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PubMed1991

Olfactory dysfunction in Parkinson's disease.

An olfactory function test in 18 patients with Parkinson's disease (PD) and 10 age-matched control subjects was performed. Both detection and recognition thresholds were measured with five kinds of synthesized odorants (T & T olfactometry). Before each test, rhinoscopic inspections were performed to exclude subjects who could have respiratory hyposmia. Both detection and recognition thresholds in patients with PD were significantly elevated in comparison with those of control subjects. Auditory acuity of PD patients, however, was well preserved and there was no significant correlation between auditory and olfactory threshold. On the basis of the present study, the authors conclude that olfactory dysfunction is one of the characteristic symptoms of PD and it may be attributed to lesions in the olfactory neural pathway including olfactory neuroepithelium.

Adult↗
PubMed2005

Distinct types of glial cells populate the Drosophila antenna.

BACKGROUND: The development of nervous systems involves reciprocal interactions between neurons and glia. In the Drosophila olfactory system, peripheral glial cells arise from sensory lineages specified by the basic helix-loop-helix transcription factor, Atonal. These glia wrap around the developing olfactory axons early during development and pattern the three distinct fascicles as they exit the antenna. In the moth Manduca sexta, an additional set of central glia migrate to the base of the antennal nerve where axons sort to their glomerular targets. In this work, we have investigated whether similar types of cells exist in the Drosophila antenna. RESULTS: We have used different P(Gal4) lines to drive Green Fluorescent Protein (GFP) in distinct populations of cells within the Drosophila antenna. Mz317::GFP, a marker for cell body and perineural glia, labels the majority of peripheral glia. An additional approximately 30 glial cells detected by GH146::GFP do not derive from any of the sensory lineages and appear to migrate into the antenna from the brain. Their appearance in the third antennal segment is regulated by normal function of the Epidermal Growth Factor receptor and small GTPases. We denote these distinct populations of cells as Mz317-glia and GH146-glia respectively. In the adult, processes of GH146-glial cells ensheath the olfactory receptor neurons directly, while those of the Mz317-glia form a peripheral layer. Ablation of GH146-glia does not result in any significant effects on the patterning of the olfactory receptor axons. CONCLUSION: We have demonstrated the presence of at least two distinct populations of glial cells within the Drosophila antenna. GH146-glial cells originate in the brain and migrate to the antenna along the newly formed olfactory axons. The number of cells populating the third segment of the antenna is regulated by signaling through the Epidermal Growth Factor receptor. These glia share several features of the sorting zone cells described in Manduca.

Animals↗
PubMed2006

Male pheromone protein components activate female vomeronasal neurons in the salamander Plethodon shermani.

BACKGROUND: The mental gland pheromone of male Plethodon salamanders contains two main protein components: a 22 kDa protein named Plethodon Receptivity Factor (PRF) and a 7 kDa protein named Plethodon Modulating Factor (PMF), respectively. Each protein component individually has opposing effects on female courtship behavior, with PRF shortening and PMF lengthening courtship. In this study, we test the hypothesis that PRF or PMF individually activate vomeronasal neurons. The agmatine-uptake technique was used to visualize chemosensory neurons that were activated by each protein component individually. RESULTS: Vomeronasal neurons exposed to agmatine in saline did not demonstrate significant labeling. However, a population of vomeronasal neurons was labeled following exposure to either PRF or PMF. When expressed as a percent of control level labeled cells, PRF labeled more neurons than did PMF. These percentages for PRF and PMF, added together, parallel the percentage of labeled vomeronasal neurons when females are exposed to the whole pheromone. CONCLUSION: This study suggests that two specific populations of female vomeronasal neurons are responsible for responding to each of the two components of the male pheromone mixture. These two neural populations, therefore, could express different receptors which, in turn, transmit different information to the brain, thus accounting for the different female behavior elicited by each pheromone component.

Animals↗
PubMed2001

Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that is important in the regulation of energy homeostasis. MCH signals via a seven-transmembrane G protein-coupled receptor, which is coupled to Galpha(i). This receptor was initially cloned in rat and human and designated SLC-1 because of its homology to the somatostatin receptor. In rat brain, it is expressed in a pattern that mirrors the previously described pattern of projections of MCH-immunoreactive fibers. In the present study we cloned the mouse MCH receptor (MCH-R) ortholog by a rapid amplification of 5'- and 3'-cDNA ends approach and have found it to be 98% homologous with the rat sequence. We have characterized MCH-R messenger RNA distribution in the mouse brain by in situ hybridization and have shown MCH-R to be expressed in diverse brain areas implicated in the regulation of feeding, body adiposity, and sensory integration of smell and gustatory inputs, including the hypothalamus [paraventricular nucleus (magnocellular part) and dorsomedial, ventromedial, and arcuate nucleus], areas of the olfactory pathway, and the nucleus of the solitary tract. We also studied MCH-R regulation and found that MCH-R expression is increased 7-fold by 48-h fasting or genetic leptin deficiency (ob/ob mice) and is completely blunted by leptin administration. In contrast, MCH-R messenger RNA expression remains unaltered in genetic MCH deficiency. Our findings suggest that MCH-R constitutes a central target of leptin action in the mammalian brain.

Amino Acid Sequence↗
PubMed2004

Is nose-to-brain transport of drugs in man a reality?

The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.

Administration, Intranasal↗
PubMed2003

Differential function of RNCAM isoforms in precise target selection of olfactory sensory neurons.

Olfactory sensory neurons (OSNs) are individually specified to express one odorant receptor (OR) gene among approximately 1000 different and project with precision to topographically defined convergence sites, the glomeruli, in the olfactory bulb. Although ORs partially determine the location of convergence sites, the mechanism ensuring that axons with different OR identities do not co-converge is unknown. RNCAM (OCAM, NCAM2) is assumed to regulate a broad zonal segregation of projections by virtue of being a homophilic cell adhesion molecule that is selectively expressed on axons terminating in a defined olfactory bulb region. We have identified NADPH diaphorase activity as being an independent marker for RNCAM-negative axons. Analyses of transgenic mice that ectopically express RNCAM in NADPH diaphorase-positive OSNs show that the postulated function of RNCAM in mediating zone-specific segregation of axons is unlikely. Instead, analyses of one OR-specific OSN subpopulation (P2) reveal that elevated RNCAM levels result in an increased number of P2 axons that incorrectly co-converge with axons of other OR identities. Both Gpi-anchored and transmembrane-bound RNCAM isoforms are localized on axons in the nerve layer, while the transmembrane-bound RNCAM is the predominant isoform on axon terminals within glomeruli. Overexpressing transmembrane-bound RNCAM results in co-convergence events close to the correct target glomeruli. By contrast, overexpression of Gpi-anchored RNCAM results in axons that can bypass the correct target before co-converging on glomeruli located at a distance. The phenotype specific for Gpi-anchored RNCAM is suppressed in mice overexpressing both isoforms, which suggests that two distinct RNCAM isoform-dependent activities influence segregation of OR-defined axon subclasses.

Animals↗
PubMed2005

Developmentally programmed remodeling of the Drosophila olfactory circuit.

Neural circuits are often remodeled after initial connections are established. The mechanisms by which remodeling occurs, in particular whether and how synaptically connected neurons coordinate their reorganization, are poorly understood. In Drosophila, olfactory projection neurons (PNs) receive input by synapsing with olfactory receptor neurons in the antennal lobe and relay information to the mushroom body (MB) calyx and lateral horn. Here we show that embryonic-born PNs participate in both the larval and adult olfactory circuits. In the larva, these neurons generally innervate a single glomerulus in the antennal lobe and one or two glomerulus-like substructures in the MB calyx. They persist in the adult olfactory circuit and are prespecified by birth order to innervate a subset of glomeruli distinct from larval-born PNs. Developmental studies indicate that these neurons undergo stereotyped pruning of their dendrites and axon terminal branches locally during early metamorphosis. Electron microscopy analysis reveals that these PNs synapse with MB gamma neurons in the larval calyx and that these synaptic profiles are engulfed by glia during early metamorphosis. As with MB gamma neurons, PN pruning requires cell-autonomous reception of the nuclear hormone ecdysone. Thus, these synaptic partners are independently programmed to prune their dendrites and axons.

Animals↗
PubMed2002

Olfactory sensitivity to changes in environmental [Ca(2+)] in the freshwater teleost Carassius auratus: an olfactory role for the Ca(2+)-sensing receptor?

Olfactory sensitivity to changes in environmental Ca(2+) has been demonstrated in two teleost species; a salmonid (Oncorhynchus nerka) and a marine/estuarine perciform (Sparus aurata). To assess whether this phenomenon is restricted to species that normally experience large fluctuations in external ion concentrations (e.g. moving from sea water to fresh water) or is present in a much wider range of species, we investigated olfactory Ca(2+) sensitivity in the goldfish (Carassius auratus), which is a stenohaline, non-migratory freshwater cyprinid. Extracellular recording from the olfactory bulb in vivo by electroencephalogram (EEG) demonstrated that the olfactory system is acutely sensitive to changes in external Ca(2+) within the range that this species is likely to encounter in the wild (0.05-3 mmol l(-1)). The olfactory system responded to increases in external calcium with increasing bulbar activity in a manner that fitted a conventional Hill plot with an apparent EC(50) of 0.9+/-0.3 mmol l(-1) (close to both ambient and plasma free [Ca(2+)]) and an apparent Hill coefficient of 1.1+/-0.3 (means +/- S.E.M., N=6). Thresholds of detection were below 50 micro mol l(-1). Some olfactory sensitivity to changes in external [Na(+)] was also recorded, but with a much higher threshold of detection (3.7 mmol l(-1)). The olfactory system of goldfish was much less sensitive to changes in [Mg(2+)] and [K(+)]. Preliminary data suggest that Ca(2+) and Mg(2+) are detected by the same mechanism, although with a much higher affinity for Ca(2+). Olfactory sensitivity to Na(+) may warn freshwater fish that they are reaching the limit of their osmotic tolerance when in an estuarine environment. Olfaction of serine, a potent odorant in fish, was not dependent on the presence of external Ca(2+) or Na(+). Finally, the teleost Ca(2+)-sensing receptor (Ca-SR) was shown to be highly expressed in a subpopulation of olfactory receptor neurones by both immunocytochemistry and in situ hybridisation. The olfactory sensitivity to Ca(2+) (and Mg(2+)) is therefore likely to be mediated by the Ca-SR. We suggest that olfactory Ca(2+) sensitivity is a widespread phenomenon in teleosts and may have an input into the physiological mechanisms regulating internal calcium homeostasis.

Animals↗
PubMed2001

Pathogenesis of experimental vesicular stomatitis virus (New Jersey serotype) infection in the deer mouse (Peromyscus maniculatus).

The pathogenesis of vesicular stomatitis virus (VSV) infection has not been investigated previously in native New World rodents that may have a role in the epidemiology of the disease. In the present study, 45 juvenile and 80 adult deer mice (Peromyscus maniculatus) were inoculated intranasally with VSV New Jersey serotype (VSV-NJ) and examined sequentially over a 7-day period. Virus was detected by means of immunohistochemistry and in situ hybridization in all tissues containing histologic lesions. Viral antigen and mRNA were observed initially in olfactory epithelium neurons, followed by olfactory bulbs and more caudal olfactory pathways in the brain. Virus also was detected throughout the ventricular system in the brain and central canal of the spinal cord. These results support both viral retrograde transneuronal transport and viral spread within the ventricular system. Other tissues containing viral antigen included airway epithelium and macrophages in the lungs, cardiac myocytes, and macrophages in cervical lymph nodes. In a second experiment, 15 adult, 20 juvenile, and 16 nestling deer mice were inoculated intradermally with VSV-NJ. Adults were refractory to infection by this route; however, nestlings and juveniles developed disseminated central nervous system infections. Viral antigen also was detected in cardiac myocytes and lymph node macrophages in these animals. Viremia was detected by virus isolation in 35/72 (49%) intranasally inoculated juvenile and adult mice and in 17/36 (47%) intradermally inoculated nestlings and juveniles from day 1 to day 3 postinoculation. The documentation of viremia in these animals suggests that they may have a role in the epidemiology of vector-borne vesicular stomatitis.

Animals↗
PubMedDate not supplied

Viruses and behavioural changes: a review of clinical and experimental findings.

This review focuses on behavioural neurovirology. Profound changes in behaviour are observed following infection of the central nervous system by some viruses. Irritability, insomnia, hyperactivity and learning disability are some of the behavioural disturbances that have been described in both humans and animals with central nervous system infection. The reticular core neurons which innervate the entire brain play an important role in regulating behaviour. Some of these neurons--locus coeruleus, raphe and diagonal bands--send projections to the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium. In infant rats, vesicular stomatitis virus is transported along the olfactory pathway by retrograde transport and reaches the reticular core neurons causing destruction of raphe, diagonal bands and, to a lesser extent, the locus coeruleus. As the neurons degenerate, the viral antigens disappear and the animals sustain severe deficits in neurotransmitter levels and behaviour. Such a "hit and run" effect of the virus suggests the possibility that a similar mechanism may be operating in some human disorders. Apart from their intrinsic interest as possible aetiological factors, viruses may provide valuable tools in experimental work seeking to correlate behaviour, morphology and neurotransmitter function.

Animals↗
PubMed2005

Continuous and overlapping expression domains of odorant receptor genes in the olfactory epithelium determine the dorsal/ventral positioning of glomeruli in the olfactory bulb.

In mammals, olfactory signals received by odorant receptors (ORs) in the olfactory epithelium (OE) are converted to a topographical map of activated glomeruli in the olfactory bulb (OB). It has been reported that the OE can be divided into four topographically distinct zones and that olfactory sensory neurons (OSNs) expressing a particular OR gene are randomly distributed within one zone. Here, we analyzed 80 different class II OR genes for their expression patterns in the OE by in situ hybridization. It was found that the expression area in the OE does not always fit into one of the four conventional zones. Expression areas are specific to each OR gene and are arranged in an overlapping and continuous manner in the OE. We also analyzed a spatial relationship between the OE and the OB for OSN projection. Our transgenic as well as DiI retrograde staining experiments demonstrated that the dorsal/ventral arrangement of glomeruli in the OB is correlated with the expression areas of corresponding ORs along the dorsomedial/ventrolateral axis in the OE. The present study indicates that the OR gene choice may be more restricted by the OSN location in the OE than what has been thought.

Animals↗
PubMed2004

Odorant-evoked nitric oxide signals in the antennal lobe of Manduca sexta.

The gaseous signaling molecule nitric oxide (NO) can affect the activities of neurons and neural networks in many different systems. The strong expression of NO synthase (NOS) in the primary synaptic neuropil (the antennal lobe in insects and the olfactory bulb in vertebrates) of the olfactory system of most organisms, and the unique spheroidal geometry of olfactory glomeruli in those neuropils, have led to suggestions that NO signaling is important for processing olfactory information. No direct evidence exists, however, that NO signals are produced in olfactory glomeruli. We investigated the production of NO in the antennal lobe of the moth, Manduca sexta, by using immunocytochemistry and real-time optical imaging with a NO-sensitive fluorescent marker, diaminofluorescein diacetate. We confirmed that NOS was expressed in the axons of olfactory receptor neurons projecting to all glomeruli. Soluble guanylyl cyclase, the best characterized target of NO, was found in a subset of postsynaptic antennal lobe neurons that included projection neurons, a small number of GABA-immunoreactive neurons, and a serotonin-immunoreactive neuron. We found that odorant stimulation evoked NO signals that were reproducible and spatially focused. Different odorants evoked spatially distinct patterns of NO production. Increased concentrations of pheromone and plant odorants caused increases in peak signal intensity. Increased concentrations of plant odorants also evoked a dramatic increase in signal area. The results of these experiments show clearly that odorant stimulation can evoke NO production in the olfactory system. The NO signals produced are likely to play an important role in processing olfactory information.

Animals↗
PubMed2006

Temporal dynamics and latency patterns of receptor neuron input to the olfactory bulb.

Odorants are first represented in the brain by distributed patterns of activity in the olfactory bulb (OB). Although neurons downstream of sensory inputs respond to odorants with temporally structured activity, sensory inputs to glomeruli are typically described as static maps. Here, we imaged the temporal dynamics of receptor neuron input to the OB with a calcium-sensitive dye in the olfactory receptor nerve terminals in anesthetized mice. We found that diverse, glomerulus- and odorant-dependent temporal dynamics are present even at this initial input stage. Instantaneous spatial patterns of receptor input to glomeruli changed both within and between respiration cycles. Glomerular odorant responses differed in amplitude, latency, rise time, and degree of modulation by sniffing in an odorant-specific manner. Pattern dynamics within the first respiration cycle recurred in a similar manner during consecutive cycles. When sniff rate was increased artificially, pattern dynamics were preserved in the first sniff but were attenuated during subsequent sniffs. Temporal response properties were consistent across individuals on a coarse regional scale and on a fine scale of individual glomeruli. Latency and magnitude of glomerular inputs were only weakly correlated and might therefore convey independent odorant information. These data demonstrate that glomerular maps of primary sensory input to the OB are temporally dynamic. These dynamics may contribute to the representation of odorant information and affect information processing in the central olfactory system of rodents.

Animals↗
PubMed2006

Wiring stability of the adult Drosophila olfactory circuit after lesion.

Neuronal wiring plasticity in response to experience or injury has been reported in many parts of the adult nervous system. For instance, visual or somatosensory cortical maps can reorganize significantly in response to peripheral lesions, yet a certain degree of stability is essential for neuronal circuits to perform their dedicated functions. Previous studies on lesion-induced neuronal reorganization have primarily focused on systems that use continuous neural maps. Here, we assess wiring plasticity in a discrete neural map represented by the adult Drosophila olfactory circuit. Using conditional expression of toxins, we genetically ablated specific classes of neurons and examined the consequences on their synaptic partners or neighboring classes in the adult antennal lobe. We find no alteration of connection specificity between olfactory receptor neurons (ORNs) and their postsynaptic targets, the projection neurons (PNs). Ablating an ORN class maintains PN dendrites within their glomerular borders, and ORN axons normally innervating an adjacent target do not expand. Likewise, ablating PN classes does not alter their partner ORN axon connectivity. Interestingly, an increase in the contralateral ORN axon terminal density occurs in response to the removal of competing ipsilateral ORNs. Therefore, plasticity in this circuit can occur but is confined within a glomerulus, thereby retaining the wiring specificity of ORNs and PNs. We conclude that, although adult olfactory neurons can undergo plastic changes in response to the loss of competition, the olfactory circuit overall is extremely stable in preserving segregated information channels in this discrete map.

Animals↗
PubMed2006

Retinoic acid receptor-dependent survival of olfactory sensory neurons in postnatal and adult mice.

To address the hypothesis that retinoids produced by synthesizing enzymes present in the primary olfactory system influence the mouse olfactory sensory map, we expressed a dominant-negative retinoic acid receptor selectively in olfactory sensory neurons. We show that neurons deficient in nuclear retinoid signaling are responsive to odors and form correct odorant receptor-specific axonal projections to target neurons in the olfactory bulb of the brain. Subsequent to the formation of the map, the neurons die prematurely by retrograde-driven caspase-3 activation, which resembles the previously described mechanism of neural death after olfactory bulb ablation. This neurodegenerative event is initiated the second postnatal week and occurs in the adult animal without a compensatory increase of progenitor cell proliferation. In addition, we find that nuclear retinoid signaling is required for the expression of a retinoic acid-degrading enzyme, Cyp26B1, in a small fraction of mature neurons. Collectively, the results provide evidence for a role of locally regulated retinoid metabolism in neuroprotection and in determining population size of neurons at a late stage of neural circuit formation.

Aging↗
PubMed2004

Enantioselectivity of projection neurons innervating identified olfactory glomeruli.

Projection neurons (PNs) with arborizations in the sexually dimorphic "lateral large female glomerulus" (latLFG) in the antennal lobe (AL) of the moth Manduca sexta previously were shown to respond preferentially to antennal stimulation with (+/-)linalool, a volatile compound commonly emitted by plants. In the present study, using intracellular recording and staining techniques, we examined the responsiveness of latLFG-PNs to the enantiomers, (+)linalool and (-)linalool and found that (1) latLFG-PNs are more responsive to antennal stimulation with (+)linalool than with (-)linalool, (2) PNs with arborizations in a glomerulus adjacent to the latLFG are preferentially responsive to (-)linalool, and (3) PNs with arborizations confined to other glomeruli near the latLFG are equally responsive to both enantiomers of linalool. Structure-activity studies showed that the hydroxyl group in this tertiary terpene alcohol is the key feature of the molecule determining the response of enantioselective PNs to linalool. In contrast, the responses of non-enantioselective PNs are less dependent on the alcoholic functionality of linalool. Our findings show that PNs innervating a uniquely identifiable glomerulus respond preferentially to a particular enantiomer of an odor substance. Moreover, PNs with arborizations in a glomerulus adjacent to the latLFG, although less sensitive than latLFG-PNs to linalool, respond preferentially to the opposite enantiomer, demonstrating that information about stimulus-absolute configuration can be encoded in different olfactory glomeruli.

Acyclic Monoterpenes↗
PubMed1997

Destruction of olfactory inputs affects the morphogenesis of the telencephalon in rats.

We unilaterally destroyed the nasal radix of rat embryos on day 15.5 of gestation (E15.5) in utero so as to block the olfactory inputs to the ipsilateral forebrain vesicle. The embryonic brains were examined after 6 days' survival (E21.5). In the deafferented half of the brain, LHRH neurons were significantly reduced in number, indicating the successful blocking of the olfactory input. On the deafferented side, the olfactory bulb failed to develop, and the telencephalic hemisphere, small in size, accompanied various histogenetic retardations in the primary olfactory cortex, in the cortical plate, and in the hippocampal formation. The striatum revealed remarkable structural differences between the ipsilateral and contralateral sides: on the ipsilateral side, the striatum was small in size and displayed numerical reductions of immunoreactive tyrosine hydroxylase (TH) fibers and substance P (SP) neurons in comparison with those in the contralateral one; in the substantia nigra, TH neurons and SP fibers were less numerous on the deafferented side. There were no remarkable differences in the distribution of TH neurons in the hypothalamus. In view of these sequential histogenetic alterations, it can be assumed that the olfactory inputs play a key role in the telencephalic morphogenesis.

Amygdala↗