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 equatorial and axial are introduced in definitions on page 30.] [xxx consolidate on angstrom or on nm throughout ] [xxx the choice of C(arboxylic)-path is more definitive than A(cidic)-path in differentiating from the H-best condition. Alternately, the label A(cetate)-path is more indicative of the actual (predominant situation. This path includes a large number of esters ending in -ate as well as the organic acids ending in -ic See Section 8.5.xxx.] [xxx G-Path clearly avoids duplication between the old and new set of path labels ] [xxx use the A-, G-, N - and P- path labels from now on, exccept in quotations. ] THIS CHAPTER IS PRESENTED IN DRAFT FORM AT THE CURRENT TIME BECAUSE OF THE NEED FOR THE INFORMATION BY THE GUSTATORY COMMUNITY. 8 Stage 1 & 2, Signal Generating & Processing Neurons1 “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 an in depth discussion of stage 1 operation (sensing) of the Gustatory Modality 8.5 The gustatory modality Excepting the group at the University of Wisconsin, there has not been a large amount of exploratory research into gustation with an academic focus since the 1980's. Most of the work continues to relate to product development in the food industry, generally under the rubric flavor rather than taste. Quoting van der Heijden in 1993, “Humans can perceive four tastes, of which sweet and bitter have received the most attention from scientists.” This will become evident when the sparse information concerning the elicitation of the acidic and salty sensations are reviewed. The literature fails to note the acidic sensation is based primarily on the sensing of organic acids. The sensation of salty is elicited almost exclusively by the hydrated sodium ion. While based on very fragmentary data, Boudreau has provided the most complete conceptual 1August 1, 2016 Signal Generation & Processing 8- 3 description of the overall gustatory modality2. Inconveniently, he uses the term ganglion in place of the more conventional nerve when speaking of the major nerves serving the oral cavity. The following discussion will repeatedly encounter conflicts between two different modalities of the neural system, the gustatory and the nocent modalities. While the gustatory modality is reasonably well understood at the concept level, its differentiation from the less well understood nocent (pain reporting) modality suffers. Many inorganic materials discussed in empirical gustation investigations (such as HCl and CaCl2 ) are actually nocentaphores. The nocentaphores will be discussed in Section 8.7. 8.5.1 Background for and summary--the gustatory modality hypothesis 8.5.1.1 Background 8.5.1.1.1 Historical documentation Cagan & Kare edited a comprehensive volume with a focus on olfactory transduction in 19813. The individual paper authors explored a broad range of potential transduction mechanisms. Some focused on the role of proteins on the surface of the sensory neuron membrane. Others focused on the potential for the lipids of the membrane to be involved in the primary mechanism. No conclusions were drawn. Kurihara, Miyake & Yoshii explored the work of Kamo et al4 in 1980. Kamo et al. attempted to mimic the sensory response of the gustatory neurons much as Hodgkin did for the visual modality sensory neurons (pages 249-286). Their equation 2 expresses the two-way operation of the proposed fundamental chemical reaction of the transduction process in abstract form. They then formulated a set of second order differential equations based on the Law of Mass Action (which requires a totally reversible reaction in solution). Unfortunately, there are a vast array of possible mechanisms that are satisfied by a second order differential equation. These include the quantum-mechanical mechanisms such as the production of nuclear isotopes. In their analysis, they ignored the rapidly rising attack transient and concentrated on the decreasing transient and the steady state value (prior to cessation of stimulation). However, their boundary conditions necessarily included the rapidly rising attack transient in their ultimate solution. While their particular solution of the differential equations is complete and includes the pulse condition (as opposed to just the impulse condition), there are two problems with their interpretation of it. First, they apparently did not treat the off-response properly by applying new boundary conditions. The off response is a direct and independent measurement of the second exponential in equation 2 and in the E/D equation of this work. Second, Kamo et al. did not treat the singularity within their equations properly. Their particular solution does not apply at w1 = w2. Removal of the singularity results in a different mathematical form that this author has labeled the Hodgkin condition (Section xxx). They noted Kashiwagura et al contained additional material on their investigation5. 2Boudreau, J. (1989) Neurophysiology and stimulus chemistry of mammalian taste systems In Teranishi, R. Buttery, R. & Shahidi, F. eds. Flavor Chemistry: Trends and Developments. Washington, DC: American Chemical Society Chapter 10 3Cagan, R. & Kare, M. ed. (1981) Biochemistry of taste and olfaction. NY: Academic Press Parts II & III 4Kamo, N. Kashiwagura, T. Kurihara, K. & Kobatake, Y. (1980) A Theory of dynamic and steady responses in chemoreception J theor Biol vol 83, pp 111-130 5Kashiwagura, T. Kamo, N. Kurihara, K. & Kobatake, Y. (1980) Interpretation by theoretical model of dynamic and steady components in frog gustatory response Am J Physiol (gastrointest.) Vol. 238, pp G445-G452 4 Neurons & the Nervous System Scott & Mark explored coding within the taste system in 19876. Their analysis relied upon the chemical theory of the neuron. Their abstract opens with; “Attempts to define the organization of the taste system in terms of the physical characteristics of stimuli have been largely unsuccessful.” They noted specifically, “Molecular weight and pH did not relate to the total organizaton of the system. “ Their work, employing multidimensional scaling (MDS)will be addressed below. Fisher & Scott reviewed the subject of food flavours in 19977. The work is entirely conceptual, with few substantive sketches, and is based on behavioral studies. It makes the conventional assumptions that taste involves either ion channels passing molecules through the sensory lemma or proteins on the surface of the sensory lemma. It does not demonstrate either of these concepts is correct, nor does it provide primary data relative to these concepts. Their table 3.1, from Kinnamon & Getchell, illustrates the continuing conceptual character of their thesis. Pages 85–87 provide a comprehensive list of conceptual gustatory features that suggest four basic taste sensory channels. Although dated, the discussion of the gustatory modality in Noback remains useful8. The description of the taste buds as bowl shaped features located behind pores in the lingual epithelium and containing on the order of 25 or more distinct gustatory sensory neurons is clear. He also notes the seldom reported high turnover rate among the sensory neurons, as opposed to just the sensory hair of each cell. “Each mature sensory neuron is replaced every 200 to 300 hours.” This turnover rate is similar to that of just the outer disks of the visual sensory neurons. It is also similar to the turnover rate of the piezoelectric proteins within the auditory sensory neurons. Like the retina of the visual system, the taste buds contain “sustentacular cells” that develop and replace the older sensory neurons. This replacement is associated with a transfer of the synapse with the orthodromic neurons from the old to the new sensory neuron. Noback also notes the neurons immediately orthodromic to the sensory neurons emerge from the taste bud and become myelinated immediately (therefore stage 3 neurons). As in the case of the auditory neurons, this suggests the encoding of the analog signals occurs at the first Node of Ranvier and not within the soma of these stage 3 neurons. This node of Ranvier occurs in what is conventionally described as the dendrite of the signal projection neuron. However, the myelinated neuron component directly after the encoding node of Ranvier is an axon segment. The number of gustatory sensory neurons is small, estimated at about 10,000 in human babies and the sensitivity of the modality is low relative to the olfactory modality (as many as 20,000 times the number of molecules are required for gustation as olfaction). However, it is probably the method of delivery more than the sensitivity of the receptors that is limiting. The quantum- mechanical character of the response of the gustatory sensory neurons suggest they are highly efficient at sensing molecules delivered to their immediate vicinity. The subject of taste modifiers (additional chemicals applied with the stimuli) and enhanced stimuli (stimuli with an additional ligand not found naturally) have not been introduced into a comprehensive theory of gustatory sensing. However, a few enhanced stimuli have been documented having perceived intensities as much as 30 to 10,000 times greater than the strongest natural materials. Most of the stimuli with an artificial gustaphore have been centered on the attempts to find artificial super-sweeteners, frequently with an auxiliary goal that they be non-caloric from a nutrition perspective.