Explore the vast range of titles available.

Glial Physiology and Pathophysiology provides a comprehensive, advanced text on the biology and pathology of glial cells. Coverae includes: * the morphology and interrelationships between glial cells and neurones in different parts of the nervous systems * the cellular physiology of the different kinds of glial cells * the mechanisms of intra- and inter-cellular signalling in glial networks * the mechanisms of glial-neuronal communications * the role of glial cells in synaptic plasticity, neuronal survival and development of nervous system * the cellular and molecular mechanisms of metabolic neuronal-glial interactions * the role of glia in nervous system pathology, including pathology of glial cells and associated diseases - for example, multiple sclerosis, Alzheimer's, Alexander disease and Parkinson's Neuroglia oversee the birth and development of neurones, the establishment of interneuronal connections (the 'connectome'), the maintenance and removal of these inter-neuronal connections, writing of the nervous system components, adult neurogenesis, the energetics of nervous tissue, metabolism of neurotransmitters, regulation of ion composition of the interstitial space and many, many more homeostatic functions. This book primes the reader towards the notion that nervous tissue is not divided into more important and less important cells. The nervous tissue functions because of the coherent and concerted action of many different cell types, each contributing to an ultimate output. This reaches its zenith in humans, with the creation of thoughts, underlying acquisition of knowledge, its analysis and synthesis, and contemplating the Universe and our place in it. * An up-to-date and fully referenced text on the most numerous cells in the human brain * Detailed coverage of the morphology and interrelationships between glial cells and neurones in different parts of the nervous system * Describes the role og glial cells in neuropathology * Focus boxes highlight key points and summarise important facts * Companion website with downloadable figures and slides

Nodes of Ranvier are regularly placed, nonmyelinated axon segments along myelinated nerves. Here we show that nodal membranes isolated from the central nervous system (CNS) of mammals restricted neurite outgrowth of cultured neurons. Proteomic analysis of these membranes revealed several inhibitors of neurite outgrowth, including the oligodendrocyte myelin glycoprotein (OMgp). In rat spinal cord, OMgp was not localized to compact myelin, as previously thought, but to oligodendroglia-like cells, whose processes converge to form a ring that completely encircles the nodes. In OMgp-null mice, CNS nodes were abnormally wide and collateral sprouting was observed. Nodal ensheathment in the CNS may stabilize the node and prevent axonal sprouting.

Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function. Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function.

Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases. Brain organoids derived from human pluripotent stem cells can model human brain development and disease, though current culture systems fail to ensure reliable production of high-quality organoids. Here the authors combine human brain extracellular matrix and culture in a microfluidic device to promote structural and functional maturation of human brain organoids.

Key Points The Müller glia of fish, birds and mammals share structure and function. A key difference between Müller glia in fish and those in mammals is their ability to participate in retinal repair. Unlike those present in birds and mammals, fish Müller glia respond to retinal injury by undergoing a reprogramming event that enables them to acquire the properties of a retinal stem cell and generate multipotent progenitors for repair. Various growth factors, cytokines and Wnts that are secreted from injured cells and Müller glia seem to drive Müller glial cell reprogramming in fish by activating signalling cascades that include mitogen-activated protein kinase (Mapk)–extracellular signal-regulated kinase (Erk), glycogen synthase kinase 3β (Gsk3β)–β-catenin and Janus kinase (Jak)–signal transducer and activator of transcription (Stat) signalling. Growth factors and cytokines can stimulate Müller glial cell proliferation in damaged retinas of birds and mice, but these proliferating cells exhibit a very limited ability to regenerate new neurons and generally do not survive. In fish, factors such as tumour necrosis factor-α (Tnfα), heparin-binding epidermal growth factor-like growth factor (Hbegf), achaete-scute homologue 1 (Ascl1a), Stat3 and Lin28 seem to regulate the earliest stages of Müller glial cell reprogramming, whereas paired box 6a (Pax6a) and Pax6b drive progenitor expansion and insulinoma-associated 1a (Insm1a) drives progenitors out of the cell cycle. In zebrafish, in addition to the activation of gene expression programmes that drive Müller glial cell reprogramming, there is suppression of gene expression programmes that inhibit Müller glial cell reprogramming, such as those controlled by let-7 microRNAs, dickkopf, TGFβ-induced factor 1 (Tgif1) and sine oculis homeobox homologue 3b (Six3b). Notch signalling stimulates the formation of Müller glial cell-derived progenitors in birds but inhibits the zone of injury-responsive Müller glia in fish. Forced ASCL1 overexpression along with epidermal growth factor treatment can stimulate Müller glia in postnatal mouse retinal explants to reprogramme and generate bipolar neurons. Müller glial cell reprogramming and retina regeneration are associated with changes in DNA methylation in fish; however, many key reprogramming genes exhibit a low basal level of methylation in the uninjured retinas of both fish and mice, suggesting that they may be poised for expression. Studies that are unravelling the mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish along with studies of Müller glia in other species, such as birds and mammals, may reveal novel strategies for stimulating retina regeneration in humans. Müller glia in the fish retina respond to injury by reprogramming to a stem-cell-like state that enables them to regenerate all of the major retinal cell types. Goldman reviews our current understanding of the mechanisms that regulate this regenerative response and considers how this knowledge might be applied to improve repair in the mammalian retina. Müller glia are the major glial component of the retina. They are one of the last retinal cell types to be born during development, and they function to maintain retinal homeostasis and integrity. In mammals, Müller glia respond to retinal injury in various ways that can be either protective or detrimental to retinal function. Although these cells can be coaxed to proliferate and generate neurons under special circumstances, these responses are meagre and insufficient for repairing a damaged retina. By contrast, in teleost fish (such as zebrafish), the response of Müller glia to retinal injury involves a reprogramming event that imparts retinal stem cell characteristics and enables them to produce a proliferating population of progenitors that can regenerate all major retinal cell types and restore vision. Recent studies have revealed several important mechanisms underlying Müller glial cell reprogramming and retina regeneration in fish that may lead to new strategies for stimulating retina regeneration in mammals.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota 1 . In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases 2 . Alterations in the microbiota can also modulate host behaviours—such as social activity, stress, and anxiety-related responses—that are linked to diverse neuropsychiatric disorders 3 . However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders. A diverse intestinal microbiota is required for mice to undergo extinction-related neuronal plasticity and normal fear extinction learning.

There is growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron-glia signaling contribute to synaptic and cognitive impairment in disease. Synaptic dysfunction is a hallmark of many neurodegenerative and psychiatric brain disorders, yet we know little about the mechanisms that underlie synaptic vulnerability. Although neuroinflammation and reactive gliosis are prominent in virtually every CNS disease, glia are largely viewed as passive responders to neuronal damage rather than drivers of synaptic dysfunction. This perspective is changing with the growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron-glia signaling contribute to synaptic and cognitive impairment in disease. Illuminating the mechanisms by which glia influence synapse function may lead to the development of new therapies and biomarkers for synaptic dysfunction.

A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.Cell-extrinsic changes in the systemic environment, transported to the site of action by the blood, have recently been shown to contribute to brain ageing. In this Review, Pluvinage and Wyss-Coray discuss how circulating molecules in the blood modulate brain function in health, ageing and disease.

Tissue maintenance and repair depend on the integrated activity of multiple cell types 1 . Whereas the contributions of epithelial 2 , 3 , immune 4 , 5 and stromal cells 6 , 7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease 8 . Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ–EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ–EGC–CXCL10 axis in immune response and tissue repair after infectious challenge. Enteric glial cells have tissue-wide immunoregulatory roles through the upregulation of IFNγ-dependent genes both at steady state and after parasite infection, promoting immune homeostasis and CXCL10-mediated tissue repair after pathogen-induced intestinal damage in mice.