The NEURONS and NEURAL SYSTEM: a 21st CENTURY PARADIGM This material is excerpted from the full β-version of the text. The final printed version will be more concise due to further editing and economical constraints. A Table of Contents and an index are located at the end of this paper. A few citations have yet to be defined and are indicated by “xxx.” James T. Fulton Neural Concepts [email protected] August 1, 2016 Copyright 2011 James T. Fulton 1 [ xxx edit carbonyl (C=O) versus carboxyl (COOH) usage. screwed up in places ] [ establish a clear demarcation between using H-best and C-best ] [ be sure Section 8.2 and 8.3 touch on anatomical computation to support chapter 0. [xxx change glucophore to glycophore after Shallenberger & Acree introduce glycophore. See glossary ] [xxx equatorial and axial are introduced in definitions on page xxx.] [xxx condense “protein” comments etc. [xxx Defined PtdTrp as the baseline for OR 2 receptor this section 8.6 in intro to Section 8.6.2.8.1 ] [xxx 8.6.7.5 addresses stage 4 information extraction ] [xxx reduce the number of places fetid is compared to sweet in the dulcal channel–Sec. 8.6.7.1.1 ] [xxx renumber after moving 8.6.11 on the VNOto the next Part of Chapter 8 ] [xxx writing in Ramachandran on olfaction1 ] 8 Stage 1, Signal Generating 2 Can you measure the difference between one kind of smell and another? It is very obvious that we have very many different kinds of smells, all the way from the odor of violets and roses up to asafetida. But until you can measure their likeness and differences you can have no science of odor. – (Alexander Graham Bell, 1914) “Science is made up with facts as a house is made from stones. But a collection of facts is no more a science than a pile of stones is a house.” —Poincare' , Hypotheses in Physics (1952) “In order to understand any part of nature, one must have both experimental data and a theory for interpreting the data and predicting new data.” – Shepherd, Outline of a Theory of Olfaction, 2005 This Part provides detailed discussion of the sensory receptors related to Olfaction 8.6 The olfactory modality The literature contains no contiguous theory of olfactory modality operation at this time. No definitive hypothesis of how stimulants are transduced into neural signals, or how those signals are processed by the brain, has appeared in the literature. Wise, Olsson & Cain confirmed this position and opened their 2000 paper with the above quotation from Alexander Graham Bell3. In March, 2011, a team at a leading research center focused on the transduction problem, “how olfactory receptors ‘read’ molecular structure remains unknown4.” While significant progress has been made 1Ramachandran, V. (2002) Encyclopedia of the Human Brain. Vol. 3 San Diegeo, CA: Academic Press 2August 1, 2016 3Wise, P. Olsson, M. & Cain, W. (2000) Quantification of odor quality Chem Senses vol 25, pp 429-443 4Franco, M. Turin, L. Mershin, A. & Skoulakis, E. (2011) Molecular vibration-sensing component in Drosophila melanogaster olfaction PNAS vol 108(9), pp 3797-3802 Signal Generation & Processing 8- 3 in understanding the interconnection of the sensory neurons and the glomeruli of the olfactory bulb, subsequent descriptions of the interconnection of the glomeruli and the CNS revert to conceptual sketches based on histology and electrophysiological traffic analysis. This work offers a comprehensive description of the olfactory modality based on the Electrolytic Theory of the Neuron. For the first time, it offers an independent parameter that describes a given odorant as perceived by human subjects. It is believed to apply to all animal species, with appropriate adjustment based on their environmental niche. It is important to distinguish between the olfactory modality and both the vomeronasal modality and the nocent modality when discussing the signaling and perception aspects of olfaction. While the complete saliency map of perception involves signals from the stage 4 engines of all of these modalities, failure to separate their individual outputs presented in the saliency map leads to endless confusion in understanding the operation of the olfactory modality. As an example, hydrochloric acid is not a stimulant of the olfactory modality but an irritant affecting the nociceptors of the nocent modality. This fact is in spite of its long time use as a reference in psychophysical testing related to olfaction. The role of naphthalene may lead to a more complex question. Can an organic molecule affect both the olfactory and nocent modalities? Naphthalene consists of a bicyclic aromatic molecule without any other chemical groups? While it exhibits a d-value (defined below) of 2.419 Angstrom, it is not generally associated with odorants with similar d-values. Its nocent properties appear to be more important than its olfactory properties. Many more complex multicyclic aliphatic ring structures, including those incorporating both simple (1 carbon) and decorated (multiple carbon) top hats have also been associated with olfaction. In the absence of associated aliphatic side chains containing orbitals and/or C=C bonds, or C=C bonds within their structure, many of these appear to be better classified as nocents than odorants. See Section 8.6.2.7. - - - - - This section will present a comprehensive theoretical description of the sensory transduction, and stage 1 signal generation, aspects of the olfactory modality of mammals. When combined with other sections related to subsequent stages, a complete description of the operation of the olfactory modality is presented in this work. It is important to differentiate between the olfactory modality of animals and a potentially equivalent modality in insects involving receptors on their external antennae. While potentially serving a similar overall function, it has not been shown that the functions are similar at the detailed level. The apparent interaction between insect and animal species, along with the interaction of both phylum with the plants appears to add an additional complexity to this part of any discussion. Section 8.6.2.4.2 & 8.6.11.9 will address the insect modality in greater detail. Those sections will note the greater physiological similarity between the olfactory pit of insects and the taste bud of mammals than the similarity between the olfactory pit of insects and the olfactory epithelium of mammals. This analysis began by building on the author’s earlier work on vision, then hearing and finally gustation as they appeared to provide an invaluable foundation for explaining olfaction. The work began with an effort to understand the previous work of others in the context of the above work. It focused on what chemical avenues were open to unlocking the secrets of olfaction. As quickly became obvious, olfaction necessarily relied upon coordinate chemistry over valence, or reaction, chemistry. The basics of coordinate chemistry are introduced in Section 8.4.4.4 and various citations within that section. The so-called coordinate (dative) bond of conventional valence chemistry does not play a significant role in coordinate chemistry. It is the London type coordinate bond that is of primary interest. The new hypothesis presented here involved a considerable degree of reiteration involving the chemistry of the odorants and the potential OR’s of olfaction before arriving at its final form. Only 4 Neurons & the Nervous System the results of those iterations can be provided here. Section 8.6.2.9 will summarize the major features of the odorants according to this hypothesis. Section 8.6.4 will summarize the proposed chemistry of the OR’s used in the first step in transduction It had long been known that no chemical residues of a reaction had ever been observed or isolated. In recent times, up through the current time, it had also become known there was no obvious relationship between the structural relationship between the chemical groups defined by both industry and the academic community and the perceived scents resulting from operation of the olfactory modality. It quickly became likely that an extension of the AH,B,X concepts of Shellenberger & Acree, of Kier and of a few others offered excellent possibilities for explaining olfaction, particularly when it became likely that the sour channel of gustation and the pungent channel of olfaction were probably separate manifestations of the same mechanism. This led to initial attempts to exam the more prominent molecules of olfaction using elementary computational chemistry techniques, including observing the vast variation in bond lengths between atoms in the formation of molecules. Fortunately, the field of computer assisted representation of three dimensional molecular structures appeared on the scene at this time. Unfortunately, this field was still new and it took several months to discover that many of the individual efforts to implement such representations were still immature. As will be noted later, the most developed representations were found to employ the representation software known as DS3.5 from Accelyrs, now BioVia with the Jmol descriptive tabulations of molecular geometry being assembled into a data base by the Royal Society of Chemistry (London). After examining a large group of molecules involved in olfaction, it became obvious that while they partitioned into (sometimes very) large groups, there was no way to establish a pivotal member among each group. This led to a search of the potential olfactory receptors (OR) that could provide a partner in a dual antiparallel coordinate bond (DACB) relationship as suggested by Kier et al. in the 1970's. The chemistry of the odorants affecting the modality were virtually devoid of protein materials for valid reasons. Hence, the likelihood that the OR’s were of protein derivation appeared small. Riddiford noted during a roundtable discussion with his peers in 1971 that, “I think if one is ever going to find receptor proteins (assuming that they exist), then the insect system is probably the best one to examine5.” Riddiform then elaborated on the difficulty in isolating the proteins extracted from various cells and then determining their functional role.