Contains research objectives and summary of research on ten research projects.National Institutes of Health (Grant 5 R01 EY01149-02)National Institutes of Health (Grant 1 T01 EY00090-01)Bell Telephone Laboratories, Inc. (Grant)National Institutes of Health (Grant 5 TO1 GM00778-19)National Institutes of Health (Grant 5 TO1 GM01555-08

Binder, Michael J.

Brill, Michael H.

Gruberg, Edward R.

Hentall, Ian D.

Lettvin, Jerome Y.

Linden, Lynette L.

Lurie, Mark

Newman, Eric A.

Odette, Louis L.

Raymond, Stephen A.

Saidel, William M.

Schoendorfer, Donald W.

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XXI. NEUROPHYSIOLOGYAcademic and Research StaffProf. Jerome Y. Lettvin Dr. Edward R. GrubergDr. Michael H. Brill Dr. Stephen A. RaymondGraduate StudentsMichael J. Binder Eric Newman Don W. SchoendorferIan D. Hentall Louis L. Odette Susan B. UdinLynette L. Linden William M. Saidel Gregory WilliamsRESEARCH OBJECTIVES AND SUMMARY OF RESEARCHAs in past years, our objectives are diverse. Our long-range goal is to understandnervous action as it relates to mental action (e.g., perception, memory, and so forth).We are exploring different avenues into the problem, some of which prove to be blindalleys, or occasionally paths into research unrelated to our main purpose. In the comingyear we expect to study the following subjects.1. Membrane ProcessesNational Institutes of Health (Grants 5 R01 EY01149-02 and 1 T01 EY00090-01)Bell Telephone Laboratories, Inc. (Grant)Stephen A. Raymond, Michael J. Binder, Louis L. Odette, Jerome Y. LettvinDr. Raymond has constructed and begun to use a device for measuring nerve thresh-old. Contrary to common expectation, we have found that the threshold for singlemyelinated fibers in sciatic nerve of frog is constant under temperature changes of ±6 °Cand probably over a much wider range. (Threshold, however, must be both carefullydefined and measured.) As would be predicted, the small noise of threshold fluctuationdoes seem to change with temperature. We have not checked whether this noise is fas it would be according to theory. After testing a few pharmacologic agents, it is evi-dent that the measure is not only sensitive but reliable.The opportunities for research that open up are twofold. First, there is the develop-ment of a theory for threshold. No such theory exists at present. The Hodgkin-Huxleyequations express clearly enough the current-voltage-time relations of the nonlinear con-ductances whose actions account for the nervous impulse. But no theory of actual thresh-old issues for the same reasons as would prohibit such a theory in a triggered nonlinearoscillator where only the current-voltage-time relations are known. (The problem isfamiliar to anyone who remembers M.I.T.' s Whirlwind computer.) One must know thepulse generator in terms of which parts exchange heat and materials, and how dimen-sions change, and so forth. In nerve there are several processes strongly and explicitlyinvolved in setting threshold, and these are not given in the Hodgkin-Huxley equations.One is the so-called ionic pump that is driven metabolically. Another is the change ofinternal (and external) composition of fluids at the axon. A third is pH, as well as traceion composition, etc. Since it is unlikely that we can gain enough information about allof these variables, our theory will be crudely empirical at best, taking account only ofthose most obvious processes that change threshold greatly and systematically. Of thesethe pump is immensely important.The second opportunity has great practical consequence. It appears that underPR No. 115 317(XXI. NEUROPHYSIOLOGY)suitable arrangement one can study and actually fingerprint on peripheral nerve theaction of drugs that are best known for central influence. The method is being patented.Of scholarly interest in the procedure is that, with it, one can make qualitative inferencesheretofore available only from voltage-clamp data.Besides the threshold studies, we are also pursuing a generating function for m, n,and h as determined by Ca++ adsorption and desorption.2. Metabolic Processes in Nervous TissueNational Institutes of Health (Grants 5 RO1 EY01149-02 and 1 TO1 EY00090-01)Bell Telephone Laboratories, Inc. (Grant)Edward R. Gruberg, Jerome Y. LettvinIn 1955, O. H. Lowry, in a remarkable paper, found that the glycolytic and oxidativemetabolisms are differently distributed in retina. At the same time various anatomistsbegan exploring the localization of enzymes in tissue by staining for them. Most inter-esting, as well as frustrating, among their tools are the tetrazolium salts, beastly toprepare, capricious to use, and ambiguous in action. These tetrazolium salts accepthydrogeh ions in redox reaction with dehydrogenases and their flavoproteins, and pre-cipitate out as insoluble formazans, some of which are either intrinsically electron denseor easily take on, say, osmium to be viewed by electron microscope. Thus they competewith cytochromes in the process by which carbohydrates power a cell - and the theaterof action is where the enzymes cluster, in the mitochondria.Most important among the reliable findings with the tetrazoliums in the retina is thatsuccinic dehydrogenase is seen only in the ellipsoids and paraboloids of the rods andcones and nowhere else. So clean, so marked is this finding that Jay Enoch(Department of Ophthalmology, Washington University School of Medicine, St. Louis,Missouri) was able to use it in making a "photographic" plate out of the receptor layerof retina in succinate medium. He found that the stain occurred earlier where the recep-tors are light-adapted.How different is the distribution for the dehydrogenases of malate, lactate, and glu-tamate, from that of succinate! We find their investments in the plexiform layers andoptic nerve layer, in those processes that the pigment epithelium insinuates between theouter segments of rods down to the outer limiting membrane, and in the Miiller cells.All of these places are rich in mitochondria, but in mitochondria that, very suprisingly,lack succinic dehydrogenase. Furthermore, these nonsuccinic dehydrogenases alsoseem to differ among themselves with respect to distribution, the most oddly varied beingthe one that handles glutamate. We cannot yet perform the necessary microethology ofoxidative and glycolytic chains, but, as Lowry himself established by more acceptedmethods, they are indeed differently distributed through the retina.One of the most mysterious anatomical features of the retina is its lack of an intrin-sic circulation. No capillaries dip into its substance. And, indeed, its major circula-tion, the choroidal bed, is divorced from retina itself by a syncytial sheet, the pigmentepithelium that generates a large, constantly flowing electric current through the retinaby some ionic pump. The retina is a thick structure many cell layers deep and with anextremely large cell-surface/cell-volume ratio, if one takes the plexiform layers intoaccount. It is one of the most actively metabolizing tissues in the body and, togetherwith the pigment epithelium, needs all the circulation it can get. An obvious riddle,therefore, is how the cells deepest from the choroid, e.g., the ganglion cells, are nour-ished. Certainly the Miiller cells are admirable pipes and profuse enough. Given dif-fusion through their substance, aided, perhaps, by the standing current from pigmentepithelium, one might imagine the exponential falloff of nutriment with depth and thePR No. 115 318(XXI. NEUROPHYSIOLOGY)collateral exponential rise of excretion products to be diminished in space constant byflow through Miller cells. An additional mechanism, however, also suggests itself, thatis, the sharing of metabolism between cells. One way of insuring an equitable sourceof energy to structures further from the choroid would be to have their food the excretaof cells closer to the choroid. That is to say, if the metabolism in the earlier cells isincomplete, intermediary metabolites issuing from them would sustain later cells.Such a theory, although still hypothetical, has some attractive consequences. Thefirst is that not only the retina but the brain is, in a sense, undersupplied by its capil-lary circulation on the basis of cell-surface/cell-volume ratio, using other active tis-sues such as liver or glands as a guide. And while glia are everywhere in the brain,pedunculated to capillaries and shaping the spaces between nervous elements, there justis too much surface around to make the plumbing intuitively plausible. (Of course ourintuitions are almost always faulty, but let the observation stand.) Metabolic sharingin the brain as much as in the retina would be an attractive way of distributing the load.The idea of metabolic sharing would force a new view of the rash of "transmitter sub-stances," all intermediary metabolites, which are now so favored by pharmacologists.As the situation stands now, the experimental neuropharmacologist plunges the equiv-alent of a large standpipe through the close-woven fretwork of neuropil in the brain andthrough it forces a solution of some chemical that he suspects of synaptic action. Helooks for changes in behavior of the animal that suggest an excitement or depression ofthat part of the brain. These effects he interprets as an "imitation of actual nervoustransmission" in that region. But, were the sharing of metabolism a tenable notion, thenno surprise would be occasioned by the changed activity of neurons when their food sup-ply is suddenly enriched. Given the sharing, none of the cells, in the ordinary case,would be running replete, but rather partly starved, since the rate process governancewould be by the turnover from other cells. There should be, then, no local controls onconsumption, and, therefore, the ability to overdrive cells by enlarging their food sup-ply could be a consequence. These considerations are not wholly fantasy. For example,a new-born rat (or human) is extremely sensitive to circulating glutamate; in fact, asingle dose can kill off many retinal ganglion cells and certain other cells in the hypo-thalamus. Oddly enough, the optic nerve fibers from the ganglion cells stain heavily forglutamic dehydrogenase. But such evidence, rather than only suggesting that glutamateis transmitter to the ganglion cells, points also to the possibility that the cells live, inpart, by glutamate turnover. We intend to explore this possibility, using the molecularbeam analysis devised by Professor John G. King and his group, especially Dr. James C.Weaver, whereby to some extent one can map enzyme activity in the tissue localizingdown to a 10-4m diameter.3. Substantia Gelatinosa in Spinal CordNational Institutes of Health (Grant 5 RO1 EY01149-02)Ian D. HentallIt now appears that the cells of the substantia gelatinosa in the spinal cord of the catare not so difficult to record as previous published investigations have indicated. Lami-nae II and III can be tapped reliably and over long periods. The cells there share, withlamina I, a coding of noxious stimuli to skin and deeper tissues, but they also respondnicely to nonnoxious modalities, notably hair movement in the fur on the skin. Theirreceptive fields can be plotted. An account of these cells will form Ian D. Hentall's doc-toral thesis.The activity of units in this region may be excited antidromically by applying localstimulating currents to Lissauer's tract although difficulties exist in interpretation ofsuch experiments because of the unpure and difiuse nature of this tract. Only cells inlaminae II and III respond in such a way, although an entraining effect on the spontaneousPR No. 115 319(XXI. NEUROPHYSIOLOGY)activity of lamina IV cells has been observed. The concomitant field potential similarlyappears to originate in the substantia gelatinosa. These are the conclusions of prelim-inary experiments, but they remain to be substantiated in full.4. Behavior of Pigment Epithelium of FrogNational Institutes of Health (Grant 5 TO1 GM00778-19)Mark Lurie, Eric NewmanWe are hoping that Mark Lurie will return to advance his study of interaction betweenretina and pigment epithelium, which was the subject of his Ph.D. thesis research.1 Thefirst part of his findings is being prepared for publication, and is too extensive toabstract here. Suffice it to say that the activity of the pigment epithelium not onlyexpresses the state of dark adaptation of the eye, but the current that it generates isdirectly implicated in governing the activity of certain ganglion cells.References1. Mark Lurie, "Aspects of Interaction between Retina and Pigment Epithelium: AnElectrophysiological Study of the Circulated Frog Eye," Ph. D. Thesis, Departmentof Biology, M.I. T., June 1973.5. Electrophysiological Study of Behavior in StentorNational Institutes of Health (Grant 5 TO1 GM00778-19)Eric NewmanStentor coeruleus is a highly contractile ciliated protozoan that displays a wide rangeof behavioral characteristics. Preliminary experiments indicate that variations in themembrane potential of Stentor are related to changes in the behavior of the cell. Intra-cellular microelectrode recordings will be made in order to investigate the relation ofmembrane potential to cell contraction, stalk extension and shrinkage, membranellarand ciliary reversal, oral pouch contraction, and sensitivity to mechanical, chemical,and photopic stimuli.6. Color VisionNational Institutes of Health (Grants 1 TO1 EY00090-01 and 5 RO1 EY01149-02)Bell Telephone Laboratories, Inc. (Grant)Michael H. Brill, Lynette L. Linden, Jerome Y. LettvinWe have extended our earlier notions of color vision to account for the space of sub-jective color, that is, the colors actually seen and named. This extension involves atransformation from the space of color matching (which has a metric) to the space ofcolor seeing (which has no metric). The details are both controversial and not com-pletely worked out.PR No. 115 320(XXI. NEUROPHYSIOLOGY)7. Visual System in PigeonsNational Institutes of Health (Grants 1 TO1l EY00090-01 and 5 RO1 EY01149-02)Bell Telephone Laboratories, Inc. (Grant)Edward R. Gruberg, Jerome Y. LettvinWe are now preparing to study the optic nerve, diencephalic and mesencephalic struc-tures in birds. Two subsystems are the subject of our main attack, the nucleus rotundusand the nucleus isthi parvocellularis that Dr. H. Karten has plotted anatomically. Ourapproach will cover two main features, first, the complex coding of visual processes insingle fibers, easily seen and dissected in pigeons; and second, the modes of generatingcomplex receptive fields in tectum and diencephalon.8. Mechanism and Occasion of Color Change. in FlounderNational Institutes of Health (Grant 5 TO1 GM01555-08)William M. SaidelFlounders, as classically known, alter the shading of their outer surface to conformto the texture of their surround. The change in color is rapid, for a vertebrate, and issaid by some observers to be most vivacious in tropical species. Of the several inter-esting problems that this phenomenon brings to mind, two have become the subject forresearch at this laboratory. First, what is the mechanism and control of the colorchange, and second, what is the strategy of the change, and can it be given abstractly?We are exploring both questions before deciding which to pursue most deeply.a. The scales are possessed of chromatophores, melanin-containing cells, that, incontrast with the chromatophores of the cephalopods, do not vary in their external shape.Instead the pigment is either withdrawn to a tight cluster intracellularly or migrates outalong definite intracellular paths. Whether the pigment is withdrawn or migrates outseems to depend on a complementary innervation to the chromatophores, the neuronsissuing from sympathetic ganglia. Neither the anatomy nor the peripheral junctionalpharmacology is known. We are exploring this control now by dissection and stimulationof skin nerves.b. The chromatophores are not distributed uniformly and under independent control.Instead, very much as reported for octopus, the surface looks as if there are positionallyfixed "dark" centers more or less widely spaced and "light" centers also spaced. Thestrategy of coloration is to change the dark tone of the dark centers and spread the darktone into the surround of each center and, similarly, change the light centers. It is sur-prising to see how much the arbitrary textures of environment can be imitated by controlof the low and high spatial frequency components where the lowest spatial frequencies arefixed. We are testing a variety of ideas that all have to do with the nature of seen tex-ture, a basic problem that is under active study both in perceptual psychology and inArtificial Intelligence.9. Prosthetic Vocal CordsBell Telephone Laboratories, Inc. (Grant)Don W. Schoendorfer, Stephen A. RaymondCurrently available means of production of artificial speech for laryngectomizedpatients are clinically and socially inadequate. Progress has been made in the designPR No. 115 321(XXI. NEUROPHYSIOLOGY)and construction of new artificial vocal cords. In collaboration with Dr. Donald Shedd,of Roswell Park Memorial Hospital, Buffalo, New York, these new cords are being eval-uated by patients.Specifically, the new design employs the use of an old reed-fistula technique. Changeshave thus far been made only on the vocal cord design, but we intend to redesign thecomplete system eventually. The problem that we are now working on is twofold. First,the shape of the air pulse through natural cords for natural speech must be determined.Second, this determined shape must be matched by the artificial cords.PR No. 115 322

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