Thesis (Ph. D.)--University of Chicago, 1919. / Caption title. Reprinted from the American journal of physiology, Vol. 49, No. 4, September, 1919. Includes bibliographical references (p. 522).

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Thesis (Ph. D.)--Indiana University, 2003. / Includes bibliographical references (leaves 114-122).

Thesis (Ph. D.)--University of Chicago, 1921. / Descriptive letterpress on versos facing the plates. "Private edition, distributed by the University of Chicago libraries, Chicago, Illinois." "Author's abstract of this paper issued by the [Wistar institute] Bibliographic service, October 22." "Reprinted from the Journal of comparative neurology, vol. 36, no. I, October, 1923." Bibliography: p. 75-77. Also available on the Internet.

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Although the quantity of glycogen in nervous tissue is small, in recent years it has been found that there is a significantly high turnover rate of this polysaccharide. Glycogen is present in sympathetic ganglia, midbrain structures, white matter, and synaptic regions. The enzymes of glycogen synthesis and breakdown exist in brain in high concentrations, which suggests that glycogenolysis may be coupled in some way to the energy-requiring processes concerned with electrical activity. In this thesis, the occurrence and activity of phosphorylase a, phosphorylase b kinase and phosphofructokinase were determined in peripheral and central nerve tissue, an attempt to purify phosphorylase b kinase was made, and the mechanisms controlling the activity of the brain kinase were studied. These experiments were carried out in an effort to learn more about the importance of glycogenolysis in the nervous system and the factors which control it. The results of a survey of dog nerve tissue and some experiments on rabbit tissue indicated that the enzyme levels in brain, superior cervical and stellate ganglia were comparable to those in heart. Other peripheral nerve tissue has approximately one-tenth the level found in brain. Heavily myelinated axonal tissue contained higher phosphorylase activity and much higher kinase activity than axons with relatively little myelination. It is suggested that glycogenolysis is likely to be concerned with synaptic transmission and Schwann cell metabolism. Attempts to purify one of the controlling enzymes in glycogenolysis, phosphorylase b kinase, from brain tissue were hampered by the instability of the enzyme and the consequent loss of activity that occurred at each purification step. A modest 3.0 to 3.5-fold purification was achieved by differential ultracentrifugation, freezing and thawing of the 100,000 x g precipitate, and a 0-35 per cent ammonium sulfate fractionation at pH 5.7. The enzyme exhibited increased stability when stored in 50 per cent glycerol at -18°, especially when it was present in a more purified state, but other attempts to increase the stability of the kinase met with little success. The maximum activity of brain phosphorylase b kinase occurred between pH 8.75 and 8.9, and a significant activity was noted at pH 7.0, which is somewhat different from that found in other tissues. However, the brain kinase is activated by mechanisms similar to those found for skeletal and cardiac muscle. The activity at pH 6.8 is increased by preincubation with Ca⁺⁺, and further increased by the addition of rabbit skeletal muscle calcium-activating factor. This is partially prevented by beef heart calcium inhibitory factor. ATP-Mg⁺⁺ and cyclic AMP also cause activation of the brain kinase. The total activation of the brain enzyme appeared much lower than that found in skeletal or cardiac muscle due to the already high activity at pH 7.0. Experiments designed to produce an accurate value for the pH 6.8/8.2 ratios of kinase activity utilized freezing of mouse brain in vivo in liquid Freon cooled to its freezing point. The value of 0.44 obtained from these procedures was similar to, or slightly higher than, the ratios in rabbit and beef brain. The kinase was not inactivated by room temperature incubation for two hours, although similar treatment would convert phosphorylase to its inactive form. The possibility remains that the pH 7.0 activity is artificially high, assuming the freezing techniques used are not fast enough. Otherwise, the high enzymatic activity may be due to the continuous electrical activity present in the brain. The possibility that glycogen catabolism is a more important source of energy in the nervous system than previously thought is supported by the high levels of enzymatic activity and similar phosphorylase b kinase control mechanisms to those in other tissues. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

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Sensory transmission was studied in trigeminal root ganglia (TRG) of guinea pigs, using intracellular recording techniques. One approach was to examine in detail the effects of applications of different K⁺-channel blockers on the membrane voltage responses and outward currents of TRG neurons, in order to better understand the fundamental processes that affect their excitabilities and repetitive spike discharge. The second approach was to examine several endogenous substances for their effects on the excitabilities of TRG neurons. In addition, a strategy was developed for electrophysiological recording from neurons in human sympathetic ganglia. Successful investigations of these neurons revealed properties similar to certain reported characteristics of sympathetic neurons in experimental animals, including high (~29 MΩ input resistances, pharmacological sensitivity of spikes to the specific Na⁺-channel blocker tetrodotoxin (TTX, 1 µM) and to selective K⁺-channel blockers -- 4-aminopyridine (4-AP, 1 mM) and tetraethylammonium (TEA, 10 mM). The investigations demonstrated the potential value of these in vitro preparations for studies of the human condition. The investigations in TRG neurons demonstrated that bath applications of TEA (0.1-10 mM) and 4-AP (0.05-5 mM) or Cs⁺ applied internally from the recording electrode, produced an increase in input resistance and a decrease threshold for spike generation in all neurons. Also, applications of 4-AP increased subthreshold oscillations of the membrane potential and enhanced the repetitive spike firing evoked by intracellular injections of current pulses, or elicited spontaneous firing. In contrast, TEA or Cs⁺ applications blocked the oscillations and the spike afterhyperpolarizations (AHPs) without exaggerating repetitive discharge. These investigations suggestedthat several pharmacologically distinct K -currents contribute to the control of excitability in TRG neurons. Comparison of combined actions of 4-AP and TEA with those of Cs⁺, suggested that other ions in addition to K⁺ may contribute to postspike events. Single electrode voltage-clamp analyses revealed transient outward currents that were evoked at the termination of hyperpolarizing voltage commands from holding potentials near -40 mV. The activation was rapid (<5ms) and inactivation (T≃19 ms) complete at potentials within the activation range (-40 to -75 mV). During combined application of TTX (1 µM) and TEA (10 mM), fast activating, sustained currents (>1 s) were evoked by depolarizing commands from holding potentials near -70 mV. These currents were blocked completely by the additional applications of 4-AP (5 mM). Applications of TEA (0.1 mM to 10 mM) produced dose-dependent reductions of the transient outward currents. Applications of Cs⁺ also blocked the currents. However, administrations of 4-AP (0.05 to 5 mM) only slightly reduced these currents and high doses of muscarinic agonists had no effect. The high sensitivity to TEA, and not to 4-AP, suggest a fundamental distinction from similar currents observed previously in other neurons of vertebrates and invertebrates, and hence this transient outward current in TRG neurons, is termed I(T)- The kinetics of I(T) suggest its involvement in the spike AHPs. Therefore, blockade of I(T) by TEA may interfere indirectly with the re-activation of voltage-dependent Na⁺-channels, leading to decreases in repetitive discharge ability. The TEA-insensitive sustained outward current presumably has an inhibiting influence on repetitive discharge. Conditions that interfere with this current, such as blockade of K⁺-channels by 4-AP without a significant blockade of I(T), strongly favour the generation of repetitive discharge in TRG neurons. The investigations using electrical stimulation of axons revealed that changes in the resting potential could inhibit the invasion of spikes into the perikarya, or facilitate the generation of ectopic spike discharges. Applications of 4-AP (1 mM) facilitated the perikaryal invasion of spikes evoked by axonal stimulation, and also resulted in the appearance of fast (~10 ms) depolarizations that reached spike threshold in the absence of applied stimuli. These investigations provided direct evidence that the perikarya of sensory neurons are capable of spike generation, and suggest that this behavior may occur in normal or pathophysiological conditions. The most notable effects of autacoids were those of substance P and histamine, whereas bradykinin did not affect neuronal membrane properties. Applications of substance P in micromolar doses evoked large (up to 45 mV), reversible depolarizations in the majority of neurons, whereas histamine applications produced similar depolarizations only in a small portion of the TRG neurons. Increases in the repetitive discharge abilities of neurons were evident during substance P-induced depolarizations. Studies on the ionic mechanism of substance P action revealed that the peptide-applications resulted in activation of inward currents as well as blockade of outward currents. In addition, it was shown that Na⁺ and Mg²⁺ were involved in the mechanism of action. These findings represent the first demonstration of the profound actions of substance P on the perikaryal membranes of sensory neurons in mammals. The excitatory actions of this endogenous peptide also give rise to the possibility of physiological actions of substance P at multiple sites in the trigeminal system. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate