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The fact that the mammalian central nervous system is mostly made up of perennial elements accounting for its well known uncapability to undergo physiological cell renewal and post-lesion repair has represented a dogma for most of the XXth century. Yet, research carried out starting from the sixties in a rather sceptic milieu, and exponentially expanded at the beginning of the nineties with the definitive demonstration that neurogenesis actually takes place in the adult brain and that it is sustained by neural stem cells, opened a new, challenging field in neuroscience. In the last fifteen years, such a field has been tackled by interdisciplinary approaches thus spreading into several ramifications, often referred either more generally to as developmental neurobiology and structural plasticity , or more specifically to as adult neurogenesis . The aims of these studies have become more focused in a wide range of topics, spanning from the detailed morphological/molecular analysis of neurogenic sites to the migration/specification/integration of newlyborn cell precursors into neuronal circuits; from the in vivo identification of cell types and their functional relationships within the neural stem cell niches to the in vitro isolation and characterization of neural stem cells in the perspective of brain repair. In the last few years, in spite of a huge amount of information gathered around the issue of neurogenesis, new elements of complexity have arisen, thus leaving open many questions. It is now clear that persistent neurogenesis do not faithfully reproduce embryonic developmental processes. Indeed, postnatal changes involving the structure/function of neurogenic sites and the neural stem cell niches contained herein, do occur in order to adapt to the mature nervous tissue. The recent finding that adult neural stem cells share a glial identity and directly derive from radial glia raises questions concerning the neuronal-glial relationships across pre- and post-natal development. The progeny of neuronal precursors must integrate into already established neural circuits, whose features change according to the pre- and post-natal developmental stages. In addition, the fact that neural stem cells isolated in vitro prevalently differentiate into astrocytes, whereas in vivo they produce mainly neurons, highlights the importance of epigenetic signals. Finally, substantial data recently obtained under a comparative profile reveal that persistent neurogenesis, although being a well preserved trait, shows remarkable differences among species and, possibly, interesting evolutionary adaptations. The comparative approach, both among mammals and among vertebrates, further reveals new elements of complexity linked to the different growth rates and lifespans. Yet, although introducing new questions about postnatal and adult stages in different species, this approach could provide insights as concerns the functional significance of persistent neurogenesis. Thus, 50 years after the first evidence that new neurons can be generated and added to a mature brain, the actual meaning of such a phenomenon in brain physiology as well as its usefulness in brain repair remain a matter of debate. We learned that neurogenesis can persist in restricted brain sites, whereby it undergoes complex cell/molecular regulation, whereas in the rest of the nervous system it remains as a potentiality. Hence, a better knowledge of the complex regulatory mechanisms underlying these processes should be attained to understand if and how endogenous neurogenesis can be exploited/modulated in the perspective of brain healing. This book, other than providing an overview of the state of the art in the field of postnatal and adult neurogenesis, tries to update our present knowledge about the postnatal changes of neurogenic processes and to place them in the context of a comparative vision. The attainment of this goal has been possible thanks to the contribution of many young scientists from different corners of the world, who have built their experience in neurogenesis during the last decade.
Most neurons are born during the embryonic period to become the building blocks for a variety of brain circuits. However, two brain regions only start to assemble during the postnatal period. Both brain areas, olfactory bulb and dentate gyrus, mainly accommodate the integration of new neurons during the postnatal period, and continuously receive new neurons throughout animals' life. In this thesis, I used the rat olfactory bulb (OB) as a model system to address two important issues regarding the integration and plasticity of new neurons generated during the postnatal period. The first feature of postnatal neurogenesis is that when new neurons arrive and integrate into an adult OB, only half of neurons can ultimately survive. However, what form of activity pattern determines the survival of new neurons remains unclear. Using NaChBac sodium channels to selectively alter the intrinsic excitability of new neurons in vivo, this manipulation reveals that neuronal survival critically depends on the level of membrane depolarization. Once neurons integrate and survive in the brain circuits, neurons have the capability of monitoring their activity level and adaptively maintain their membrane excitability within the operational range. How they achieve the long-term stability of membrane excitability remains unclear. By altering the resting membrane potential of individual neurons in vivo, OB granule neurons are found to use a subthreshold parameter, resting membrane potential, to guide the compensatory changes of intrinsic ion channels and synaptic receptors. In summary, studies from this thesis have revealed the cellular mechanisms underlying neuronal survival in an in vivo brain circuit. I also uncover a novel form of homeostatic computation by which granule neurons preferentially use the subthreshold membrane potential response rather than spiking rates as a set point.
The brain is a complex organ that contains hundreds of diverse cellular subtypes which organize into unique regions and build intricate neural circuits. Neurons all transition through developmental stages where they must specify into cellular subtypes, migrate to appropriate brain regions, and extend axons to innervate postsynaptic targets as well as elaborate dendritic trees to receive incoming information. These stages are shaped by a balance of intracellular transcriptional programs and extracellular signals such as guidance molecules, adhesion proteins, and neuronal activity. While an extensive list of factors contributing to these processes has been catalogued, the details remain unclear on how they converge within a cell to direct its development. Therefore, we developed novel genetic systems to decipher the rules that shape neuronal development and circuit formation. In one set of studies, we selectively blocked synaptic activity from a subset of neurons within the rodent olfactory bulb to investigate their role in shaping olfactory circuit development. We observed a dramatic impact on the maturation of newborn inhibitory neurons which could not be completely rescued by inhibiting cell death. By assessing the transcriptome of these developmentally-stalled neurons, we identified gene networks that regulate the maturation and integration of neurons into established circuits. For the second set of experiments, we injected rat stem cells into mouse blastocysts to generate rat-mouse brain chimeras and determine whether rat neurons are flexible to develop into, and contribute to foreign neural circuits. In brain-complemented chimeras, we observed diverse rat neuronal subtypes that adopt their host's developmental timeline and functionally integrate into the mouse brain. Furthermore, we identified species-specific barriers to rat complementation when these neurons are challenged to reconstitute degenerated mouse circuits. Together, these studies provide insights into the mechanisms governing neuronal integration into foreign and compromised neural circuits, which will inform efforts in regenerative medicine.
Neurogenesis in the adult brain has emerged as one of the most dynamic and rapidly moving fields in modern neuroscience research. The implications of adult neurogenesis for health and well-being are wide-ranging, with findings in this area having distinct relevance for treatment and rehabilitation in neurology and psychopathology. Adult Neurogenesis in the Hippocampus addresses these implications by providing an up-to-date account on how neurogenesis in the adult hippocampus contributes to critical psychological and physiological processes, such as learning and memory, and how it is modified by life experiences, such as aging, environmental enrichment, exercise, and dieting. The book also provides the most current reviews of how adult hippocampal neurogenesis influences the pathogenesis of mood disorders, addiction, and key neurological disorders. This book is the ideal resource for researchers and advanced graduates seeking focused knowledge on the role of adult neurogenesis in brain health and disease. Provides a unique overview of how adult hippocampal neurogenesis contributes to adaptive processes, brain psychopathology, and disease Includes state-of-the-art reviews by leading world experts in adult neurogenesis
Traumatic brain injury (TBI) remains a significant source of death and permanent disability, contributing to nearly one-third of all injury related deaths in the United States and exacting a profound personal and economic toll. Despite the increased resources that have recently been brought to bear to improve our understanding of TBI, the developme
Comprehensive Overview of Advances in OlfactionThe common belief is that human smell perception is much reduced compared with other mammals, so that whatever abilities are uncovered and investigated in animal research would have little significance for humans. However, new evidence from a variety of sources indicates this traditional view is likely
This volume brings together authors working on a wide range of topics to provide an up to date account of the underlying mechanisms and functions of neurogenesis and synaptogenesis in the adult brain. With an increasing understanding of the role of neurogenesis and synaptogenesis it is possible to envisage improvements or novel treatments for a number of diseases and the possibility of harnessing these phenomena to reduce the impact of ageing and to provide mechanisms to repair the brain.
The enteric nervous system (ENS) is a complex neural network embedded in the gut wall that orchestrates the reflex behaviors of the intestine. The ENS is often referred to as the “little brain” in the gut because the ENS is more similar in size, complexity and autonomy to the central nervous system (CNS) than other components of the autonomic nervous system. Like the brain, the ENS is composed of neurons that are surrounded by glial cells. Enteric glia are a unique type of peripheral glia that are similar to astrocytes of the CNS. Yet enteric glial cells also differ from astrocytes in many important ways. The roles of enteric glial cell populations in the gut are beginning to come to light and recent evidence implicates enteric glia in almost every aspect of gastrointestinal physiology and pathophysiology. However, elucidating the exact mechanisms by which enteric glia influence gastrointestinal physiology and identifying how those roles are altered during gastrointestinal pathophysiology remain areas of intense research. The purpose of this e-book is to provide an introduction to enteric glial cells and to act as a resource for ongoing studies on this fascinating population of glia. Table of Contents: Introduction / A Historical Perspective on Enteric Glia / Enteric Glia: The Astroglia of the Gut / Molecular Composition of Enteric Glia / Development of Enteric Glia / Functional Roles of Enteric Glia / Enteric Glia and Disease Processes in the Gut / Concluding Remarks / References / Author Biography
The discovery of adult neurogenesis and of stem cells in the brain has changed our view of the mature brain. Though we now know that the adult brain can make new neurons, it normally does so only in two privileged regions, the olfactory bulb and the hippocampus. Yet stem cells, which have the potential to produce new neurons, can be found throughout the adult brain. So why does the brain not make wider use of its potential for neurogenesis? And what is the function of new neurons and of neural stem cells in areas where they occur? After all, the brain regenerates poorly and many neurological and psychiatric disorders are chronic because cell replacement has not taken place. This is the first comprehensive, integrated account of one of the most exciting areas of neuroscience. It begins with the historical background and discusses theories of adult neurogenesis and neural stem cell biology in the context of learning and memory processes as well as structural plasticity. It describes in detail neurogenesis in the adult hippocampus and olfactory system and then surveys the regulatory, functional, and comparative aspects, concluding with a chapter on the provocative hypotheses that link failing adult neurogenesis with such diseases as temporal lobe epilepsy, major depression, brain tumors, and dementias. For graduate students, investigators, and clinicians in the neurosciences, developmental biology, and stem cell research, this book is a unique resource that sifts through the evidence for exciting scientific ideas and fosters a realistic view of the therapeutic possibilities for the use of stem cells in the adult brain.
