R. W. Gerard

OXYGEN DIFFUSION INTO CELLS

The question of diffusion of oxygen into cells, in distinction to tissues, requires examination of several factors not previously considered. The relation between external oxygen pressure and rate of respiration may be complicated by the existence of different diffusion constants and respiration rates in separate cell zones.Equations are developed covering such cases for two concentric zones in a sphere and relating rate of respiration to oxygen concentration, cell radius, and diffusion coefficient.When the assumption, made in similar studies for tissues, that consumption in any one region is independent of oxygen pressure if above zero, is avoided, the observed consumption-pressure curve can be corrected for diffusion effects to give the true consumption-pressure relation. Equations for this correction are presented.Available data on bacteria, marine eggs, and other material, are examined quantitatively. It appears very probable that oxygen consumption in each region is dependent on oxygen concentration ...

Mechanism of Nerve Asphyxiation: With a Note on the Nerve Sheath as a Diffusion Barrier.

In the absence of oxygen nerve conduction is suspended in several hours, the activity of each fibre becoming gradually less until it blocks. Conduction has been shown to depend on oxidations, and the long persistence of activity with outside oxygen excluded to depend on the existence in nerve of an oxidizing reserve. The rapid recovficial action of Ringer on a nerve that has failed to recover from cold block. Finally nerves soaked in isotonic NaCl for 40 minutes before the start of asphyxia, though still fully recovering in oxygen, no longer show any recovery in Ringer. Nerves soaked in NaCl followed by Ringer behave as if they had been in Ringer throughout.

Experimental studies of behavioral effects of meprobamate on normal subjects.

With the increasing use of meprobamate, it is important to know its effects on the behavior of relatively normal subjects, on persons who take the drug without discontinuing their usual activities. We need detailed information about the effects of the drug on those common but complex acts in which most people engage as part of their daily lives. One of these activities-potentially dangerous if not properly carried out-is driving an automobile. How does meprobamate affect the motor skills, the sensory processes, and the judgment necessary for safe driving? Does meprobamate in usual doses, alone or in combination with a martini or a drink of whiskey, make it likely that a driver will endanger his own life or the lives of others? The answers to these and related questions have become increasingly important in view of the rapid changes occurring in our modern world. Although some information on these issues can be obtained from general observation and from subjective reports, our knowledge about the drug’s effects will be much sounder if the data are obtained under standardized and controlled conditions. Our research, including studies of reaction time, driving skills, steadiness, and visual performance, was designed to accomplish this.

Cerebral Action Potentials.

The following observations, some confirmatory, based on experiments on 8 cats and 2 monkeys, were made during an exploration of the cerebral cortex and underlying structures for spontaneous and evoked activity. Anatomical relations given are only approximate; the work is being continued with the aid of a Horsley-Clark stereotaxic instrument. Action potentials picked up by an Adrian-Bronk electrode, amplified, and fed into a loud speaker and high-voltage cathode ray oscillograph, were the index of activity. Numerous controls have convinced us that extraneous pick-up did not confuse true action potentials in the phenomena described. For example, during penetrating movement of the needle of less than 1 mm. there appeared successively: nothing, strong auditory responses, nothing, strong optic responses, nothing. Clearly, responses may be highly localized, and a non-specific spread is excluded. Auditory responses were obtained from the temporal cortical surface, projection tracts, auditory thalamus, and lower structures in the monkey, from all but cortex in the cat. With the electrodes on a large tract, responses were obtained to stimuli near the human threshold. Different sounds (e. g., watch tick and voice) and pitches are recorded most strongly at different needle positions, indicating a spatial separation of impulses set up by different pitches. Similarly, a fairly sharp di-, tri- or polyphasic wave appears on the oscillograph for each watch tick. The form differs from R. to L. ear for one needle position, and for one ear at different needle positions. Considerable discharge was usually present in the pathways even without deliberate sound stimulation. In the monkey, a stimulus at 660 d.v. gave a standing wave of the same frequency on leading from auditory tracts, a completely asynchronous discharge, stronger at the start, from the cortical surface. In the cat and monkey, melodies could usually be recognized on leading from auditory tracts, although words were garbled.

Nerve Conduction in Relation to Nerve Structure

The Department of Physiology, The University of Chicago IT IS historically true in all science that structural knowledge usually precedes functional. In biology, anatomy was far advanced when physiology hardly existed. This is natural enough, since dynamics are more complicated than statics, and since, moreover, the anatomy of a machine may be described with no knowledge of its action while its action is usually meaningless if the structure is not understood. The anatomy may be described, but it remains a jumble of parts and dimensions until seen in relation to its function. In the nervous system, beyond comparison with any other organ, the cell structure and the intercellular connections are so elaborate that even the anatomical facts have been slow to appear. The physiological knowledge is correspondingly very meagre; but enough exists even so to suggest some of the ways in which this complicated structure may be understood in terms of function. As an indication of the type of correlalation possible, it will be recalled that different axons and dendrites in the individual peripheral nerves have variable fibre diameters (96, I27, i28). It is now known that the functioning of a nerve fiber depends in a very direct manner on its diameter and that nerve fibers of larger diameter conduct more rapidly (6i), are more asily excited (I03, IO5), and respond to external influences in different ways than do other fibers of smaller diameter. It has been shown, in fact, that the fiber groups of a given size tend to carry impulses related to definite functions; the large fibers, for example, carry motor and proprioceptive impulses, the smaller ones transmit impulses aroused by pain stimuli (46, 6z). The above does not imply that for every type of sensation or effector action there exists a unique type of nerve fiber. It has been shown histologically that a single sensory fiber may branch and reach endorgans of quite different anatomical character and presumably, therefore, of not identical function (II4, I33). Also, there is physiological evidence in the trigeminal nerve, nearly all fibers of which divide on entering the medulla and run to separate nuclei, that touch sensations are relayed only through one nucleus, pain only through the other (63, I40). The separation of impulses carrying these two sensations apparently occurs at the synapses in these two regions. The purpose of this paper is to indicate some of the relations that can now be stated or surmised between structure and function in nervous tissue, and still more, to point the direction in which further information isneeded. Before considering this problem, it is necessary to introduce some of the present knowledge and concepts regarding the nature of conduction in the nerve fiber and across the synapse.

Automaticity of Central Neurones After Nicotine Block of Synapses

The discovery that central neurones manifest a rhythmic electrical potential in the absence of deliberate sensory stimulation suggested that these cells possess an automatic beat homologous to that of the cardiac nodal cells. The possibility of nerve impulses, either from receptors or injured nerves or from closed circuits of interneurones∗ with long maintained activity, had not, however, been excluded. The persistence of a marked potential rhythm in the frogs olfactory bulb for hours after its complete removal and at a time when its only neural connections—the olfactory nerves and cerebral hemispheres—were electrically dead 1 seemed to eliminate any action of impulses from receptors or injured neurones. Since, however, stimulation of the olfactory nerves of such a preparation increases the bulb potentials or even reinitiates them after they have stopped and since this enhancement may persist for many minutes or hours following a brief stimulation 2 the existence of trapped impulses in closed circuits remained a definite possibility. This has been urged especially by Lorente de No. 3 In the present experiments it is shown that when synaptic conduction is blocked by nicotine the rhythmic slow potential waves of the isolated bulb are increased rather than abolished. It may be concluded, therefore, that the activity rhythm originates in single neurones and is immediately independent of any maintained or recurrent bombardment by conducted nerve impulses. Nicotine has long been used to block synaptic transmission in autonomic ganglia 4 and is also known to exert a curarizing action. 5 , 6 We have found no reference, however, to a similar effect on central synapses, though Langley 7 reported some experiments indicating its occurrence. The following facts evidence such a central blockade at all synapses tested: 1. Local application of 0.1 % nicotine to the exposed spinal cord in the frog abolishes in 15 min. cross reflex responses to stimulation of the central end of a cut sciatic. Peripheral sciatic stimulation remains effective. Langley 7 published a similar observation. Even after strychninization, reflex block is produced by nicotine. Stronger nicotine (0.5%) abolishes motor responses to electrical stimulation of the cord itself though the lower concentrations do not.

An analysis of some correlates of steady potentials in mammalian cerebral cortex.

Abstract An analysis of some aspects of steady potential (SP) phenomena, especially in relation to some earlier experiments on SP correlates of hyperventilation and of epileptiform potentials during spreading depression is presented. The findings by others of SP shift with asphyxia, anoxia, cerebral ischemia and excess CO2 do not appear to explain the positive cortical SP shift during brief hyperventilation. While the polarity (and amplitude) and the incidence of epileptiform (and other) potentials show some correlations with intrinsic SP level and polarity across cell layers, such as the cerebral cortex, these correlations are far from consistent in degree or direction in all different conditions or neural tissues. On the other hand, the correlations of these functions with changes in SP that are induced by polarizing currents applied across such cell layers are highly consistent. Reasons are offered for considering this latter relationship to be a more significant index of the role of SP in these functions. In discussing the possible mechanisms that may produce the observed synchronization or coupling of epileptiform potentials at different points on the cortex, it is suggested that the local process which permits or facilitates the development of such potentials should be considered as one that is potentially distinct from more purely synchronizing mechanisms.

NERVE METABOLISM AND FUNCTION: A CRITIQUE OF THE ROLE OF ACETYLCHOLINE

Clearly, the acetylcholine system is the theme around which these papers have been arranged. The various hypotheses as to its functional significance, and especially the one regarding it as an essential coiiiponent in conduction in the nerve fiber, have proven most fertile in rcsearch suggestions-withcss the many studics here reported and the animated discussion of them. Yet, I must close with the judgment, on the basis of what has been said here, that this hypothesis lius now exliaustcd its usefulness. May I first offer, as evidence of my own long sympathy to the view I shall shortly be dissecting, a quotation or two from my early writings? “It remains to correlate this material [on heat and metabolism] with some actual mechanism of conduction. The current view that activity of one portion of a nerve fiber is the stimulus to the adjacent portion and so along the entire fiber has much to support it, especially in tlie form developed by Lillie. Recent evidence indicates that conduction itself may be analyzed into two phases occurring repeatedly in eucccssion. The first is an explosive type of chcmical change in a portion of the membrane surrounding the nerve fiber, and it leads, probably by local potentials, to ion movements within the fibcr, which constitutc the second phase. Local concentration of ions against an adjacent portion of membrane initiates here the explosive change, and so on. Yrobably the ion movements are associated with only a small fraction of tlic energy changes, and with the behavior of the membrane during and after conduction’’ (p. 499’). “ . . . In this way, i t is obvious, a wave of electric and chemical change must spread along the nerve fibcr in both directions from tlie point first stimulated. This is the nerve impulse, a propagated excitation. . . . Certain steps in this dcvelcpmcnt are hypotlictical, and i t must bc rccognizcd that the picture has been simplified to a incrcst skclcton.

The two phases of heat production of nerve

IN a previous paper(l) it was shown that medullated nerve (sciatic of Rana esculenta) produces more heat during activity than rest, the excess amounting to 6-9 x 105 cal. per gram per sec. of stimulation. An approximate analysis was presented which suggested that there exist two phases-a relatively short and intense one lasting during stimulation, and a less intense one prolonged for nine or more minutes. This analysis, however, was not exact enough to make us certain of the interpretation, and the present study was undertaken to secure more decisive evidence.

Phosphate (P32) exchange in brain phospholipids in vivo and in vitro.

Summary In vitro, the specific activity of the phospholipid phosphate reaches a maximum within 20 minutes after the start of incubation, while in vivo the specific activity of this fraction rises continuously for at least 20 hours after the intraperitoneal administration of P32. When the lipid extract is divided into crude fractions, it is observed in in vitro experiments that the specific activities of these fractions are markedly dissimilar. Conversely, the specific activities of these fractions are approximately the same when obtained from the brains of rats that had been injected with P32 20 hours previously. some of the factors involved in these findings have standard microbiological method.