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The article reports the In vivo peptide-based delivery of a gene-modifying enzyme into cells of the central nervous system. It describes the mechanism of how Cre delivery activates the expression of a reporter gene in both neurons and astrocytes of the cortex without tissue damage. It mentions the applications of this approach which are beneficial to the transient introduction of proteins into cells in vivo.

Cerebrospinal fluid (CSF) is responsible for maintaining brain homeostasis through nutrient delivery and waste removal for the central nervous system (CNS). Here, we demonstrate extensive CSF flow throughout the peripheral nervous system (PNS) by tracing distribution of multimodal 1.9-nanometer gold nanoparticles, roughly the size of CSF circulating proteins, infused within the lateral cerebral ventricle (a primary site of CSF production). CSF-infused 1.9-nanometer gold transitions from CNS to PNS at root attachment/transition zones and distributes through the perineurium and endoneurium, with ultimate delivery to axoplasm of distal peripheral nerves. Larger 15-nanometer gold fails to transit from CNS to PNS and instead forms "dye-cuffs," as predicted by current dogma of CSF restriction within CNS, identifying size limitations in central to peripheral flow. Intravenous 1.9-nanometer gold is unable to cross the blood-brain/nerve barrier. Our findings suggest that CSF plays a consistent role in maintaining homeostasis throughout the nervous system with implications for CNS and PNS therapy and neural drug delivery.

The article discusses that how social connections predict brain structure in a multidimensional free-ranging primate society. It mentions that findings of the study demonstrate that the size of specific brain structures varies with the number of direct affiliative social connections and suggest that relationship may arise during development.

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8+ TRM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+ TRM. Subsequently, CD8+ TRM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8+ T cells. However, in the absence of CD4+ T cells, TCF-1+ CD8+ TRM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8+ T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, our study provides evidence for CD8+ TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions. A local contribution to CNS autoimmunity: Aberrantly activated tissue-resident memory T cells (TRM) have been shown to contribute to inflammatory conditions. Their role in the CNS remains unclear. Now, in two complementary studies, Vincenti et al. and Frieser et al. investigated the role of TRM in the CNS. Vincenti and colleagues reported that after viral brain infection, TRM triggered CNS inflammation, promoting autoimmune reactions in mice. Cells with TRM-like phenotype were also identified in brain tissue from patients with CNS autoimmune diseases. Frieser et al. used rodent models of CNS autoimmunity to show that pathogenic CD8+ T cells infiltrating the CNS adopted a TRM phenotype that contributes to the disease. The results suggest that targeting TRM can be effective in treating CNS autoimmune diseases. [ABSTRACT FROM AUTHOR]

The article offers information on Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. It mentions that Microglia control small vessel calcification via TREM2, along with discusses the role of microglia in the biology of the neurovascular unit (NVU).

The article discusses the decline in expression of ATG16L in the brains of human patients with Alzheimer's disease (AD) suggests the possibility that a similar mechanism may contribute in human disease. It mentions that pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in the AD model.

The article focuses on the Somatostatin (SST), a neuropeptide expressed in a major subtype of GABAergic interneurons in the cortex. It mentions that SST application in the primary visual cortex (V1) improves visual discrimination in freely moving mice and enhances orientation selectivity of V1 neurons; and the neuropeptide SST improves visual perception by enhancing visual gain of V1 neurons via a reduction in excitatory synaptic transmission to parvalbumin-positive (PV+) inhibitory neurons.

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. [ABSTRACT FROM AUTHOR]

Astrocytes, the most abundant cell population in the central nervous system (CNS), are essential for normal neurological function. We show that astrocytes are allocated to spatial domains in mouse spinal cord and brain in accordance with their embryonic sites of origin in the ventricular zone. These domains remain stable throughout life without evidence of secondary tangential migration, even after acute CNS injury. Domain-specific depletion of astrocytes in ventral spinal cord resulted in abnormal motor neuron synaptogenesis, which was not rescued by immigration of astrocytes from adjoining regions. Our findings demonstrate that region-restricted astrocyte allocation is a general CNS phenomenon and reveal intrinsic limitations of the astroglial response to injury. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in the mammalian central nervous system (CNS). It is involved in multiple physiological functions and is a target for treatment of various CNS disorders, including schizophrenia. We report that Norbin, a neuron-specific protein, physically interacts with mGluR5 in vivo, increases the cell surface localization of the receptor, and positively regulates mGluR5 signaling. Genetic deletion of Norbin attenuates mGluR5-dependent stable changes in synaptic function measured as long-term depression or long-term potentiation of synaptic transmission in the hippocampus. As with mGluR5 knockout mice or mice treated with mGluR5-selective antagonists, Norbin knockout mice showed a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations both in sensorimotor gating and psychotomimetic-induced locomotor activity. [ABSTRACT FROM AUTHOR]

Glutamate receptors of the AMPA-subtype (AMPARs), together with the transmembrane AMPAR regulatory proteins (TARPs), mediate fast excitatory synaptic transmission in the mammalian brain. Here, we show by proteomic analysis that the majority of AMPARs in the rat brain are coassembled with two members of the cornichon family of transmembrane proteins, rather than with the TARPs. Coassembly with cornichon homologs 2 and 3 affects AMPARs in two ways: Cornichons increase surface expression of AMPARs, and they alter channel gating by markedly slowing deactivation and desensitization kinetics. These results demonstrate that cornichons are intrinsic auxiliary subunits of native AMPARs and provide previously unknown molecular determinants for glutamatergic neurotransmission in the central nervous system. [ABSTRACT FROM AUTHOR]

Every organ depends on blood vessels for oxygen and nutrients, but the vasculature associated with individual organs can be structurally and molecularly diverse. The central nervous system (CNS) vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier, whereas blood vessels of other organs are more porous. Wnt7a and Wnt7b encode two Wnt ligands produced by the neuroepithelium of the developing CNS coincident with vascular invasion. Using genetic mouse models, we found that these ligands directly target the vascular endothelium and that the CNS uses the canonical Wnt signaling pathway to promote formation and CNS-speciflc differentiation of the organ's vasculature. [ABSTRACT FROM AUTHOR]

Examines the dendrodendritic inhibition through reversal of dopamine transport. Source of synapses in the central nervous system; Use of amperometric and patch-clamp recordings for inhibition; Details on the blockade of the dopamine transporter.

Focuses on floor plate induction. Definition of the floor plate, its location in the neural tube, and its influence in the embryonic development of the vertebrate central nervous system; Evidence that the differentiation of the floor plate requires inductive signals provided by axial mesoderm cells of the notochord that lie under the midline of the neural plate.

Presents research which studied the site of impulse initiation for integrative actions of rat central neurons. Recent studies; Examination of olfactory mitral cell in bulb slices; Location of impulse initiation; Control of initiation site.

Presents results from computational studies suggesting that acquisition of motor skill involves learning an internal motor of the dynamics of the task, which enables the brain to predict and compensate for mechanical behavior. Use of functional imaging of the brain; Methods used to carry out the various studies involved; Findings.

Reports information pertaining to the stem cells in the central nervous system. Definition of a stem cell; Factors controlling the differentiation of fetal stem cells to neurons and glia; Response mechanisms and transitions in vitro; Stem cells and disease in the adult central nervous system; Implications.

Investigates whether central nervous system (CNS) activity in vivo produces an agonist-induced receptor translocation. Internalization of the substance P (SP) receptor (SPR) tachykinin NK-1 in the spinal cord; SP-induced change in the SPR-positive spinal cord neurons; Region with greatest internalization of SPRs; Agonist-induced SPR internalization.

The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The article discusses a report in a 2012 issue of the journal "Nature" regarding developmental biology research by D. G. Southwell et al. that suggests programmed cell death (apoptosis) in cortical interneurons in the central nervous system (CNS) is caused by an intrinsic program that is independent of external cues. Topics include the role of programmed cell death in many tissues, such as the vertebrate nervous system, a brief overview of the anatomy and physiology of the neocortex of higher vertebrates, the elimination of both excitatory and inhibitory neurons during synaptogenesis, and a diagram comparing the regulation of apoptosis in the peripheral and CNS.

Presents research which observed resistance to apoptosis in the developing central nervous system (CNS) of mice after ionizing radiation. The ATM gene and ataxia telangiectasia (AT); Lack of cell death in regions of the CNS; Impact of up-regulation of p53; ATM-dependent apoptosis in the CNS mediated by p53; Traits of p53 null mice; ATM in development.

Studies the vertebrate central nervous system (CNS) gene encoding astrotactin, which predicts a protein with three epidermal growth factor repeats and two fibronectin type III repeats. CNS histogenesis that depends on glia-guided migration of postmitotic neurons to form neuronal laminae; Transfection of astrotactin complementary DNA into 3T3 cells along astroglial fibers.

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation and phagolysosomal membrane rupture and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters, including apolipoprotein E. Stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals and thereby inducing a maladaptive immune response that impedes tissue regeneration., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The article discusses neuroscience research. An overview of a report within the issue regarding research by Paolicelli and colleagues is presented. Topics include a brief overview of the role of microglia, which are highly mobile immune cells in the central nervous system, a demonstration by Paolicelli and colleagues showing the involvement of microglia in the development of brain circuitry in newborn mice, and how the disruption of microglia-synapse interactions delays the maturation of synaptic circuits.

The article offers information on the concept of synaptic mechanism of neurons in the brain which create the basis of information processing and storage in the brain. Neurons communicate rapidly via millisecond time scale of plasticity. An exchange of desensitized glutamate receptors without active reception can counteract the effects of desensitization at the synapse. Neurons communicate by releasing neurotransmitter which activates AMPA receptors in the postsynaptic density. It is mentioned that short-term depression arises predominantly from presynaptic depletion of vesicles.

Extracellular let-7b, a microRNA found in the central nervous system, affects neurons through its interaction with Toll-like receptor 7 (TLR7), but with divergent outcomes in different neurons. Lehmann et al. found that let-7b stimulation of cortical and hippocampal neurons led to neuronal apoptosis, whereas Park et al. report that let-7b activation of TLR7 stimulated the cation channel transient receptor potential A1 (TRPA1) on dorsal root ganglia sensory neurons and induced pain responses. The primary difference that may influence these distinct responses to let-7b is the localization of TLR7 to the endosome in the cortical and hippocampal neurons or the plasma membrane in the sensory neurons. These studies suggest that different types of neurons traffic TLR7 to distinct membrane locations, affecting the functional response of neurons to let-7b stimulation., (Copyright © 2014, American Association for the Advancement of Science.)

In animals, appendages develop in proportion to overall body size; when individual size varies, appendages covary proportionally. In insects with complete metamorphosis, adult appendages develop from precursor tissues called imaginal disks that grow after somatic growth has ceased. It is unclear, however, how the growth of these appendages is matched to the already established body size. We studied the pattern of cell division in the tobacco hornworm Manduca sexta and found that both the rate of cell division and the duration of growth of the wing imaginal disks depend on the size of the body in which they develop. Moreover, we found that both of these processes are controlled by the level and duration of secretion of the steroid hormone ecdysone. Thus, proportional growth is under hormonal control and indirectly regulated by the central nervous system.

Despite the importance of myelin for the rapid conduction of action potentials, the molecular bases of oligodendrocyte differentiation and central nervous system (CNS) myelination are still incompletely understood. Recent results have greatly advanced this understanding, identifying new transcriptional regulators of myelin gene expression, elucidating vital roles for microRNAs in controlling myelination, and clarifying the extracellular signaling mechanisms that orchestrate the development of myelin. Studies have also demonstrated an unexpected level of plasticity of myelin in the adult CNS. These recent advances provide new insight into how remyelination may be stimulated in demyelinating disorders such as multiple sclerosis.

The calpains are a class of cellular cysteine proteases that require calcium and are functionally active at neutral pH. Calpain activation can take place in two modes: controlled activation under physiological conditions (in which only a few molecules of calpain are activated per cell), and hyperactivation under pathological conditions that involve sustained calcium overload (in which all available calpain molecules are activated). Regulated activation of calpain in the central nervous system (CNS) may be critical to synaptic function and memory formation, with possible substrates including various structural and scaffolding proteins, enzymes, and glutamate receptors. Hyperactivation of calpain in the central nervous system is generally associated with severe cellular challenge or damage. Calpain cleavage products may thus provide useful biomarkers for the presence of neurodegenerative processes or neuronal injury.

Two new reports offer exciting evidence of novel roles for components of the nuclear factor kappaB (NF-kappaB) pathway in the nervous system. Transcriptional activation by NF-kappaB and chromatin remodeling by inhibitor of kappaB (IkappaB) kinase complex (IKK) have been linked to recall and reconsolidation of conditioned fear memories in the mammalian central nervous system. In the Drosophila neuromuscular junction, a member of the NF-kappaB family has been reported to regulate glutamate receptor clustering. Both reports could have important implications for the function of the NF-kappaB signaling pathway in neuronal plasticity.

Endometriosis is a disease defined by the presence of endometrial tissue outside of the uterus. Severe pelvic pain is often associated with endometriosis, and this pain can be diminished with therapies that suppress estrogen production. Many women with endometriosis also suffer from other chronic pain conditions. Recent studies suggest that mechanisms underlying these pains and sensitivity to estrogen involve the growth into the ectopic endometrial tissue of a nerve supply, which could have a varied and widespread influence on the activity of neurons throughout the central nervous system.

We investigated decision-making in the leech nervous system by stimulating identical sensory inputs that sometimes elicit crawling and other times swimming. Neuronal populations were monitored with voltage-sensitive dyes after each stimulus. By quantifying the discrimination time of each neuron, we found single neurons that discriminate before the two behaviors are evident. We used principal component analysis and linear discriminant analysis to find populations of neurons that discriminated earlier than any single neuron. The analysis highlighted the neuron cell 208. Hyperpolarizing cell 208 during a stimulus biases the leech to swim; depolarizing it biases the leech to crawl or to delay swimming.

Most excitatory synapses in the brain use the neurotransmitter glutamate to carry impulses between neurons. During fast transmission, glutamate usually activates a mixture of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic cell. Experimental scrutiny of NMDARs provides insight into their involvement in excitatory synaptic transmission and related processes such as as synaptic plasticity, neural development, and pain perception. There is increasing awareness that subtle variation in NMDAR properties is imparted by specific receptor subunits, and recent studies have started to provide perspective into some of the discrete tasks carried out by individual receptor subtypes.

In the intact brain, neurons are constantly subjected to both excitatory and inhibitory inputs to their dendritic trees. Although it is accepted that the overall response of a neuron--its train of output spikes--depends on the balance of excitation and inhibition, we continue to lack specific knowledge of the rules that govern how excitatory and inhibitory inputs interact in space and time within the confines of individual neurons. In a recent paper, Liu starts by providing evidence that the relative locations and numbers of excitatory and inhibitory synapses are tightly regulated in cultured neurons from the hippocampus. This is consistent with findings in other labs that suggest neurons work hard, and in a variety of different ways, to maintain their inputs in proper balance and their outputs within appropriate ranges. On this backdrop, Liu's most important finding of a functional nature is that inhibition appears to act quite locally; that is, an inhibitory synapse effectively opposes an excitatory synapse only when it is very close by within the same dendritic branch (Fig. 1). This finding provides further support for the view--anticipated by neural theorists more than 20 years ago--that the brain's principal neurons contain a potentially large number of separate computational subunits.

Ionotropic glutamate receptors excite nerve cells by forming cation-selective pores in the membrane. Recent work, however, provides evidence that atypical signaling by glutamate receptors regulates the production and maintenance of dendritic spines, the short outgrowths that receive most central excitatory synapses. The control of spine formation involves the amino-terminal extracellular domain of the GluR2 subunit of AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors. How interactions with this domain elicit signals to downstream effectors remains to be elucidated, but ion flux through the channel may not be required. This Perspective discusses the possibility that regulation of spines by GluR2 may be one of a growing collection of cases in which ionotropic glutamate receptors can elicit biochemical changes that are conventionally attributed to metabotropic receptors. It is suggested that proteins in contact with specific glutamate receptor subunits may directly sense the conformational changes produced by agonist binding.

The first chordates appear in the fossil record at the time of the Cambrian explosion, nearly 550 million years ago. The modern ascidian tadpole represents a plausible approximation to these ancestral chordates. To illuminate the origins of chordate and vertebrates, we generated a draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome contains approximately 16,000 protein-coding genes, similar to the number in other invertebrates, but only half that found in vertebrates. Vertebrate gene families are typically found in simplified form in Ciona, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development. The ascidian genome has also acquired a number of lineage-specific innovations, including a group of genes engaged in cellulose metabolism that are related to those in bacteria and fungi.

A synapse is a stable adhesive junction between two cells across which information is relayed by directed secretion. The nervous system and immune system utilize these specialized cell surface contacts to directly convey and transduce highly controlled secretory signals between their constituent cell populations. Each of these synaptic types is built around a microdomain structure comprising central active zones of exocytosis and endocytosis encircled by adhesion domains. Surface molecules that may be incorporated into and around the active zones contribute to modulation of the functional state of the synapse.

Neuraxial patterning is a continuous process that extends over a protracted period of development. During gastrulation a crude anteroposterior pattern, detectable by molecular markers, is conferred on the neuroectoderm by signals from the endomesoderm that are largely inseparable from those of neural induction itself. This coarse-grained pattern is subsequently reinforced and refined by diverse, locally acting mechanisms. Segmentation and long-range signaling from organizing centers are prominent among the emerging principles governing regional pattern.