Contemporary Neuroscience – serie

This text is a treatise drawing together and critically examining the current explosion of experimental and clinical research on the metabolism, nutrition, pharmacology, toxicology, pathology, neuropsychology, and developmental neurobiology of trace elements.

F. Macfarlane Burnet I have been an interested onlooker for many years at research on the biology of trace elements, particularly in its bearing on the pas­ toral and agricultural importance of copper, zinc, cobalt, and mo­ lybdenum deficiencies in the soil of various parts of Australia. More recently I have developed a rather more specific interest in the role of zinc, particularly in relation to the dominance of zinc metalloenzymes in the processes of DNA replication and repair, and its possible significance for human pathology. One area of special significance is the striking effect of zinc deficiency in the mother in producing congenital abnormalities in the fetus. The fact that several chapters in the present work are concerned with this and other aspects of zinc deficiency is, I fancy, the editors jus­ tification for inviting me to write this foreword. In reading several of the chpaters before publication, my main impression was of the great potential importance of the topic of trace metal biology in both its negative and positive aspects-the effects of deficiency of essential elements and the toxicity of such pollutants of the modern world as lead or mercury mainly as or­ ganic compounds.

This book, covering many key aspects of autonomic nervous system maturation, was suggested by the success of a symposium on the developing autonomic nervous system held at the Spring 1982 meeting of the Federation of American Scientists for Experi­ mental Biology (Federation Proceedings 1983, 42, 1609). It was obvi­ ous from the F ASEB symposium that there is increasing interest in the developing autonomic nervous system, particularly with respect to its role in regulating visceral function. Some additional topics that were not covered in the F ASEB symposium are also included in this book. The editor feels that the readers of this volume are, in all probability, already cognizant of the state of knowledge of the adult autonomic nervous system. Therefore, a review of classical autonomic physiology, pharmacology, and neuroanatomy is not provided. For a recent detailed discussion of the ontogeny and phylog­ eny of the developing nervous system, I would recommend the book published not long ago by D. Purves and J. W. Lichtman, Principles of Neural Development (Sinauer, Sunderland, MA, 1985). Another recent book, Autonomic Nerve Funtion in the Vertebrates by F. Nilsson (Springer-Verlag, New York, 1984), presents a compar­ ative examination of autonomic nervous system function in verte­ brates. For a summary of recent advances in the many aspects of catecholamines as they bear on autonomic nervous system re­ search, I would recommend the series of three books edited by E.

Scientific investigations of a descriptive nature involve in­ creasingly refined definitions of a problem. An idea is trans­ formed after initial experiments into a working hypothesis that has a number of testable consequences. Rarely in the neurosci­ ences do such tests completely falsify the hypothesis; more commonly they lead to a modified, more general hypothesis. One could argue that in order to define a scientific problem, one must first understand it. This monograph is an attempt to draw together knowledge and understanding from various disciplines, collected from studies carried out over more than 80 yr, of the functions of the auditory midbrain. This part of the brain has been of continuing interest to me, from my days as a postgraduate student in the mid-1960s to the present time, because so many ideas about central auditory organization and function have developed from studies of this region. This book is dedicated to Jerzy E. Rose, Professor Emer­ itus of Neurophysiology atthe University of Wisconsin. His intellect and clarity of mind have been responsible for many of the modern ideas of auditory neurophysiology. These ideas have been incorporated into a series of classic papers on audi­ tory neuroscience that will be important for a long time to corne. In addition, Jerzy Rose has been an inspired teacher whose precepts of brain structure and function have been a major influence on his students, including the author.

Psychopharmacology may be defined as the study of the effects of drugs on behavior. As an established scientific discipline, this is a relatively new area of research. Despite its short history, however, psychopharmacology has achieved a considerable degree of sophistication in the variety of experi­ mental approaches that are currently employed. Consequently, the interpretation of data accumulated through the use of various experimental laboratory techniques has become increasingly difficult and complex. Numerous excelIent texts and review articles are available that serve to outline recent progress in psychopharmacology (particularly the Handbook of Psychopharmacology series, edited by L. L. Iversen, S. D. Iversen, and S. H. Synder). Volumes such as these serve to usefully review the available litera­ ture without attempting a critical appraisal of the utility and limitations of methods and the difficulties of interpreting empirical data. Such conceptual and methodological problems are now an issue of paramount importance in studying the behavioral effects of drugs. The present volume can be regarded as a "conceptual cookbook" that examines the utility and limitations of various experimental approaches commonly taken in psychopharmacology. This practically oriented text should prove particularly useful for pharmacologists and neurochemists who have no formal training in behavioral research and require an intro­ duction to the actuallaboratory practice of the field. In addition, the useful and informative treatment of current issues in psychopharmacology will undoubtedly appeal to the majority of active researchers.

The idea for this book has evolved from our desire to present a conceptual approach to the study of neurotransmitters in epilepsy. Such an approach requires an understanding of the function of neurotransmitter systems in various experimental models of epilep­ sy. Toward this goal we have included in this book chapters on neurotransmitter systems in nine different epilepsy models. To com­ plete the coverage of this topic, there is a chapter on the role of selected neurotransmitters in the various types of human epilep­ sies. In the final chapter the editors integrated the neurotransmit­ ter data from the various epilepsy models into a matrix from which a better understanding of the function of these neurotransmitters in modulating epileptogenesis may be obtained. The information found in this book is not the result of a sym­ posium on this topic, but rather a review of available information on neurotransmitters in each of the experimental models. The evi­ dence is presented by knowledgeable researchers using these models. This approach gives a current, broader, and more thorough presentation of each of the topics. We therefore feel that this is not just a glimpse at the subject matter, but a panoramic view of the topic.

Even before the time of organized scientific investigation, hu­ mans had begun pondering and attempting to explain the work­ ing of the brain and the mental and behavioral states it produces. In the last twenty years there has been an almost explosive in­ crease in brain research. Beginning perhaps with the pioneering efforts of Francis O. Schmitt to establish the Neuroscience Re­ search Program and the later development of the Society for Neuroscience, there has emerged a large and powerful multi­ disciplinary research force devoted to understanding even the ru­ dimentary aspects of brain functioning. Chemists, physicists, and engineers with their special expert­ ise in quantitative physical measurements have teamed up with the neurobiologists, who best know the texture and design of brains, to produce particularly effective new approaches. No­ where is this more evident than in the recently developed meth­ ods like positron emission tomography and magnetic resonance imaging-techniques that allow one to observe on-going brain ac­ tivity in humans. This volume concerns a considerably more modest approach: the use of microelectrodes to electrochemically monitor certain aspects of chemical dynamics in functioning ani­ mal brain systems. The method provides signals that can be di­ rectly related to chemical neurotransmission. It is a relatively new technique, the first practical measurements having been made in the 1970s, and it is continuously undergoing refinement. The organizer of this book, Jay Justice, is eminently qualified for the task.

Research into the processes of tolerance and sensitization has escalated at a substantial rate in recent years, presumably because of the fundamental importance of understanding the long-term, as opposed simply to the initial, acute effects of drugs. The rapid of such research in recent years is documented c1early by growth the editors in the introductory chapter to this text. However, despite the fact that there is a very large amount of literature concemed with the effects of long-term drug treatment, there is, to the best of our knowledge, no published text that has ever attempted to integrate some of the many diverse findings that have been made in this area. Basic research has uncovered a num­ ber of different mechanisms by which tolerance and sensitization to drugs can develop. Such mechanisms are of very different types, involving psychological behavioral, metabolic, neuronal, and subcellular processes. Because of the complexity of each of these different types of mechanisms, with few exceptions, individual re­ searchers usually tend, understandably, to concentrate on their own specific areas of expertise, paying relatively little attention to rele­ vant research occurring in other areas. Consequently, they neglect or simply ignore the important question of the relative importance of the specific mechanism that they are studying, and the related question of the possible interrelationships that may exist between different mechanisms for the production of tolerance and sensitiza­ tion.

Leading experts critically summarize the state of knowledge concerning the molecular, anatomical, physiological, and behavioral aspects of NPY and its congeners. Each article provides a comprehensive and in-depth survey, an overview of the role of NPY in the discipline covered, a discussion of the likely future direction that the field will take, and an up-to-date bibliography. Chapters include a treatment of the evolution of the PP family of genes, the structure of the NPY gene, and the distribution of NPY on the cardiovascular system, actions of NPY on the electrophysiological properties of nerve cells, and the effects of NPY on feeding and behavior. The chapters are written in an accessible style and serve both as an introduction to the field and as an extensive and detailed treatment of the current state of knowledge.

In Neurotherapeutics: Emerging Strategies neuroscientists, clinicians, and industry-based pharmacologists and chemists review emerging approaches for the treatment of diseases of the central nervous system. The contributors - all key investigators of novel therapeutics - focus on developing rational strategies for drug design based on the new understanding of the underlying pathophysiology of central nervous system diseases. In the process, the contributors review the efficacy and mechanisms of current treatments as well as the latest research results and their potential therapeutic impact. Common to all chapters is the promise held out by newly cloned receptor subtypes of therapeutics with improved selectivity and potency. Also explored is the potential for novel therapeutics from a developing understanding of signal transduction. The diseases discussed range from affective disorders and Alzheimer's disease to Parkinson's disease and schizophrenia, as well as anxiety, panic disorders, stroke, epilepsy, and Huntington's disease.

It is now established that neuroglia are the intimate partners of neurons and that neuronal function is a result of neuron-glia interrelations at several levels of organization. The literature shows that the study of phylogeny has contributed a deeper understand- ing of the complex functions of the neuroglia and the neuron-glia unit. It is the purpose of Neuron-Glia Interrelations During Phylog- eny: I. Phylogeny and Ontogeny of Glial Cells, as well as its compan- ion volume Neuron-Glia Interrelations During Phylogeny: II. Plasticity and Regeneration, to present to the scientific community a broad spectrum of information on neuroglia through phylog- eny and ontogeny, the focus of this volume. In view of the role of neuroglia in plasticity and regeneration, the companion volume will cover this aspect of neuroglia during phylogeny. Neuron-Glia Interrelations During Phylogeny: I. Phylogeny and Ontogeny of Glial Cells begins with the elegant chapter "Glial Types, Gliogenesis, and Extracellular Matrix in Mammalian CNS" by Amico Bignami, to whom this volume is dedicated.He was one of the pioneers in describing gliogenesis and this chapter brings together everything we know today on this critical topic. It also includes the latest views of Bignami on the role of extracellular matrix in gliogenesis and glial functions. "Evolution of Astrocytes in the Vertebrate CNS" by Suarez et al. complements and extends the information in Bignami's chapter by including ependymal astrocytes.

It has been established that neuroglia are involved in early neu- ronal growth, differentiation, and migration; these issues are well discussed in the companion volume entitled Neuron-Glia Interrela- tions During Phylogeny: I. Phylogeny and Ontogeny of Glial Cells. The present volume, Neuron-Glia Interrelations During Phylogeny: II. Plas- ticity and Regeneration, focuses on two aspects: (1) neuron-glia inter- relations as they relate to the physiological and metabolic homeostasis of neurons; and (2) the role of neuroglia and neuronal plasticity in regeneration and aging. Neuron-Glia Interrelations During Phylogeny: II. Plasticity and Regeneration begins with the unique presentation, "Neuron-Glia In- teractions in the Human Fetal Brain," by Sogos et al. The interesting issue discussed in this chapter is the immunocompetence of the CNS, a field that is now rising. The chapter by Oland et al. , "Glial Cells Playa Key Role in the Construction of Insect Olfactory Glomeruli," discusses a unique role of glial cells as intermediates in afferent- axon induction of substructure with the CNS.The chapter by Vanhems, "Insect Glial Cells and Their Relationships with Neurons," compliments the information presented in the companion volume by Fredieu and Mahowald and, in this volume, the chapter by Tobert and Oland. The chapter by Tsacopoulos and Poitry, "Metabolite Exchanges and Signal Trafficking Between Glial Cells and Neurons in the Insect Retina," provides evidence of the nutritive functions of glial cells and the important role of alanine supplied by glial cells to photoreceptors, a clear neuron-glia interaction.

In Motor Activity and Movement Disorders thirteen state-of-the-art articles explicate forefront research methodologies for measuring and interpreting motor activity in animals, as well as their applications to preclinical and clinical research involving motor disorders. The contributors emphasize motor asymmetries, turning behavior, and dyskinetic movements. They also present a variety of quantitative approaches designed to assess specific aspects of motor activity and illustrate numerous computerized measuring techniques that permit detailed and objective approaches to quantifying motor behavior. Motor Activity and Movement Disorders will contribute to a greater understanding of brain behavior relationships through its focus on methodology and its application to current animal models and to human disorders.

The past decade has witnessed a revolution in the attempts of scientists to under­ stand the molecular basis of dementia. Although dementia, as defined by global cogni­ tive decline involving gradual loss of memory, reasoning, judgment, and orientation, presents most commonly in the form of Alzheimer's disease (AD), an assortment of other less common disorders, such as prion and Pick's disease, can also lead to symp­ toms that are similar to those observed in patients with AD. The primary goal of Molecular Mechanisms of Dementia is to address the various mechanisms and multi­ faceted approaches currently being employed to more clearly delineate the etiological and pathogenic events responsible for the onset of dementia. Perhaps the greatest boon to obtaining a clearer understanding of the causes of AD has come from genetic and molecular biological studies carried out over the past decade. At the genetic level, it has become increasingly clear that AD is a heteroge­ neous disorder that can be broadly classified into two categories. "Late onset" (>60 yr) cases, which account for the vast majority of AD, genetically involve "susceptibility" genes representing risk factors for the disease (e. g. , inheritance of the 84 allele of the Apolipoprotein E gene). In many cases, the susceptibility gene can act as a "modifier" that modulates the pathogenic cascade occurring subsequent to a separate etiological event "initiating" or "causing" the disorder.

A distinguished international panel of authors define our current understanding of neuronal damage after ischemia and critically review the significant recent developments and progress in cerebrovascular accident (CVA) drug trials, both in animal models and in the clinical setting. These leading basic and fundamental authorities survey such important new drugs as calcium-influx inhibitors, free-radical scavenging drugs, glutamate and glycinergic antagonists, and immune suppressors. They also evaluate all the latest findings concerning calcium homeostasis, glutamate toxicity, gene activation, and the role of free radicals, glycine, and hormones. Chapters devoted to the neuroimaging of stroke, clinical trials, and the role of cerebral immune activation complete this informative collection of cutting-edge reviews.

Distinguished medical researchers from around the world review novel neural reconstructive techniques that appear to be beneficial for Parkinson's disease and hold promise for treating Huntington's disease, pain, demyelinating diseases, and stroke. The contributors focus on those diseases for which clinical trials are either ongoing or likely to occur in the near future. Among the topics reviewed are results and rationale for some of the leading transplant programs for the treatment of Parkinson's disease, the use of PET scanning for patient evaluation, autopsy studies of transplant recipients, transplant immunology, fetal tissue transplantation for Huntington's disease, cellular transplantation for the treatment of pain and stroke, and transplantation of myelinating cells. A full discussion of the important ethical issues surrounding the use of fetal tissue for transplantation purposes is also included.

Expert researchers critically review and evaluate the most common and important neurotoxins used today in neuroscience research. Each informative chapter thoroughly describes the significant mechanisms of action of a neurotoxin, as well as fully discussing the limits on their use and their clinical applicability. Several clinically oriented chapters are significant for neurologists treating Parkinsonism, for psychiatrists treating drug abuse and neurodegenerative disorders, and for primary care physicians treating patients with appetite suppressants. Highly Selective Neurotoxins provides all the basic knowledge needed to obtain a predictable experimental outcome with these neurotoxins.

In this book, leading-edge investigators offer effective strategies to improve current antidepressive therapies and suggest molecular, biological, and genetic approaches that will lead to the development of novel antidepressants. The contributors' critical reviews and commentaries illuminate our understanding of the mechanism(s) responsible for antidepressant action. The book's goal is to move beyond current biogenic amine-based concepts and therapies to the development of new and improved antidepressants that are more effective and have a more rapid onset than current.

Prominent researchers and clinicians dissect the signaling pathways of an array of neuroprotective factors, ranging from neurotrophins (NGF, BDNF, NT-3, and NT-4/5) to growth factors (bFGF, IGF-1, GDNF), to cytokines (TNF, IL-1b, and TGFb), to secreted amyloid precursor proteins, to protease nexin-1. Also treated are cytoprotective signaling events that occur with injured neurons independently of intercellular signals. In elucidating the molecular cascades evolved by the nervous system to protect itself, the contributors lay the basis for powerful new drug discovery and gene therapy strategies, and shed light on potential effective strategies for preventing neuron degeneration in such conditions as stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Leading gene therapy researchers and clinicians illuminate the field-from basic vector technology to current and future clinical applications in neurology. The authoritative contributors provide cutting-edge reviews of the vectors available for gene transfer to the central nervous system, the strategies against CNS tumors, the potential strategies against neurologic disorder, and the limitations of today's gene therapy approaches. Also discussed are significant applications of gene therapy to brain tumors, Parkinson's disease, ischemia, and Huntington's chorea. Readers will learn the current delivery methods for transgenes, will learn the characteristics of transgene delivery vectors, and come to understand the therapy for both neuro-oncologic and neurologic disorders.

Wolfgang Walz and a panel of leading authorities illuminate those cellular and molecular mechanisms brought into play during a stroke that lead to neuronal dysfunction. Such damaging factors as spreading depression waves and postischemic depolarization, cell swelling, calcium overload, and oxygen radicals leading to necrosis and apoptosis are described in detail. Also examined are the body's repair mechanisms involving altered gene expression that lead to trophic factor production and heat shock protein synthesis, as well as to astrogliosis and microgliosis. All factors are presented in relation to their therapeutic value and the possible treatment approaches that evolve from their interactions. Cerebral Ischemia: Molecular and Cellular Pathophysiology offers clinicians, interested practitioners, and experimentalists alike a systematic evaluation of all the major biological systems that contribute to brain dysfunction after a vascular accident.

A distinguished panel of internationally recognized neuroscientists comprehensively review the involvement of and changes in glial cells both during the normal aging process and in the major disorders of old age. Topics range from the cellular and molecular changes that occur with aging - especially aging-associated activation of astrocytes and microglia and its relation to neuronal injury and repair - to neuron glia intercommunication. The contributors show how glial signals may be modulated by hormones, growth factors, neurotransmitters, intracellular metabolism, and intercellular exchanges, as well as by aging of the blood brain barrier.

A team of leading experts comprehensively review and synthesize the most recent advances in our understanding of the role of cerebral signaling in neuronal and cerebral function. The authors emphasize the functional role of the various signaling pathways in memory, apoptosis and degeneration, depression, and drug dependence in both health and diseased states. By taking full advantage of the newfound ability to selectively remove, reduce, or enhance specific components of the signaling pathways, the investigators writing here illuminate the varied signaling cascades, their crosstalk, and the many possibilities for changes in gene expression underlying long-term changes in brain function. Cutting-edge and comprehensive, Cerebral Signal Transduction: From First to Fourth Messengers advances our understanding of the mechanistic underpinnings of complex behavioral processes and clinically relevant brain diseases. A major contribution to the development of the novel pharmacotherapeutics targeting downstream events in the cascade of second, third, and fourth messengers, it will serve experimental and clinical neuroscientists as the best and most complete guide to neuronal signaling.

Distinguished researchers review the latest scientific understanding of spinal cord injury (SCI), focusing on the mechanisms causing paralysis after spinal cord trauma, the molecular determinants of neural regeneration, and methods for improving damaged function. The authors examine the role of intracellular Ca2+ in neuronal death, the possibility of spinal learning, growth-promoting molecules for regenerating neurons, and the biochemistry and cell biology of microtubules. Among the treatment possibilities discussed are cell transplantation strategies beyond the use of fetal spinal cord tissue, remyelination in spinal cord demyelination models, high steroid therapy immediately after SCI, and the mixed use of anti- and proinflammatories. Comprehensive and highly promising, Neurobiology of Spinal Cord Injury summarizes and integrates the great progress that has been made in understanding and combating the paralysis that follows spinal cord injury.

Prominent experimentalists critically review the animal models widely used in developing powerful new therapies for central nervous system diseases. Coverage includes novel uses of animal models of Alzheimer's, Parkinson's, and Huntington's diseases, and studies of aging. Techniques that rely heavily on behavioral analyses, as well as models developed from infusions of neurotoxins and from advances in molecular biology, are thoroughly explicated, as are models developed for more acute neurological conditions, including traumatic brain injury and stroke. Comprehensive and authoritative, Central Nervous System Diseases: Innovative Animal Models from Lab to Clinic offers neuroscientists, pharmacologists, and interested clinicians a unique survey of the most productive animal models of the leading neurological diseases currently employed to develop today's innovative drug therapies.

Mitochondria have long been the Rodney Dangerfield of cellular organelles. Believed to be the remnants of bacterial infection of eukaryotic cells eons ago, the mitochondrion evolved a symbiotic relationship in which it dutifully served as the efficient source of A TP for cell function. The extraordinary dependence of cells on the energy provided by mito­ chondrial oxidative metabolism of glucose, especially through critical organs such as the heart and brain, is underlined by the fatal consequences of toxins that interfere with the mitochondrial electron transport system. Consistent with their ancestry, the mitochondria have their own DNA that encodes many but not all of their proteins. The mitochon­ dria and their genes come from the mother via the ovum since sperm do not possess mitochondria. This extranuclear form of inheritance derived exclusively from the female side has proven to be a powerful tool for tracing the evolution by the number of base substitutions in mtDNA. That mitochondrial gene mutations might be a source of human dis­ ease became evident a decade ago with the characterization of a group of multisystem disorders, typically involving the nervous system, which are transmitted from mother to child. Specific point mutations in mtDNA have been associated with the different syndromes.

As the average life expectancy of many populations throughout the world increases, so to does the incidence of such age-related neurodegenerative disorders as Alzheimer's, Parkinson's, and Huntington's diseases. Rapid advances in our understanding of the molecular genetics and environmental factors that either cause or increase risk for age-related neurodegenerative disor­ ders have been made in the past decade. The ability to evaluate, at the cellular and molecular level, abnormalities in postmortem brain tissue from patients, when taken together with the development of valuable animal and cell-culture models of neurodegenerative disorders has allowed the identification of sequences of events within neurons that result in their demise in specific neurodegenerative disorders. Though the genetic and environmental factors that pro­ mote neurodegeneration may differ among disorders, shared biochemical cascades that will ultimately lead to the death of neurons have been identified. These cascades involve oxyradical production, aberrant regulation of cellular ion homeostasis and activation of a stereotyped sequence of events involving mitochondrial dysfunction and activa­ tion of specific proteases. Pathogenesis of Neurodegenerative Disorders provides a timely compilation of articles that encompasses fundamental mechanisms involved in neurodegenerative disorders. In addition, mechanisms that may prevent age-related neurodegenerative disorders are presented. Each chapter is written by an expert in the particular neurodegenerative disorder or mechanism or neuronal death discussed.

Leading neuroscience researchers offer a fresh perspective on neuronal function by examining all its many components - including their pertubation during major disease states - and relate each element to neuronal demands. Topics range from the dependency of neurons on metabolic supply, as well as on both ion and transmitter homeostasis, to their close interaction with the myelin sheath. Also addressed are the astrocytic signaling system that controls synaptic transmission, the extracellular matrix and space as communication systems, the role of blood flow regulation in neuronal demand and in blood brain barrier function, and inflammation and the neuroimmune system. Insightful and integrative, The Neuronal Environment: Brain Homeostasis in Health and Disease demonstrates a clear new understanding that neurons do not work in isolation, that they need constant interactions with other brain components to process information, and that they are not the only information processing system in the brain.

Stem Cells and CNS Development critically reviews recent findings on stem cells, their involvement in neurogenesis and gliogenesis, and the therapeutic implications of these findings. It defines by consensus the classes of stem cells in the nervous system, compares their similarities and differences, discusses the gains made in identifying human homologs of neural stem cells, and describes how these cells are beginning to be usedfor therapeutic purposes. Comprehensive and cutting-edge, this book provides all developmental scientists and neurobiologists not only an authoritative account of the current results in neural stem cell research, but also an incisive review of the rapidly emerging therapeutic uses of stem cells.