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Michael Leon

Publications and source records attributed to Michael Leon.

17 recordsLinked to original sources
PubMed2007

Effects of double and triple bonds on the spatial representations of odorants in the rat olfactory bulb.

Many naturally occurring volatile chemicals that are detected through the sense of smell contain unsaturated (double or triple) carbon-carbon bonds. These bonds can affect odors perceived by humans, yet in a prior study of unsaturated hydrocarbons we found only very minor effects of unsaturated bonds. In the present study, we tested the possibility that unsaturated bonds affect the recognition of oxygen-containing functional groups, because humans perceive odor differences between such molecules. We therefore compared spatial activity patterns across the entire glomerular layer of the rat olfactory bulb evoked by oxygen-containing odorants differing systematically in the presence, position, number, and stereochemistry of unsaturated bonds. We quantified activity patterns by mapping [(14)C]2-deoxyglucose uptake into anatomically standardized data matrices, which we compared statistically. We found that the presence and number of unsaturated bonds consistently affected activity patterns, with the largest effect related to the presence of a triple bond. Effects of bond saturation included a loss of activity in glomeruli strongly activated by the corresponding saturated odorants and/or the presence of activity in areas not stimulated by the corresponding saturated compounds. The position of double bonds also affected patterns of activity, but cis vs. trans configuration had no measurable impact in all five sets of stereoisomers that we studied. These results simultaneously indicate the importance of interactions between carbon-carbon bond types and functional groups in the neural coding of odorant chemical information and highlight the emerging concept that the rat olfactory system is more sensitive to certain types of chemical differences than others.

Analysis of Variance↗
PubMed2006

Differential responses to branched and unsaturated aliphatic hydrocarbons in the rat olfactory system.

In an effort to understand mammalian olfactory processing, we have been describing the responses to systematically different odorants in the glomerular layer of the main olfactory bulb of rats. Previously, we demonstrated chemotopically organized and distinct olfactory responses to a homologous series of straight-chained alkanes that consisted of purely hydrocarbon structures, indicating that hydrocarbon chains could serve as molecular features in the combinatorial coding of odorant information. To better understand the processing of hydrocarbon odorants, we now have examined responses to other types of chemical changes in these kinds of molecules, namely, branching and carbon-carbon bond saturation. To this end, we used the [14C]2-deoxyglucose method to determine glomerular responses to a group of eight-carbon branched alkane isomers, unsaturated octenes (double-bonded), and octynes (triple-bonded). In contrast to the differential responses we observed previously for straight-chained alkanes of differing carbon number, the rat olfactory system was not particularly sensitive to these variations in branching and bond saturation. This result was unexpected, given the distinct molecular conformations and property profiles of the odorants. The similarity in activity patterns was paralleled by a similarity in spontaneous perceptual responses measured using a habituation assay. These results demonstrate again the functional relationship between bulbar activity patterns and odor perception. The results further suggest that the olfactory system does not respond equally to all aspects of odorant chemistry, functioning as a specific, rather than a general, chemical analysis system.

Animals↗
PubMed2006

Differential specificity in the glomerular response profiles for alicyclic, bicyclic, and heterocyclic odorants.

As part of our ongoing effort to relate stimulus to response in the olfactory system, we tested the hypothesis that the unique chemical structures and odors of various cyclic odorants would be associated with unique spatial response patterns in the glomerular layer of the rat olfactory bulb. To this end, rats were exposed to sets of odorants, including monocyclic hydrocarbons, bicyclic compounds, and various heterocyclic structures containing oxygen or nitrogen in the ring. Relative activity across the entire layer was assessed by mapping uptake of 2-deoxyglucose into anatomically standardized data matrices. Whereas monocyclic hydrocarbons evoked patterns similar to those evoked by open-chained hydrocarbon odorants, a set of bicyclic compounds with structures and odors similar to camphor evoked uptake in paired ventral domains not previously associated with any other odorant chemical structures. Despite their unique odors as judged by humans, heterocyclic odorants either evoked uptake in previously characterized areas corresponding to their functional groups or stimulated weak or patchy patterns involving isolated glomeruli. Although the patchiness of the patterns may be partially related to the rigidity of the compounds, which would be expected to restrict their interactions to only a few receptors, the weakness of the patterns suggests the possibility of species-specific odorant representations. We conclude that, whereas some of the novel cyclic structures indeed were represented by unique patterns in the rat bulb, other unique structures were poorly represented, even when they evoked intense and unique odors in humans.

Animals↗
PubMed2006

Broad activation of the glomerular layer enhances subsequent olfactory responses.

Early olfactory experience with a specific odorant enhances the subsequent response of the glomerular layer of the rat olfactory bulb to that same odorant. Because different odorants activate different glomerular layer regions, it seemed plausible that experience with a large number of odorants might result in enhanced glomerular activation during subsequent exposure to both the previously experienced odorants and the novel odorants evoking activity in regions that overlapped with those previously stimulated by different odorants. To this end, 7 odorants were selected using our glomerular response data archive that together stimulated much of the glomerular layer (alpha-phellandrene, benzaldehyde, L-carvone, decanal, pentanol, santalol, and valeric acid). Young rats were exposed to a different odorant each day for 7 days, and this cycle was repeated 3 times from postnatal days 1-21. The [(14)C]2-deoxyglucose technique was used to measure neural activity in response to both previously experienced and novel odorants. The 2 novel odorants (alpha-ionone and L-menthone) activate regions of the glomerular layer that overlap with those stimulated by the 7 enrichment odorants. Our results indicate that early experience with multiple odorants results in increased responsiveness both to previously experienced odorants and to novel odorants that stimulate previously activated regions of the bulb.

Animals↗
PubMed2006

Long hydrocarbon chains serve as unique molecular features recognized by ventral glomeruli of the rat olfactory bulb.

In an effort to understand mammalian olfactory processing, we have been describing the responses to systematically different odorants in the glomerular layer of the main olfactory bulb of rats. To understand the processing of pure hydrocarbon structures in this system, we used the [(14)C]2-deoxyglucose method to determine glomerular responses to a homologous series of alkanes (from six to 16 carbons) that are straight-chained hydrocarbons without functional groups. We found two rostral regions of activity evoked by these odorants, one lateral and one medial, that were observed to shift ventrally with increasing alkane carbon chain length. Furthermore, we successfully predicted that the longest alkanes with carbon chain length greater than our previous odorant selections would stimulate extremely ventral glomerular regions where no activation had been observed with the hundreds of odorants that we had previously studied. Overlaps in response profiles were observed in the patterns evoked by alkanes and by other aliphatic odorants of corresponding carbon chain length despite possessing different oxygen-containing functional groups, which demonstrated that hydrocarbon chains could serve as molecular features in the combinatorial coding of odorant information. We found a close and predictable relationship among the molecular properties of odorants, their induced neural activity, and their perceptual similarities.

Alkanes↗
PubMed2006

Chemotopic representations of aromatic odorants in the rat olfactory bulb.

Our laboratory has characterized spatial patterns of evoked neural activity across the entire glomerular layer of the rat olfactory bulb using primarily aliphatic odorants that differ systematically in functional groups and hydrocarbon structures. To represent more fully the true range of odorant chemistry, we investigated aromatic compounds, which have a more rigid molecular structure than most aliphatic compounds and are particularly salient olfactory stimuli for humans. We first investigated glomerular patterns of 2-deoxyglucose uptake in response to aromatic compounds that differ in the nature and position of their functional groups (e.g., xylenes, trimethylbenzenes, tolualdehydes, benzaldehydes, methyl toluates, and anisaldehydes). We also studied the effects of systematic increases in the number and length of alkyl substituents. We found that most aromatic compounds activated glomeruli in the dorsal part of the bulb. Within this general area, aromatic odorants with oxygen-containing substituents favored activation of more rostral regions, and aromatic hydrocarbons activated more posterior regions. The nature of substituents greatly affected the pattern of glomerular activation, whereas isomers differing in substitution position evoked very similar overall patterns. These relationships between the structure of aromatic compounds and their spatial representation in the bulb are contrasted with our previous findings with aliphatic odorants.

Administration, Inhalation↗
PubMed2006

Exposure to a broad range of odorants decreases cell mortality in the olfactory bulb.

Experience with multiple odorants during early postnatal development increases the number of cells in the olfactory bulb of rats. In this study, we asked whether at least part of this increase was due to decreased cell death. We selected 30 natural odorants or synthetic odorant mixtures to stimulate a broad area of the bulb during postnatal days 1-15, and counted the number of cells with DNA damage associated with cell death in both the glomerular and the granule cell layers of the main olfactory bulb. Early olfactory enrichment significantly decreased cell death in both bulbar laminae. Thus, olfactory enrichment can spare bulbar cells during early development, possibly leading to increased efficacy in bulb function and enhanced bulbar responses.

Age Factors↗
PubMed2006

Predicting odorant quality perceptions from multidimensional scaling of olfactory bulb glomerular activity patterns.

Odorants and their perceptions differ along multiple dimensions, requiring that a critical examination of any putative neural code directly assess the multidimensional nature of the encoding process. Previous work has examined simple, systematic odorant differences that, regardless of coding strategy, would be expected to produce simple, systematic predictions in neural and behavioral responses. In the present study, an odorant identification confusion matrix task that extracts precise quality relationships across odorants was used to determine whether spatially specific glomerular activity patterns predict perceptual quality relationships for odorants that cannot easily be classified a priori along a single chemical dimension. Multidimensional scaling (MDS) analysis of odorant pattern similarity measures derived from the comparison of [14C]-2-deoxyglucose glomerular activity pattern data yielded a two-dimensional odorant activity space that was highly significantly predictive of similarly obtained odorant perceptual spaces, uniformly across animals. These results strongly support the relevance of global spatial patterns in the olfactory bulb to the encoding of odor quality.

Animals↗
PubMed2005

Interactions between odorant functional group and hydrocarbon structure influence activity in glomerular response modules in the rat olfactory bulb.

To investigate the effect of odorant hydrocarbon structure on spatial representations in the olfactory bulb systematically, we exposed rats to odorant chemicals possessing one of four different oxygen-containing functional groups on one of five different hydrocarbon backbones. We also used several hydrocarbon odorants lacking other functional groups. Hydrocarbon structural categories included straight-chained, branched, double-bonded, alicyclic, and aromatic features. Activity throughout the entire glomerular layer was measured as uptake of [(14)C]2-deoxyglucose and was mapped into anatomically standardized data matrices for statistical comparisons across different animals. Patterns evoked by straight-chained aliphatic odorants confirmed an association of activity in particular glomerular response modules with particular functional groups. However, the amount of activity in these same modules also was affected significantly by differences in hydrocarbon structure. Thus, the molecular features recognized by receptors projecting to these response modules appear to involve both functional group and hydrocarbon structural elements. In addition, particular benzyl and cyclohexyl odorants evoked activity in dorsal modules previously associated with the ketone functional group, which represents an exception to the rule of one feature per response module that had emerged from our previous studies. These dorsal modules also responded to nitrogen-containing aromatic compounds involving pyridine and pyrazine rings. The unexpected overlap in modular responses to ketones and odorants seemingly unrelated to ketones may reflect some covert shared molecular feature, the existence of odorant sensory neurons with multiple specificities, or a mosaic of sensory neuron projections to these particular modules.

Animals↗
PubMed2005

Effects of functional group position on spatial representations of aliphatic odorants in the rat olfactory bulb.

Principles of olfactory coding can be clarified by studying the olfactory bulb activity patterns that are evoked by odorants differing systematically in chemical structure. In the present study, we used series of aliphatic esters, ketones, and alcohols (27 odorants total) to determine the effects of functional group position on glomerular-layer activity patterns. These patterns were measured as uptake of [(14)C]2-deoxyglucose and were mapped into standardized data matrices for statistical comparison across different rats. The magnitude of the effect of position differed greatly for the different functional groups. For ketones, there was little or no effect of position on evoked patterns. For esters, uptake in individual glomerular modules increased, whereas uptake in others decreased with changing group position, yet the overall patterns remained similar. For alcohols, group position had a profound effect on evoked activity patterns. For example, moving the hydroxyl group in either heptanol or nonanol from the first to the fourth carbon changed the activity patterns so greatly that the major areas of response did not overlap. Within every functional group series, however, responses were globally chemotopic, such that pairs of odorants with the smallest difference in functional group position evoked the most similar patterns. These results help to define further the specificities of glomeruli within previously described glomerular modules, and they show that functional group position can be an important feature in encoding an odorant molecule.

Alcohols↗
PubMed2004

Local and global chemotopic organization: general features of the glomerular representations of aliphatic odorants differing in carbon number.

To determine whether there is a general strategy used by the olfactory system to represent odorants differing in carbon chain length, rats were exposed to homologous series of straight-chained, saturated aliphatic aldehydes, ethyl esters, acetates, ketones, primary alcohols, and secondary alcohols (32 odorants total). Neural activity across the entire glomerular layer of the olfactory bulb was mapped quantitatively by measuring uptake of [14C]2-deoxyglucose evoked by each odorant. Uptake was observed both in dorsal glomerular modules previously associated with the particular odorant functional groups and in more ventral and posterior modules. Aldehyde-evoked activity patterns were dominated by ventral modules that included the area receiving projections from octanal-responsive sensory neurons expressing the I7 odorant receptor. The dorsal area that has been the focus of optical imaging studies of aldehyde responses contained only minor activity. For all functional groups except for ketones, uptake within functional group-sensitive modules displayed local chemotopy, with longer odorants stimulating more ventral and rostral glomeruli. In more posterior regions, chemotopy was observed for all functional groups, again with uptake shifting ventrally and rostrally with increasing chain length. In addition to these local shifts in activity, correlations analysis of entire activity patterns revealed a global chemotopic organization for all odorant series, with each odorant evoking a pattern most similar to odorants possessing the same functional group but differing by only one carbon in length. Thus, global chemotopy and local modular chemotopy appear to be fundamental principles underlying the representation of odorants differing in carbon chain length.

Animals↗
PubMed2003

Olfactory coding in the mammalian olfactory bulb.

There have been a number of recent approaches to the study of olfactory coding, each of which has its advantages and disadvantages. In the present review, we discuss our own work on this topic, which has involved mapping uptake of [14C]2-deoxyglucose across the entire glomerular layer of the rat main olfactory bulb in response to systematically selected pure odorant molecules. Our strategy to understand the olfactory code has involved four approaches. In the first, we determined whether the system encodes odorants in their entirety, or whether it encodes odorants by representing combinations of molecular features that add together to comprise a neural picture of each odorant. Multiple odorant features appeared to be coded by multiple receptors. Our second strategy examined the ways that such features are represented. We stimulated rats with odorants that differed greatly in their molecular structure to be able to identify a set of odorant feature response domains. Our third approach asked how odorants with very small differences in molecular structure are coded, and we found systematic differences in the representation of such features within response domains. Finally, we were able to predict odor perception from the neural representations of odorants that differed in only a single aspect of their structure. Using these strategies, we have been able to learn some of the rules by which the olfactory code operates. These rules have allowed us to predict where previously unmapped molecules would be represented and how differences in molecular representations affect olfactory perceptions.

Animals↗
PubMed2003

Spatiotemporal distribution of the insulin-like growth factor receptor in the rat olfactory bulb.

Insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) are involved in growth of neurons. In the rat olfactory epithelium, we previously showed IGF-IR immunostaining in subsets of olfactory receptor neurons. We now report that IGF-IR staining was heaviest in the olfactory nerve layer of the rat olfactory bulb at embryonic days 18, and 19 and postnatal day 1, with labeling of protoglomeruli. In the adult, only a few glomeruli were IGF-IR-positive, some of which were unusually small and strongly labeled. Some IGF-IR-positive fibers penetrated deeper into the external plexiform layer, even in adults. In developing tissues, IGF-IR staining co-localized with that for olfactory marker protein and growth associated protein GAP-43, but to a lesser extent with synaptophysin. In the adult, IGF-IR-positive fibers were compartmentalized within glomeruli. IGF-I may play a role in glomerular synaptogenesis and/or plasticity, possibly contributing to development of coding patterns for odor detection or identification.

Aging↗
PubMed2002

Spontaneous versus reinforced olfactory discriminations.

When the major response domains in the rat olfactory bulb that are evoked by odorant enantiomers are compared, some of these odorant pairs do not show significantly different activity patterns. Such pairs are not spontaneously discriminated in a behavioral test. We show here that even these similar odorants appear to evoke different activity patterns when every data point in a glomerular activity array is compared. These odorants also can be discriminated if they are subjected to differential reinforcement. These data suggest that the method chosen to assess olfactory discrimination will reveal different olfactory capabilities of rats. The small differences in glomerular activity that probably exist between any pair of odorants may serve as a basis for odor discrimination when rats are differentially reinforced, thereby establishing the remarkable limits of rat olfactory perception. At the same time, the major differences in glomerular responses appear to serve as the normal basis for spontaneous odor discrimination.

Administration, Inhalation↗
PubMed2002

Functional mapping of the rat olfactory bulb using diverse odorants reveals modular responses to functional groups and hydrocarbon structural features.

In an effort to understand the olfactory code of rats, we collected more than 1,500,000 measurements of glomerular activity in response to 54 odorants selected to provide differences in functional groups and hydrocarbon structure. Each odorant evoked a unique response pattern by differentially stimulating clusters of glomeruli, called modules. Odorants sharing specific aspects of their structure activated the same modules, allowing us to relate responses to structure across approximately 80% of the glomerular layer. The most obvious relationship was between the presence of particular oxygen-containing functional groups and the activity of glomeruli within dorsal modules. Functional group-specific responses were observed for odorants possessing a wide range of hydrocarbon structure, including aliphatic, cyclic, and aromatic features. Even formic acid and acetone, the simplest odorants possessing acid or ketone functional groups, respectively, stimulated modules specific for these functional groups. At the same time, quantitative analysis of pattern similarities revealed relationships in activation patterns between odorants of similar hydrocarbon structure. The odorant responses were reliable enough to allow us to predict accurately specific aspects of odorant molecular structure from the evoked glomerular activity pattern, as well as predicting the location of glomerular activity evoked by novel odorants.

Administration, Inhalation↗
PubMed2002

Internucleosomal DNA fragmentation during deprived and non-deprived olfactory development.

DNA fragmentation is a key marker of neuronal death during development, yet little is known about the size, pattern or quantities of fragments generated during normal and sensory-deprived development. Since there are few neurons dying at any particular time, it has not been possible to obtain sufficient quantities of material to make such a determination. By using a highly sensitive Taq polymerase-based technique, we revealed DNA fragments of 180 base pairs and multiples thereof both in bulbs and cortex of young rats (P4-P31). The bulbs subjected to olfactory deprivation at P1 had higher levels of internucleosomal DNA fragmentation at P16 than the contra-lateral, non-deprived bulbs. Interestingly, the DNA fragmentation induced by olfactory deprivation displayed a characteristic internucleosomal fragmentation pattern, suggesting that the cells induced to die may do so by apoptosis. A significant inverse correlation between DNA fragmentation and the natural variation in normal bulb size was found, suggesting that bulb size may be related to cell death.

Animals↗