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| Study Materials: Sensory encoding of olfaction at olfactory neuro-epithelium |
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 Anonymous writes "Ramakrishna Reddy Reddem.
Research Graduate Assistant
Laboratory of Integrative neuroscience.
University of Illinois at Chicago.
mailto:rredde1@uic.edu
Though the human nose is often considered something of a luxury, for the rest of the animal world from bacteria to mammals, detecting chemicals in the environment has been critical to the survival of organism. Odors are easily learned, memorized and recognized emphasizing the great importance of chemical senses during evolution. The proximity of olfactory system to the memory circuits and the higher cognitive centers in the neocortex of the forebrain makes it an important research avenue of neuroscience. Though the perception of smell is a construct of nose and brain together, the rapid leap in the studies at the nose [olfactory receptor neuron] level is because of the simplicity of its organization and easy accessibility for experimentation with several molecular, biochemical and electrophysiological tools. A thorough understanding of the physical odorant characteristics, the odorant receptor kinetics, the molecular events at signal transduction level, the formatting of the transduced information in to trains of action potential spikes in individual ORN's, and finally the spatiotemporal orientation of a bunch of ORN's projecting selectively into the olfactory bulb and to the higher centers from there, helps us understand the perception of odorants in a better way. Unless the issues at the ORN level are thoroughly addressed and well defined for the odorants, the progress in understanding the psychophysics of odor identification, discrimination and memory remain halfway.
Basics of information coding and processing.
Ever since Shannon and Weaver published their popular Mathematical theory to quantify communication through noisy channels [1], half a century back from now, the interest to apply it for biological systems particularly for the information processing in nervous system kept growing. Because sensory circuits are evolved to detect selective patterns relevant for survival and that they also create qualities that do not exist outside the brain, few basic questions need to be clear in applying physical modeling to the biological machinery. The questions like what parameters are coded, how are they coded and what the source and receiver are, are to be borne in mind. Brain codes can be studied from many perspectives of which atleast 2 approaches are of significant interest. The physicist or engineer will look for external features about which neural processes can inform. In olfaction what amuses him are the features such as chemical species, concentration, location, stationariness or rate of encounter of the odorant, and their effects on neurons. While the biologist or an ethologist start with the animal's viewpoint, emphasizing the pattern recognition more than segmentation of the individual properties of the odorants. [2] In this context it is to be noted that biological systems, particularly neural codes owe as much to the animals needs, if not more, as to the physics of the external world. The goal should be to bridge the gap between the technical and biological world of odor detection by electronically recording chemical images of any odor environment with high resolution in both space and time.
Any neural code is spatiotemporal. In vision and somatosensory systems spatial representation is pretty clear meaning that the receptor codes the location of the stimulus, inherently as it codes various other parameters of the stimulus, so that the brain interprets signal in right place. In Olfaction though organism locates the source of odors and the direction the odors are reaching it, it is probably more a construct of brain than because of the spatial projection of neurons. There is no evidence that ORN's organize themselves into areas specific to pick up either the quality or concentration of a specific odorant, leave alone the direction or location of the odorant. Olfactory receptors are widely scattered with in the olfactory epithelium but not randomly distributed. ORN's expressing distinct receptor types are topographically distributed in one of several rostrocaudal zones [Ressler Vassar Strotman] However it has no significance in terms of identifying odors or even pure odorant molecules because, on presenting a odorant molecule a percentage of whole ORN population across the zones responded in a mosaic distribution..
The unique problems with olfaction.
The wealth of anatomical and histological discoveries in the last century and biochemical and molecular discoveries of last decade answered some of the questions essential for understanding the coding mechanisms and characteristics. There is a current renaissance in computational neuroscience as is seen particularly clearly in the studies of olfaction, due to these discoveries.
In understanding olfaction one confronts questions common to all sensory systems such as how feature detection, background suppression, selective attention are implemented, how receptor arrays are mapped into interneuron population and how prior experience modifies sensory processing. More than these, olfactory system presents a unique sort of problem to the brain. The range and sensitivity of olfactory system being remarkable, a vertebrate nose can detect and discriminate among thousands of low molecular weight organic compounds those possess an enormous diversity of chemical structures and properties. Unlike for vision there are no primaries (as in overlapping wavelengths of light for colors) or unlike for audition, no fundamentals (as in harmonic frequencies in sound waves) into which complex stimuli can be resolved. How the brain maps this diverse stimulus set onto neural space remains a puzzle. All attempts to compose complex odors by well-defined amounts of a limited number of standard primary odors failed so far. There is not even a direct correlation between chemical structure and odor perception. In olfaction ‘hedonic valence’ is often discussed but it is more of a theoretical assumption than a scientific truth based on physiological evidence. Nothing in the physical world has been figured out, which indicates whether a odor is pleasant or not to an organism. A lack of odorant vector space is another unique feature.
The picture across the animal kingdom.
Molecular sensing by G protein coupled receptors, so well developed in olfactory sense is biologically ubiquitous. The nematode olfactory system (as reported in C.elegans) seems to be built more on a strategy more comparable to vertebrate taste than olfaction. The drosophila odor receptor family was perhaps the most important advance in olfactory studies made recently. Numbering some 60 or few more olfactory receptors in the adult drosophila bear no homology to vertebrate OR. However the system in drosophila is organized along the lines of a vertebrate in the issues like each neuron expressing only a single OR, and all cells expressing the same receptor.
Across the animal kingdom, the environment in which odors are delivered to the organism, specifically to the chemosensory receptor cells [ORNs] varies. While mammals are terrestrial and have access to a vast number of volatile compounds, fishes have access to a lesser number of water-soluble odorants. Comparative studies at the vertebrate level revealed that the basic organization of olfactory system is same from Pisces to mammals. All have a vast repertoire of gene family that encodes receptor proteins that are crucial in encoding odor information. However there are some significant differences among species to account for the difference in their living ambiance and the individual dependence on olfactory system for survival.
The present understanding
1.The Odorant parameters and access of odorants to the ORN cell membrane.
Any volatile chemical molecule is a potential odorant. However odorants are typically small organic molecules of less than 400Da,varying in size shape functional group and charge [Amoore etal 1970, Liljefors 1988]. The human odor perception experiments conducted in the middle of last century revealed some startling facts regarding the differences in odorant perception with changes in structure, concentration and the subject. Octanol smells rose like, while octanoic acid [structurally differing by substitution of hydroxyl group with carboxylic group] is rancid and sweaty. Indole in low concentrations smells mild and floral, while at higher concentration smells putrid. Sensitivity of odorant varies from individual to individual. Androsterone was pleasant at same concentration for some one, while disgustingly urinous in another, while some can’t smell it at all. Neither mechanism by which the olfactory system accomplishes its perceptual feat, nor the bases of these perplexing features of olfactory perception are well understood. The recent advances in molecular biology placed odor receptor interaction and its aftermath second messenger signaling at a key place for coding odorants.
Crucial step in this transduction (of chemical stimuli into electrical response) is the interaction of the ligand molecules with receptor proteins borne by the cell membrane [28,29]. Two basic types of interaction are proposed [9]- First a single step simple binding and Second, a two step interaction (of odorant binding followed by activation of receptor odorant complex)- for transduction cascade to set on. Based on the mode of access of odorant molecules and the possibilities of the fate of the odorant molecules in the aftermath of its binding and stimulating the receptor neuron, three different models of odorant detection are possible.
Concentration detector model [31,32,33] implies a biological system where the odorants can relatively freely access and leave the perireceptor space. e.g. taste receptors, hormone receptor systems and unicellular organisms. Flux detector model [34,36] refers to a system in which the diffusion of ligand to the perireceptor space is irreversible as in insect olfactory sensilla.[35]. Because the odorant molecule cannot leave the system it has to get degraded, usually enzymatically [Kasang 1988 and Ziegelberger 1995]
General Model [36] is a more flexible model for systems in which the diffusion to and from the perireceptor space is asymmetrical. Using the above three models and the two different interactions stated earlier, and making several realistic assumptions [36] Rospars and Lansky came to the following conclusions.
1. The dynamic range 1-99% never exceeds 4 log units [CD1] and it can be as narrow as 2[FD1].
2. Magnitude 100percent for type 1 interactions but 57% for type 2 interactions in all the models
3. Sensitivity is less in a flux detector model, moderate in a General model (depending on the variables) and extremely high in a concentration detector. However this sensitivity at the receptor-odorant binding level means nothing in terms of the response produced by an ORN and thus the sensitivity of odor perception, due to the amplification at the transduction apparatus, the G protein cascade and the conductance to voltage conversion. However an important conclusion drawn from their exp. on moth pheromone receptors is that the low affinity of receptor to its ligand would be a secondary adaptation but not a limiting factor for sensitivity of the system.
Assuming a specified level of resolution in the response of cellular or neural systems downstream from the membrane that read the odorant concentration code, Wayne M Getz and Petr Lansky calculated the range of the concentrations over which the coding efficiency of the membrane is maximized.
2.The anatomical organization
The anatomical and molecular organization of the early olfactory system reflects the strategy for discriminating between a large number of diverse stimuli. The main olfactory epithelium in the nose is specialized to detect fluctuations in the concentration of a large diversity of air borne molecules and to transduce this transformation into a stream of neuronal activity that is conveyed to the brain. We have a clear picture of the neuronal wiring atleast in the early parts of the system. The molecular aspects of the transduction mechanism, discovered and being deciphered since 1991, initially gave the impression that molecular coding at a single ORN level shall explain most of the odorant parameters (like the chemical species and its concentration) and that higher anatomical circuitry just decodes it. Though compelling in its simplicity and partly, in its feasibility; the recent discoveries suggest a combination coding system to be more plausible than a single neuron coding for the characteristics of an odorant.
Gross circuitry
The cable over which the coded information has to be transferred is the neuronal axon. And then there is a bewildering problem of what a receiver or the decoder is? Gilles Laurent [5] aptly says, that establishing a code requires showing that the receiver actually decodes the incoming signal and he offers an exception for neural systems, in view of the complexity involved in understanding the circuitry and process of decoding.
There is a convergence of ORN axons in their relay station, the olfactory bulb. Thousands of ORN axons synapse onto 5-25 mitral cells in each glomerulus. Individual ORNs are specific in projecting to the one among some 2000 odd glomeruli that make the olfactory bulb. Given the fact that the ORN life span is only few days and that new ORNs are constantly produced by the basal cells to replenish the lost ones, it is a question of great relevance, "how ORNs identify specific glomeruli, they are destined to." to explain the hard wiring of neuronal circuitry. The mitral cells in Olfactory bulb (OB) carry signals to the primary olfactory cortex. From there olfactory information is relayed onto the higher cortical areas and to the limbic system, thereby allowing for both the conscious perception of odors and their emotional and motivational effects.
Histology and cell biology of olfactory epithelium.
Histology is important because, auxiliary supporting cells forming tight junctions with ORNs compartmentalize the neuron environment and introduce extraneuronal voltage sources. Thus the effect is that amplitude of response is inversely proportional to the length and number of dendrites of ORN and that the sensitivity of ORN is lower. In absence of auxiliary cells, the maximum amplitude of receptor potential is supposed to be independent of dendrite morphology and the sensitivity of ORN improves, as found by physical modeling [XX]
There are 6-10 million ORN’s, along with the supporting auxiliary cells and the basal stem cells, forming a neuro-epithelium that lines a series of cartilaginous outcroppings (turbinates). The turbinates serve to increase the surface area of epithelium. ORN’s are bipolar neurons with a single dendrite that reaches unto the surface of the tissue and ends in a knob like swelling from which project 20-30 very fine cilia. Cilia lie in thin layer of mucus covering the tissue and are the sites of sensory transduction apparatus. This mucus layer makes the general detector model more appropriate in modeling the case of olfactory receptor-odorant interactions, which means that ORs sense the flux of odorants, rather than their absolute concentration in the nasal cavity. The input resistance of the nonsensory part (cell body and soma) is the only physical parameter that is likely to influence the sensitivity and dynamic range of receptor potential.
Molecular biology-relevance in coding.
The identification of novel multigene family that encode proteins with seven transmembrane domains that bind odor molecules and transduce odor reception signal through interaction with G proteins [3] constitutes a major contribution of molecular biology to odor transduction issue. Olfactory receptors are G protein coupled receptors, so diverse that a big chunk [2-4%] of any mammal’s gene pool is devoted for coding these proteins. Some interesting facts about these proteins and their coding genes are that the coding region of these genes lack introns. The proteins structurally have 7 alpha helical membrane-spanning domains with loops of variable lengths and numerous conserved short sequences. The hypervariability regions in the 3rd 4th and 5th transmembrane regions are assumed to form a pocket to recognize and to allow the odorant molecule to adsorb at this pocket. Several findings indicate that ORN expresses only one OR gene producing homogenous population of ORs on its cell membrane. First individual OR gene probes hybridize to only near 1% of ORNs insitu {Strotmann’92 Ressler’ 93}. Second by rt-PCR analysis of small number of ORNs, it is shown that a single neuron expresses only one OR protein.
A recently discovered receptor, named I7, has mouse and rat orthologues, showing differential responses (one is more sensitive to Heptanal and the other to Octanal). The two structurally differed by 15 aminoacids but it is proved that the difference in ligand sensitivities is due to a single residue in transmembrane domain 5 (valine to Isoleucine). I7 is the only receptor fully characterized for the ligand specificity and the range of molecules that it can code for. The pharmacology of odor receptors, that would produce activity matrices of large numbers of receptors tested against equally large chemical libraries, needs to be developed. That is the only reliable way of assessing odorant coding at receptor level and answering questions like.... How broadly are receptors tuned? How many different molecules can a receptor code for? What exactly does an ORN looks for or recognizes in an odorant molecule, is it the length of carbon chain or functional group or the stereoscopic orientation [as it differs in enantiomers]. The possibility of overexpression of receptor proteins in bacterial cells and when reconstituted in liposomes, the ability of purified receptor protein to gain its original tertiary structure and thus interact with certain odorants (Kiefer etal1996), shows a promise for more invitro experiments to correlate the exact chemical coding at receptor level. Questions like, What functional group or what length of Carbon chain is identified by a particular ORN can be answered in near future, if these techniques are taken up in a large scale.
The receptor ligand interaction initiates a cascade of second messenger reactions, which is proved essential for sensing odorants. BY inactivating the genes encoding G alpha olf (a G protein), adenylyl cyclase 3 (an enzyme that produces the cAMP) or one cyclic nucleotide gated ion channel subunit, these three were shown to play the key role in the events between ligand binding and ions conductance [14, 15]. Though IP3 was shown to rise, its role remains elusive given that functional cAMP mechanism is dominant in the amplification [16].
3.The Physiological advances.
Olfactory transduction process starts with the binding of odorant molecules to receptor proteins in sensory dendrites. The activation of the receptors is believed to trigger a second messenger systems discussed earlier, that ultimately opens the odorant dependent ionic channels. This conductance change gives rise in turn to a depolarization of the membrane, the so-called receptor potential, which spreads passively from the stimulated sensory dendrites to the nonsensory part of the neuron-dendrite knob, soma and axon-and triggers the generation of action potentials at axon initial segment. An ORN's physiological activity can be discussed in terms of magnitude, sensitivity and dynamic range of its responses in ionic conductance, voltage (receptor potential) and firing (action potential) as a function of the neuron's biochemical and electrical characteristics. Magnitude reflects odor intensity (or concentration) while sensitivity reflects the lowest possible concentration of an odorant that can be transduced into a neuronal signal. Dynamic range refers to the range of stimuli over which a neuron can respond and discriminate.
The electrical responses to odor stimulation can be studied at several levels. The slow voltage changes at the epithelial surface reflecting the changes of the transepithelial potential between the interstitial and mucus fluid compartments, and represent the summed activity of many olfactory receptor neurons in the recording area is called the electro-olfactogram. A different and more specific approach is studying the receptor currents through the patch clamp or voltage clamp techniques. This has lot of relevance and applications in terms of defining the relation between odorant induced conductance and receptor potential. The receptor potential of an ORN as a function of the logarithm of the odorant dependent conductance is a curve of sigmoid shape [18], characterized by its magnitude (maximum possible response), its sensitivity (such as conductance at half maximum response) and its dynamic range (ratio of the conductance at threshold and saturation). The odor-induced current loads the cell’s capacitance and depolarizes the membrane potential from the resting potential to the cell’s firing threshold. The high resting impedance 10Gohms makes ORN extremely sensitive and generate action potential upon depolarizing currents of only a few pA. The depolarization activates the voltage-gated conductance of the receptor neurons causing action potentials at axon hillock. [2]
Electrophysiology
The present understanding with electrophysiological techniques can be summed up in to few points. One, In absence of stimuli, atleast in mammals, there is definite evidence that ORNs show spontaneous discharges. Two, On maximal stimulation of an ORN with an odorant there can be as many as 20-30 spikes per second. Three, responses to natural stimuli show well reproducible phasic and tonic response patterns. Four, Many different ORNs are necessary to code the intensity of an odorant over the whole concentration range. By suction pipette technique, where only cell body soma is patch clamped, in amphibian and mammal the following results were obtained. The firing frequency got saturated for just a three-fold increase in the stimulus odor concentration, where as the receptor current showed a gradual raise over a 100-fold increase of odor concentration. In fact they were not able to saturate the receptor current in their experiment. This indicates that the dynamic range is more for the receptor current of ORN than for the spiking frequencies of the ORN. However when whole-cell voltage clamping is done, the receptor current had steeper concentration dependence in contrast to the gradual response with the suction pipette receptor current. The spike morphology in an ORN, with stimulus of different odor concentrations and for different duration have been studied For a brief 30sec low odor concentration [just above threshold] sporadic firing of action potentials is seen. While at high concentrations, short burst of action potentials with large receptor current is seen. The receptor current returned back to base line in few seconds (4-6).
The same group [11] gave some insights on the timing of olfactory events. Mammalian species [rat] had faster response kinetics, in comparison to amphibians [frog]. This has been explained on the demands, the terrestrial living environment of rat imposes on its olfactory system. At receptor level the time of onset of odor is faithfully encoded, while the higher centers take care of determining subsequent time course of odor exposure from analyzing complex bursting response pattern that accompanies continued stimulation. The ability of ORNs to discriminate odors was thought to be directly proportional to their selectivity (specificity). The interesting point is that now even the nonselective ORNs are envisaged to discriminate between two odors which elicit two distinct temporal response patterns, the time coding mode and the rate coding mode.
Odor quality is specified through identity of activated ORN’s, if not individually, by a unique combination of ORN’s. Odor intensity or concentration is coded by at least two mechanisms. First being the varying rates of spiking by ORN’s, which preserves the sensitivity in the detection of varying concentrations over a narrow range. Second being the recruitment of new ORN’s at higher concentrations, which preserves the broad range of concentrations the olfactory system can identify. The distortion of odor perception at higher concentrations is often attributed to this recruitment of new ORN’s thus recruiting new Glomeruli in the olfactory bulb. The mechanisms behind this new recruitment, rather different ORN’s coding for different range of concentrations can be either intrinsic mechanisms of cell like level of cell maturity or different receptor genes being expressed in such newly recruited cells. The latter seems to be more plausible explanation in the light of new discoveries in the olfactory bulb, where not only strong response in a single glomerulus, but also recruitment of new Glomeruli is seen with high concentration ranges.
Calcium labeling studies
The question of what portion of the total receptor pool respond to a given odorant has been answered using the calcium labeling techniques. There is a Calcium inflow current when an ORN is stimulated by an odorant. Exploiting this fact with florescent-labeled calcium dyes, it is shown that 4-9% of total population of ORNs get excited and there is a overlap of the responding neurons for chemically dissimilar odorants. The only unique feature of response for a giver odorant is the subset of ORNs getting excited. The responding subsets of neurons were consistent over time, over repeated stimulation with same odorant and with minor changes in the concentration of odorant presented. With larger variations in the odor concentration, new ORNs are recruited in to the coding process.
Consensus on combination codes.
The discriminatory power of the mammalian olfactory system is such that thousands of volatile chemicals are perceived as having distinct odors. The slight alterations in the chemical structure of odorants, or a change in its concentrations can change its code, potentially explaining how such changes can alter perceived odor quality. Sensory coding has been recently dealt by two functional studies by two different groups differing in the methods they used to answer the question of degree of specificity of odor receptor interaction. Malnic etal (1999) has taken up molecular biology methods (calcium imaging coupled with rt-PCR) on rat ORNs invitro to conclude that ORNs express only one OR each but suggest that 0odor ant coding is realized through multiple combinations of OR odorant interactions. This gives an idea that one OR can code for only one parameter of the chemical species like superficially either for the number of carbons in the backbone [as realized in I7 receptor] or specifically for the functional groups [ketone aldehyde or alcohol group etc.] In contras another led by Duchamp-Viret etal. Worked on the electrophysiology and proved that, an individual ORN responded to a variety unrelated odors. The two studies seem to be speaking contrary to each other. But of late, a consensus is evolving in the form of combination coding system unique to each odorant. Thus one odor molecule will be recognized by several receptors, while one OR will be able to bind multiple odor molecules, which share some common parameter that has to be characterized for each receptor.
The plausibility of combination coding system lies in the fact that there are only near 1000OR genes in the genome, and each ORN expresses only one of it but the olfactory system is able to identify and discriminate a vast number of diverse odorants. The maintenance of connections between ORNs and brain is likely to require atleast occasional odor induced neuronal activity {Brujes etal 94}. Use of individual ORs to recognize a single common parameter in a variety of odorants could serve to maintain the components of the code for an odorant, even in its absence. This assures perceptual fidelity overtime as well as the ability to perceive novel odors. The response spectra of ORNs insitu support the combination coding system of olfactory quality and intensity by different ORN subsets. Ma and Shepherd [20] proved in their intact epithelial preparation (of mouse olfactory epithelium) with perforated patch clamping, recording and calcium imaging of odor responses that consistently and reliably, a unique subset of Ors scattered all over the olfactory neuro-epithelium got activated for any given concentration of an odorant. Some 4-9% of total ORNs got activated with each of the 12 odorants they used as stimulus. There is an overlapping of ORN population getting activated with two different odorant stimuli.
Summary and future directions.
Olfaction being closely related to higher mental functions like memory and cognition on one hand and the stimulating odorants being of wide range of unrelated chemical compounds on the other hand, has stimulated interest in the minds of both biologists and physicists alike. The mechanisms of coding the various parameters of an odorant are seen in a new light today, thanks to some of the marvelous discoveries in the fields of molecular biology, genetics calcium imaging and electro-physiology. The transduction of a chemical stimulus into an electrical response in a phased manner , amplified by the second messenger cascades is the agreed upon issue. The how and the role of receptors in defining various parameters is under constant revision as new discoveries are poring in. The trend of the day seems to be the combinational coding system, where many neurons code for a single molecule and a single receptor codes many diverse molecules, however in a n unique fashion for each chemical species. The key for deciphering the coding mechanisms lie at two levels; Understanding the receptor range , specificity and magnitude at one level and understanding how and where these combinations codes formed by the receptor epithelium are deciphered or organized at higher levels like olfactory bulb and the cortex. Once the receptor role is well characterized and defined by pharmacological methods, the shift of emphasis would be in understanding the way the ORN axons project into defined areas of OB, the circuitry at the olfactory bulb and cortex, and how it works in integrating the pieces of information sent by each ORN to make the sense of a smell. Some relevant questions in trying to understand the circuitry at lower level are , How olfactory receptors recognize the specific glomeruli in the olfactory bulb, as they do it, what do they recognize in the specific glomeruli. Is it chemoattractive clues or positional gradient coordinates?
Bridging the gap between technological and biological world of odor detection by electronically recording chemical images of any odor environment with high resolution in both space and time can pave way for designing effective chemosensors, which have utility in food and perfume industry(quality control). Study of OR sensitivities can throw light on manipulating them to keep rodents, insects and pests off the agriculture and industry by using cost effective and nontoxic means. Besides the commercial uses, science is to be studied for its own sake[Roy],for the excitement of unraveling the facts so ubiquitous yet so elusive. In neurobiology, the goal is to unravel the truths of brain with its inputs, outputs and their integration. Olfactory system offers a great opportunity to answer many questions that reveal spectacular truths because of simplicity in its organization at input level.
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RE: Bondyvebyxe (Score: 1)
by fizo38402 on Saturday, June 30 @ 23:07:04 GMT
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