This work was originally undertaken to establish whether there are cells in the cerebral cortex which repolarize at different rates along their length during recovery from a discharge. This property of cortical cells was suggested by the fact that many responses to electrical stimulation of the cerebral cortex could be accounted for by the presence of such differentially-repolarizing cells in the cortex. Of these responses the paroxysmal or epileptiform afterdischarge caused by strong repetitive stimulation of the cerebral cortex seemed a likely candidate for investigation.

One of the earliest observations relating to the absorption of fat was made by William Hewson (1) in 1770. Although it had previously been suggested that the milky appearance of blood serum was due to “an admixture of chyle with the blood” (1) Hewson’s description of lipemic serum was the first to show that its turbidity was caused by the presence of fat. These remarkable observations apparently went unnoticed for many years, although numerous workers saw and described Hewson’s “globules” in blood.

The presynaptic events in cholinergic transmission raise three distinct problems: first, how the transmitter is produced; second, the form in which it is stored; and third, the means by which it is released. The postsynaptic events pose two further questions: how ACh. combines with the postsynaptic membrane and how it excites (or inhibits) the postsynaptic cell. The last of these questions is now fairly well understood (for recent reviews see Castillo & Katz, 1956; Weidmann, 1956), but little is known of how ACh. combines with the postsynaptic membrane. [...]

It is now over a century since Ludwig’s faaous discovery (1851) in which he demonstrated that the secretory pressure developed in the occluded submaxillary duct exceeded the carotid blood pressure. With this simple experiment Ludwig proved that the secretion is a process sui generis and not a simple filtration of plasma water and solutes through the glandular cells. However, most of the early workers on salivary secretion confined their studies chiefly to the investigation of the organic matter (protein and mucin) in saliva, and there was considerable debate as to the mode of elaboration of this organic material (Heidenhain, 1868, 1878; Langley & Fletcher, 1890; Henri & Malloizel, 1902; Carlson, Greef and Becht, 1907-8; Babkin, 1913).

In the present investigation, an attempt has been made to determine the neuronal mechanism underlying spreading depression. The objective has been to elucidate one of the ways in which the neurones of the cerebral cortex may influence one another in their activity, rather than to assess the role of spreading depression in the overall picture of cortical function.

An examination of the current and past literature reveals that there has been no lack of investigation on salivary glands, their secretions and secretory constituants. It is found, however, that of all the papers, monographs and theses dealing with the electrolytes present in saliva, only an insignificant number approach the subject of bicarbonate. Many explanations can be offfered for the apparent lack of interest in this ion, for the problems that it poses are considerable. [...]

During development, neuronal activity plays an important role in shaping functionalsynaptic networks. Moreover, in adults, neuronal activity is thought to produce long-termchanges during learning and memory. For these changes to persist, however, neuronalactivity must engage signaling pathways that result in alterations in gene expression.Pathways that activate the transcription factor CREB (cAMP-response element-bindingprotein), which binds to CREs (cAMP response elements) in gene promoters, have beenimplicated in this long-term, activity-dependent plasticity. The focus of my research is toinvestigate the mechanisms of CRE-dependent gene expression induced by physiologicalsynaptic activity. Together with my supervisor, I developed a sensitive biosensor tomeasure CRE-dependent gene expression in neurons; this biosensor consists of apromoter-reporter construct derived from the major immediate-early promoter/enhancerof the human cytomegalovirus (hCMV promoter) coupled to Green Fluorescent Protein(GFP). Our studies show that this promoter acts as an activity-dependent switch inneurons. The hCMV promoter functions poorly in unstimulated neurons, but is stronglyinduced by neuronal activity or other stimuli that activate CREB; moreover, site-directedmutagenesis of the five CREs in the promoter eliminated this inducibility. To express thisbiosensor in neurons, we used adenoviral-mediated gene transfer which has an efficiencyof>95%, allowing one to monitor reporter gene expression in individual neurons of afunctional network for several days. Using this system we, discovered that nicotine, atlow-levels in the range that circulates in smokers, acts in a distributed manner throughout a neuronal network to alter CRE-dependent gene expression induced by network activity . Further, exploiting the sensitivity of this biosensor, we found that weak neuronal activity,including spontaneous release of neurotransmitter, is a sufficient stimulus to recruitsignaling pathways that resu

This work arose from the chance observation of a phenomenon which had received almost no attention in the literature. The problem, because it was a new one, required exploration before the definitive experiment could be designed. The results described here are from these exploratory experiments; they do not explain the underlying mechanism of the phenomenon, and indeed they pose more questions than they answer. [...]

The experiments reported in this thesis were designed to answer three questions about the nature of respiration, 1 - Where are the respiratory neurones? 2 - What mechanism is responsible for their maintained bursts of activity? 3 - What mechanism initiates these bursts periodically? Thus this report is divided into three sections dealing respectively with the localization of respiratory cells, the mechanism of burst activity of respiratory neurones and the mechanism of respiratory rhythmicity.

Since biblical times, physicians have been challenged by the difficulties of finding the proper treatment for the disease of epilepsy. That challenge has not gone unanswered at any time in the recorded history of medical science. The quest for the solution of this problem is being carried out vigorously today on many fronts. The clinician and the research worker are helping each other to understand the nature of the disease, and to provide a rationale for its causes and treatment. Advances in the treatment of all diseases have gone hand in hand with increasing knowledge of fundamental biological phenomena.