of 55 years and older.

Differentiated olfactory sensory neurons express specific presynaptic proteins, including enzymes involved in neurotransmitter transport and proteins involved in the trafficking and release of synaptic vesicles. Studying the regulation of these presynaptic proteins will help to elucidate the presynaptic differentiation process that ultimately leads to synapse formation. It has been postulated that the formation of a synapse between the axons of the sensory neurons and the dendrites of second order neurons in the olfactory bulb is a critical step in the processes of sensory neuron maturation. One approach to study the relationship between synaptogenesis and sensory neuron maturation is to examine the expression patterns of synaptic molecules through the olfactory neuron lineage. To this end we designed specific in situ hybridization probes to target messengers for proteins involved in presynaptic vesicle release. Our findings show that, as they mature, mouse olfactory neurons sequentially express specific presynaptic genes. Furthermore, the different patterns of expression of these presynaptic genes suggest the existence of discrete steps in presynaptic development: genes encoding proteins involved in scaffolding show an early onset of expression, whereas expression of genes encoding proteins involved in the regulation of vesicle release starts later. In particular, the signature molecule for glutamatergic neurons vesicle glutamate transporter 2 shows the latest onset of expression. In addition, contact with the targets in the olfactory bulb is not controlling presynaptic protein gene expression, suggesting that olfactory sensory neurons follow an intrinsic program of development.

To investigate factors that influence the degree of neural regeneration and recovery, we studied 2 olfactory nerve injury models. Transection of the olfactory nerves along the surface of the olfactory bulb was performed in OMP-tau-lacZ mice using either a flexible Teflon blade (mild injury) or a stainless steel blade (severe injury). Histological assessment of recovery within the olfactory bulb was made at 5, 14, and 42 days after injury. We used X-gal staining to label the degenerating and regenerating olfactory nerve fibers and immunohistochemical staining to detect the presence of reactive astrocytes and macrophages. Areas of injury-associated tissue were significantly smaller in the mild injury model, and at 42 days, the regenerated nerves had reestablished connections to the glomerular layer of the bulb. With severe injury, there were larger areas of injury-associated tissue, more astrocytes and macrophages, and a decrease in regenerated nerve fibers. When dexamethasone (DXM) was injected after severe injury, there was a significant reduction in injury-associated tissue, better nerve recovery, and fewer astrocytes and macrophages. These results demonstrate that recovery in the olfactory system varies with the severity of injury and that DXM treatment may have therapeutic value by reducing injury-associated tissue and improving recovery outcome.

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

Rationale: Anhedonia, or hyposensitivity to normally pleasurable stimuli, is a cardinal symptom of depression. As such, reward circuitry may comprise a substrate with relevance to this symptom of depression., Objectives: Our aim was to characterize in the rat changes in the rewarding properties of a pharmacological and a natural stimulus following olfactory bulbectomy (OBX), a pre-clinical animal model of depression., Methods: We measured amphetamine enhancement of brain stimulation reward, changes in sucrose intake, as well as striatal cAMP response element binding protein (CREB) activity, a molecular index previously associated with depressant-like behavior. Moreover, since alteration of psychomotor activity is also a common symptom of depression, and psychostimulant reward and locomotion are thought to share common neurobiology, we used the same treatment schedule of amphetamine to probe for changes in locomotion., Results: Our findings show that OBX produces a behavioral phenotype characterized by both anhedonia and exaggerated locomotor activation. Thus, we observed a blunted response to the rewarding properties of amphetamine (1 mg/kg, 21 days post-lesion), a long-lasting reduction in sucrose intake and increased striatal CREB activity. In addition, the same dose of amphetamine, at a coincident time post-lesion, triggered an exaggerated response to its locomotor-stimulant actions., Conclusions: These paradoxical findings are not consistent with the notion that reward and locomotion are mediated by a common substrate; this dissociation may be useful in modeling psychiatric disorders such as mixed depressive states. In addition, our findings suggest that central reward circuitry may constitute a possible target for rationally designed therapeutics for depression.

Aberrant behaviors related to learning and memory in olfactory bulbectomized (OBX) mice have been documented in the previous studies. We reported that the impairment of long-term potentiation (LTP) of hippocampal CA1 regions from OBX mice was associated with down-regulation of CaM kinase II (CaMKII) and protein kinase C (PKC) activities. We now demonstrated that the nootropic drug, nefiracetam, significantly improved spatial reference memory-related behaviors as assessed by Y-maze and novel object recognition task in OBX mice. Nefiracetam also restored hippocampal LTP injured in OBX mice. Nefiracetam treatment restored LTP-induced PKCalpha (Ser657) and NR1 (Ser896) phosphorylation as well as increase in their basal phosphorylation in the hippocampal CA1 region of OBX mice. Likewise, nefiracetam improved LTP-induced CaMKIIalpha (Thr286) autophosphorylation and GluR1 (Ser831) phosphorylation and increased their basal phosphorylation. The enhancement of PKCalpha (Ser657) and CaMKIIalpha (Thr286) autophosphorylation by nefiracetam was inhibited by treatment with (+/-)-alpha-Methyl-(4-carboxyphenyl)glycine and DL-2-Amino-5-phosphonovaleric acid, respectively. The enhancement of LTP induced by nefiracetam is inhibited by treatment with 2-methyl-6-(phenylethynyl)-pyridine, but not by treatment with LY367385, suggesting that metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement. Taken together, nefiracetam ameliorates OBX-induced deficits in memory-related behaviors and impairment of LTP in the hippocampal CA1 region through activation of NMDAR and mGluR5, thereby leading to an increase in activities of CaMKIIalpha (Thr286) and PKCalpha (Ser657), respectively.