Showing papers on "Nervous system published in 1999"
TL;DR: Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
Abstract: The glucocorticoid receptor (Gr, encoded by the gene Grl1) controls transcription of target genes both directly by interaction with DNA regulatory elements and indirectly by cross-talk with other transcription factors. In response to various stimuli, including stress, glucocorticoids coordinate metabolic, endocrine, immune and nervous system responses and ensure an adequate profile of transcription. In the brain, Gr has been proposed to modulate emotional behaviour, cognitive functions and addictive states. Previously, these aspects were not studied in the absence of functional Gr because inactivation of Grl1 in mice causes lethality at birth (F.T., C.K. and G.S., unpublished data). Therefore, we generated tissue-specific mutations of this gene using the Cre/loxP -recombination system. This allowed us to generate viable adult mice with loss of Gr function in selected tissues. Loss of Gr function in the nervous system impairs hypothalamus-pituitary-adrenal (HPA)-axis regulation, resulting in increased glucocorticoid (GC) levels that lead to symptoms reminiscent of those observed in Cushing syndrome. Conditional mutagenesis of Gr in the nervous system provides genetic evidence for the importance of Gr signalling in emotional behaviour because mutant animals show an impaired behavioural response to stress and display reduced anxiety.
1,754 citations
TL;DR: It is shown that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration and can exert a beneficial effect by protecting injured neurons from the spread of damage.
Abstract: Autoimmunity to antigens of the central nervous system is usually considered detrimental. T cells specific to a central nervous system self antigen, such as myelin basic protein, can indeed induce experimental autoimmune encephalomyelitis, but such T cells may nevertheless appear in the blood of healthy individuals. We show here that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration. After a partial crush injury of the optic nerve, rats injected with activated anti–myelin basic protein T cells retained approximately 300% more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other antigens. Electrophysiological analysis confirmed this finding and suggested that the neuroprotection could result from a transient reduction in energy requirements owing to a transient reduction in nerve activity. These findings indicate that T–cell autoimmunity in the central nervous system, under certain circumstances, can exert a beneficial effect by protecting injured neurons from the spread of damage.
865 citations
TL;DR: Recent work in mice that are genetically deficient for different cytokines (MCSF, IL1, IL6, TNFalpha, TGFbeta1) has begun to shed light on the molecular signals that regulate this cellular response.
861 citations
Patent•
05 Aug 1999
TL;DR: A neurological control system for modulating activity of any component or structure comprising the entirety or portion of the nervous system, or any structure interfaced thereto, generally referred to herein as a “nervous system component,” is described in this article.
Abstract: A neurological control system for modulating activity of any component or structure comprising the entirety or portion of the nervous system, or any structure interfaced thereto, generally referred to herein as a “nervous system component.” The neurological control system generates neural modulation signals delivered to a nervous system component through one or more intracranial (IC) stimulating electrodes in accordance with treatment parameters. Such treatment parameters may be derived from a neural response to previously delivered neural modulation signals sensed by one or more sensors, each configured to sense a particular characteristic indicative of a neurological or psychiatric condition.
822 citations
TL;DR: The cellular interactions and molecular mechanisms that direct neuronal cell fates in the dorsal half of the vertebrate central nervous system are discussed.
Abstract: ▪ Abstract The generation of distinct classes of neurons at defined positions within the developing vertebrate nervous system depends on inductive signals provided by local cell groups that act as organizing centers. Genetic and embryological studies have begun to elucidate the processes that control the pattern and identity of neuronal cell types. Here we discuss the cellular interactions and molecular mechanisms that direct neuronal cell fates in the dorsal half of the vertebrate central nervous system. The specification of dorsal neuronal cell fates appears to depend on a cascade of inductive signals initiated by cells of the epidermal ectoderm that flank the neural plate and propagated by roof plate cells within the neural tube. Members of the transforming growth factor−β (TGFβ) family of secreted proteins have a prominent role in mediating these dorsalizing signals. Additional signals involving members of the Wnt and fibroblast growth factor (FGF) families may also contribute to the proliferation and...
554 citations
TL;DR: New results about artificial excitation are based on a compartmental model of a target neuron and its equivalent electrical network, as well as on the theory of the generalized activating function, which gives hints to understanding the blockage of neural activity.
548 citations
TL;DR: It is demonstrated that MEF2 is a calcium-regulated transcription factor and a function for MEF 2 during nervous system development that is distinct from previously well-characterized functions of MEF1 during muscle differentiation is defined.
Abstract: During mammalian development, electrical activity promotes the calcium-dependent survival of neurons that have made appropriate synaptic connections. However, the mechanisms by which calcium mediates neuronal survival during development are not well characterized. A transcription-dependent mechanism was identified by which calcium influx into neurons promoted cell survival. The transcription factor MEF2 was selectively expressed in newly generated postmitotic neurons and was required for the survival of these neurons. Calcium influx into cerebellar granule neurons led to activation of p38 mitogen-activated protein kinase-dependent phosphorylation and activation of MEF2. Once activated, MEF2 regulated neuronal survival by stimulating MEF2-dependent gene transcription. These findings demonstrate that MEF2 is a calcium-regulated transcription factor and define a function for MEF2 during nervous system development that is distinct from previously well-characterized functions of MEF2 during muscle differentiation.
511 citations
TL;DR: This work has shown that the high excitability of recurrently connected, developing networks and the presence of activity-induced transient depression of network excitability in the spinal cord is of particular importance for spontaneous, periodic activity in mice.
419 citations
TL;DR: Results indicate that complex gangliosides function in central myelination and maintaining the integrity of axons and myelin, and support the theory that complex Ganglioside ligands are endogenous ligands for MAG.
Abstract: Gangliosides are a family of sialic acid-containing glycosphingolipids highly enriched in the mammalian nervous system Although they are the major sialoglycoconjugates in the brain, their neurobiological functions remain poorly defined By disrupting the gene for a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase; EC 24192) we generated mice that express only simple gangliosides (GM3/GD3) and examined their central and peripheral nervous systems The complex ganglioside knockout mice display decreased central myelination, axonal degeneration in both the central and peripheral nervous systems, and demyelination in peripheral nerves The pathological features of their nervous system closely resemble those reported in mice with a disrupted gene for myelin-associated glycoprotein (MAG), a myelin receptor that binds to complex brain gangliosides in vitro Furthermore, GM2/GD2 synthase knockout mice have reduced MAG expression in the central nervous system These results indicate that complex gangliosides function in central myelination and maintaining the integrity of axons and myelin They also support the theory that complex gangliosides are endogenous ligands for MAG The data extend and clarify prior observations on a similar mouse model, which reported only subtle conduction defects in their nervous system [Takamiya, K, Yamamoto, A, Furukawa, K, Yamashiro, S, Shin, M, Okada, M, Fukumoto, S, Haraguchi, M, Takeda, N, Fujimura, K, et al (1996) Proc Natl Acad Sci USA 93, 10662–10667]
390 citations
Journal Article•
TL;DR: Steroid hormones, which are synthesized in the adrenal gland, gonads and placenta, exert a large array of biological effects on the nervous system, including development, growth, maturation, and differentiation of the central nervous system.
Abstract: Steroid hormones, which are synthesized in the adrenal gland, gonads and placenta, exert a large array of biological effects on the nervous system. In particular, steroid hormones play an important role in the development, growth, maturation, and differentiation of the central nervous system (CNS)2
365 citations
TL;DR: The nervous system has provided an excellent model system for understanding this question as it contains two main classes of cell types, neurons and glia, and presynaptic neurons are believed to be precisely matched.
Abstract: How are the numbers of different cell types matched together during tissue development? The nervous system has provided an excellent model system for understanding this question as it contains two main classes of cell types, neurons and glia. Presynaptic neurons are believed to be precisely matched
TL;DR: An important role for erbB2 is revealed during normal peripheral nervous system development and motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues.
TL;DR: The data demonstrate that gp130 expression is essential for survival of subgroups of differentiated motor and sensory neurons and for the differentiation of major populations of astrocytesin vivo.
Abstract: gp130 is a signal-transducing receptor component used in common by the interleukin-6 (IL-6) family of hematopoietic and neurotrophic cytokines, including IL-6, IL-11, leukemia-inhibitory factor, ciliary neurotrophic factor, oncostatin-M, and cardiotrophin-1. We have examined in this study a role of gp130 in the nervous system by analyzing developmental cell death of several neuronal populations and the differentiation of astrocytes in gp130-deficient mice. A significant reduction was observed in the number of sensory neurons in L5 dorsal root ganglia and motoneurons in the facial nucleus, the nucleus ambiguus, and the lumbar spinal cord in gp130 −/− mice on embryonic day 18.5. On the other hand, no significant neuronal loss was detectable on day 14.5, suggesting a physiological role of gp130 in supporting newly generated neurons during the late phase of development when naturally occurring cell death takes place. Moreover, expression of an astrocyte marker, GFAP, was severely reduced in the brain of gp130 −/− mice. Our data demonstrate that gp130 expression is essential for survival of subgroups of differentiated motor and sensory neurons and for the differentiation of major populations of astrocytes in vivo .
TL;DR: It is demonstrated that IRSp58/53 is expressed in the synapse-rich molecular layer of the cerebellum and is highly concentrated at the synapses of cultured hippocampal neurons, where it co-localizes with the insulin receptor.
Abstract: The synapse is the primary locus of cell-cell communication in the nervous system. It is now clear that the synapse incorporates diverse cell signaling modalities in addition to classical neurotransmission. Here we show that two components of the insulin pathway are localized at CNS synapses, where they are components of the postsynaptic density (PSD). An immunochemical screen revealed that polypeptides of 58 and 53 kDa (p58/53) were highly enriched in PSD fractions from rat cerebral cortex, hippocampus, and cerebellum. These polypeptides were purified and microsequenced, revealing that p58/53 is identical to the insulin receptor tyrosine kinase substrate p58/53 (IRSp53). Our analysis of IRSp58/53 mRNA suggests that within rat brain there is one coding region for IRSp58 and IRSp53; we find no evidence of alternative splicing. We demonstrate that IRSp58/53 is expressed in the synapse-rich molecular layer of the cerebellum and is highly concentrated at the synapses of cultured hippocampal neurons, where it co-localizes with the insulin receptor. Together, these data suggest that insulin signaling may play a role at CNS synapses.
TL;DR: The formation of precise neural circuits in the visual system is used to illustrate the principles of activity-dependent development and to revolutionize the ability to identify, prevent, and treat developmental disorders resulting from disruptions of neural activity that interfere with the formation of precisely neural circuits.
Abstract: Neural activity is critical for sculpting the intricate circuits of the nervous system from initially imprecise neuronal connections. Disrupting the formation of these precise circuits may underlie many common neurodevelopmental disorders, ranging from subtle learning disorders to pervasive developmental delay. The necessity for sensory-driven activity has been widely recognized as crucial for infant brain development. Recent experiments in neurobiology now point to a similar requirement for endogenous neural activity generated by the nervous system itself before sensory input is available. Here we use the formation of precise neural circuits in the visual system to illustrate the principles of activity-dependent development. Competition between the projections from lateral geniculate nucleus neurons that receive sensory input from the two eyes shapes eye-specific connections from an initially diffuse projection into ocular dominance columns. When the competition is altered during a critical period for these changes, by depriving one eye of vision, the normal ocular dominance column pattern is disrupted. Before ocular dominance column formation, the highly ordered projection from retina to lateral geniculate nucleus develops. These connections form before the retina can respond to light, but at a time when retinal ganglion cells spontaneously generate highly correlated bursts of action potentials. Blockade of this endogenous activity, or biasing the competition in favor of one eye, results in a severe disruption of the pattern of retinogeniculate connections. Similar spontaneous, correlated activity has been identified in many locations in the developing central nervous system and is likely to be used during the formation of precise connections in many other neural systems. Understanding the processes of activity-dependent development could revolutionize our ability to identify, prevent, and treat developmental disorders resulting from disruptions of neural activity that interfere with the formation of precise neural circuits.
TL;DR: Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.
TL;DR: It is concluded that GAD activity and GABA are not necessary for the development or maintenance of neuromuscular junctions in C. elegans.
Abstract: The neurotransmitter GABA has been proposed to play a role during nervous system development. We show that the Caenorhabditis elegans gene unc-25 encodes glutamic acid decarboxylase (GAD), the GABA biosynthetic enzyme. unc-25 is expressed specifically in GABAergic neurons. Null mutations in unc-25 eliminate the UNC-25 protein or alter amino acids conserved in all known GADs, result in a complete lack of GABA, and cause defects in all GABA-mediated behaviors. In unc-25 mutants the GABAergic neurons have normal axonal trajectories and synaptic connectivity, and the size and shape of synaptic vesicles are normal. The number of synaptic vesicles at GABAergic neuromuscular junctions is slightly increased. Cholinergic ventral nerve cord neurons, which innervate the same muscles as GABAergic ventral cord neurons, have normal morphology, connectivity, and synaptic vesicles. We conclude that GAD activity and GABA are not necessary for the development or maintenance of neuromuscular junctions in C. elegans.
TL;DR: In this review, histochemical and immunocytochemical data on the distribution of the amine neurons in the larval and adult nervous system, are summarized and the implications of the molecular genetic approach in Drosophila are discussed.
Abstract: Biogenic amines are important neuroactive molecules of the central nervous system (CNS) of several insect species. Serotonin (5HT), dopamine (DA), histamine (HA), and octopamine (OA) are the amines which have been extensively studied in Drosophila melanogaster. Each one of the four aminergic neuronal systems exhibits a stereotypic pattern of a small number of neurons that are widely distributed in the fly CNS. In this review, histochemical and immunocytochemical data on the distribution of the amine neurons in the larval and adult nervous system, are summarized. The majority of DA and 5HT neurons are interneurons, most of which are found in bilateral clusters. 5HT innervation is found in the feeding apparratus as well as in the endocrine organ of the larva, the ring gland. The octopaminergic neuronal population constists of both interneurons and efferent neurons. In the larval CNS all OA immunoreactive somata are localized in the midline of the ventral ganglion while in the adult CNS both unpaired neurons and bilateral clusters of immunoreactive cells are observed. One target of OA innervation is the abdominal muscles of the larval body wall where OA immunoreactivity is associated with the type II boutons in the axonal terminals. Histamine is mainly found in all photoreceptor cells where it is considered to be the major neurotransmitter molecule, and in specific mechanosensory neurons of the peripheral nervous system. Similarities between specific aminergic neurons and innervation sites in Drosophila and in other insect species are discussed. In addition, studies on the development and differentiation of 5HT and DA neurons are reviewed and data on the localization of 5HT, DA, and OA receptors are included as well. Finally, an overview on the isolation of the genes and the mutations in the amine biosynthetic pathways is presented and the implications of the molecular genetic approach in Drosophila are discussed. Microsc. Res. Tech. 45:106–121, 1999. © 1999 Wiley-Liss, Inc.
TL;DR: These findings raise the possibility that exposure to environmental neurotoxins that affect cholinergic systems may seriously compromise brain development and have long-lasting morphologic, neurochemical, and functional consequences.
Abstract: In the adult nervous system, neurotransmitters mediate cellular communication within neuronal circuits. In developing tissues and primitive organisms, neurotransmitters subserve growth regulatory and morphogenetic functions. Accumulated evidence suggests that acetylcholine, (ACh), released from growing axons, regulates growth, differentiation, and plasticity of developing central nervous system neurons. In addition to intrinsic cholinergic neurons, the cerebral cortex and hippocampus receive extensive innervation from cholinergic neurons in the basal forebrain, beginning prenatally and continuing throughout the period of active growth and synaptogenesis. Acute exposure to ethanol in early gestation (which prevents formation of basal forebrain cholinergic neurons) or neonatal lesioning of basal forebrain cholinergic neurons, significantly compromises cortical development and produces persistent impairment of cognitive functions. Neonatal visual deprivation alters developmental expression of muscarinic acetylcholine receptors (mAChR) in visual cortex, whereas local infusion of mAChR antagonists impairs plasticity of visual cortical neurons. These findings raise the possibility that exposure to environmental neurotoxins that affect cholinergic systems may seriously compromise brain development and have long-lasting morphologic, neurochemical, and functional consequences.
TL;DR: The protein localization of several retinoic acid receptors and retinoid X receptors did not correlate with the distribution of the corresponding RNA transcripts, as studied by in situ hybridization and RNase protection assays, which suggests that the expression of retinoids receptors could be post-transcriptionally regulated, which may contribute to their specific localization in the adult nervous system.
TL;DR: The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho‐adrenal nervous system and to determine if these differences support the hypothesis that, in females, theregulation of the sympathetic nervous system (SNS) is altered such that sympathy activation is attenuated or sympathy inhibition is augmented.
Abstract: 1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho-adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented. 2. The central control of sympatho-adrenal function is different in females and responses vary during the oestral and menstrual cycles. Pathways regulating the SNS appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli in females compared with males. 3. Gender differences in arterial baroreflex sensitivity suggest that females may have a greater baroreflex sensitivity, such that alterations in blood pressure are more efficiently controlled than in males. Cardiopulmonary reflex inhibition of sympathetic nerve activity is greater in females, possibly resulting in a greater renal excretory function. 4. An attenuated sensitivity to adrenergic nerve stimulation, but not to noradrenaline (NA), suggests that gender differences in noradrenergic neurotransmission may protect females against sympathetic hyperactivity. Gender differences in the regulation of NA release via presynaptic alpha 2-adrenoceptors, the vasoconstrictor response to the cotransmitter neuropeptide Y and the clearance of catecholamines are consistent with this hypothesis. 5. Similarly, attenuated stress-induced increases in plasma catecholamines in women suggest that females are less sensitive and/or less responsive to adrenal medullary activation. This is supported by findings of gender differences in adrenal medullary catecholamine content, release and degradation. 6. We conclude that there is strong evidence that supports the hypothesis that, in females, the regulation of the SNS is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented.
TL;DR: Knock-out mice in which individual ecto-nucleotidases have been deleted from the germline promise to be important tools to unravel their functional roles in the nervous system and also in other tissues.
Abstract: Publisher Summary This chapter discusses the molecular structures, catalytic properties, and functional roles of ecto-nucleotidases in the nervous system. Only one ecto-5’-nucleotidase gene is known in vertebrates. Ecto-5’-nucleotidase plays a critical role in the extracellular hydrolysis cascade of nucleotides and in neural development. Several families of ectonucleotidases function in the nervous system. They differ in their catalytic and other functional properties and consist of several members each. The chapter presents that nucleotidergic signaling pathways are widely distributed in the nervous system and that the ecto-nucleotidases play a significant part in it. The functional properties of the presently known ecto-nucleotidases and also of the sequenced but uncharacterized potential ecto-nucleotidases need to be investigated. An evaluation of their role in defined signaling pathways requires that the cellular location of the enzymes is determined. Knock-out mice in which individual ecto-nucleotidases have been deleted from the germline promise to be important tools to unravel their functional roles in the nervous system and also in other tissues.
TL;DR: Findings suggest that factors which modulate glucocorticoid action (e.g. cytokines and antidepressants) will be relevant contributors to disease expression including behavioral toxicity and sickness behavior.
Abstract: A large body of data has been amassed which convincingly demonstrates that the immune system and the nervous system extensively interact (Ader, Cohen, & Felten, 1991; Miller, In Press). Immune cells and tissues express receptors for a wide range of transmitters associated with and regulated by the nervous system including neuro-transmitters, peptides and hormones, and nervous system innervation of lymphoid tissues has been well characterized. Moreover, the presence of soluble immune products (cytokines) and their receptors have been found in multiple nervous system and endocrine tissues (Besedovsky & del Rey, 1996). Alterations of nervous system function by exposure to a variety of stressors has been shown to result in dramatic changes in immune system function, and exposure to cytokines or various types of immune activation has been shown to significantly alter CNS function (Miller, In Press; McEwen, Biron, Brunson, Bulloch, Chambers, Dhabhar, Goldfarb, Kitson, Miller, Spencer, & Weiss, 1997; Kent, Bluthe, Kelley, & Dantzer, 1992). Given the vast potential for mutual regulation involving the immune system and the brain, there has been considerable interest in the possibility that immune system processes may be involved in the pathophysiology of psychiatric syndromes including major depression. One possible mechanism whereby the immune system might contribute to the development of pathology which manifests as depressive symptomatology involves the capacity of cytokines to inhibit functioning of the receptors for glucocorticoids, thus inducing a state of glucocorticoid resistance.
TL;DR: Some tentative ideas concerning the importance of this nervous system in cardiac disease states are provided with a view to stimulating further interest in neural control of the heart so that appropriate neurocardiological strategies can be devised for the management of heart disease.
Abstract: The intrinsic cardiac nervous system has been classically considered to contain only parasympathetic efferent postganglionic neurones which receive inputs from medullary parasympathetic efferent preganglionic neurones In such a view, intrinsic cardiac ganglia act as simple relay stations of parasympathetic efferent neuronal input to the heart, the major autonomic control of the heart purported to reside solely in the brainstem and spinal cord Data collected over the past two decades indicate that processing occurs within the mammalian intrinsic cardiac nervous system which involves afferent neurones, local circuit neurones (interconnecting neurones) as well as both sympathetic and parasympathetic efferent postganglionic neurones As such, intrinsic cardiac ganglionic interactions represent the organ component of the hierarchy of intrathoracic nested feedback control loops which provide rapid and appropriate reflex coordination of efferent autonomic neuronal outflow to the heart In such a concept, the intrinsic cardiac nervous system acts as a distributive processor, integrating parasympathetic and sympathetic efferent centrifugal information to the heart in addition to centripetal information arising from cardiac sensory neurites A number of neurochemicals have been shown to influence the interneuronal interactions which occur within the intrathoracic cardiac nervous system For instance, pharmacological interventions that modify β-adrenergic or angiotensin II receptors affect cardiomyocyte function not only directly, but indirectly by influencing the capacity of intrathoracic neurones to regulate cardiomyocytes Thus, current pharmacological management of heart disease may influence cardiomyocyte function directly as well as indirectly secondary to modifying the cardiac nervous system This review presents a brief summary of developing concepts about the role of the cardiac nervous system in regulating the normal heart In addition, it provides some tentative ideas concerning the importance of this nervous system in cardiac disease states with a view to stimulating further interest in neural control of the heart so that appropriate neurocardiological strategies can be devised for the management of heart disease
TL;DR: Otx1 mutant mice are defective in the refinement of these exuberant projections, suggesting that Otx1 is required for the development of normal axonal connectivity and the generation of coordinated motor behavior.
TL;DR: Results indicate that formation of a normal compact myelin sheath is required for normal maturation of the neuronal cytoskeleton in large CNS neurons.
Abstract: Although traditional roles ascribed to myelinating glial cells are structural and supportive, the importance of compact myelin for proper functioning of the nervous system can be inferred from mutations in myelin proteins and neuropathologies associated with loss of myelin. Myelinating Schwann cells are known to affect local properties of peripheral axons (de Waegh et al., 1992), but little is known about effects of oligodendrocytes on CNS axons. The shiverer mutant mouse has a deletion in the myelin basic protein gene that eliminates compact myelin in the CNS. In shiverer mice, both local axonal features like phosphorylation of cytoskeletal proteins and neuronal perikaryon functions like cytoskeletal gene expression are altered. This leads to changes in the organization and composition of the axonal cytoskeleton in shiverer unmyelinated axons relative to age-matched wild-type myelinated fibers, although connectivity and patterns of neuronal activity are comparable. Remarkably, transgenic shiverer mice with thin myelin sheaths display an intermediate phenotype indicating that CNS neurons are sensitive to myelin sheath thickness. These results indicate that formation of a normal compact myelin sheath is required for normal maturation of the neuronal cytoskeleton in large CNS neurons.
TL;DR: The phenotype and functional characteristics of fetal microglia are outlined in this review, and the need for specific cellular interactions and targeting is greater within the central nervous system than in other tissues.
Abstract: Microglia are the immune effector cells of the nervous system. The prevailing view is that microglia are derived from circulating precursors in the blood, which originate from the bone-marrow. Colonisation of the central nervous system (CNS) by microglia is an orchestrated response during human fetal development related to the maturation of the nervous system. It coincides with vascularisation, formation of radial glia, neuronal migration and myelination primarily in the 4th-5th months and beyond. Microglial influx generally conforms to a route following white matter tracts to gray areas. We have observed that colonisation of the spinal cord begins around 9 weeks, with the major influx and distribution of microglia commencing around 16 weeks. In the cerebrum, colonisation is in progress during the second trimester, and ramified microglial forms are widely distributed within the intermediate zone by the first half of intra-uterine life (20-22 weeks). A distinct pattern of migration occurs along radial glia, white matter tracts and vasculature. The distribution of these cells is likely to be co-ordinated by spatially and temporally regulated, anatomical expression of chemokines including RANTES and MCP-1 in the cortex; by ICAM-2 and PECAM on radiating cerebral vessels and on capillaries within the germinal layer, and apoptotic cell death overlying this region. The phenotype and functional characteristics of fetal microglia are also outlined in this review. The need for specific cellular interactions and targeting is greater within the central nervous system than in other tissues. In this respect, microglia may additionally contribute towards CNS histogenesis.
TL;DR: This article used ultrasound image-guided injections of high-titer retroviral vectors to obtain widespread introduction of genes into the mouse nervous system in utero as early as embryonic day 8.5 (E8.5).
Abstract: We used ultrasound image-guided injections of high-titer retroviral vectors to obtain widespread introduction of genes into the mouse nervous system in utero as early as embryonic day 8.5 (E8.5). The vectors used included internal promoters that substantially improved proviral gene expression in the ventricular zone of the brain. To demonstrate the utility of this system, we extended our previous work in vitro by infecting the telencephalon in vivo as early as E8.5 with a virus expressing Sonic Hedgehog. Infected embryos showed gross morphological brain defects, as well as ectopic expression of ventral telencephalic markers characteristic of either the medial or lateral ganglionic eminences.
TL;DR: A recent demonstration of high carnosine-like immunoreactivity in the subependymal layer of rodents, an area of the forebrain which shares with the olfactory neuroepithelium the occurrence of continuous neurogenesis during adulthood, supports the hypothesis that carnosin-related dipeptides could be implicated in some forms of structural plasticity.
TL;DR: This review will examine the effect of IGF-I on central nervous system (CNS) development, a complex series of biological events which result from the interaction between the cells' genetic program and environmental influences.
Abstract: Insulin-like growth factor-I (IGF-I), a 70-amino acid-protein structurally similar to insulin, promotes cell proliferation and differentiation in multiple tissues. Most of its effects are mediated by the Type I IGF receptor (IGF-IR), a heterotetramer that has tyrosine kinase activity and phosphorylates insulin receptor substrates (IRS-1 and 2) which leads to the activation of two downstream signaling cascades: the MAP kinase and the phosphatidylinositol 3-kinase (P3K) cascades. The growth-promoting effects of IGF-I are prominent in the nervous system, qualifying this molecule as a neurotrophin. Although the primary regulator of IGF-I expression is growth hormone (GH), the developmental expression of IGF-I in various tissues precedes that of GH, supporting an independent role of IGF-I in embryonic and fetal life [1]. This review will examine the effect of IGF-I on central nervous system (CNS) development. The specialized structure of the CNS is the product of a complex series of biological events which result from the interaction between the cells' genetic program and environmental influences. CNS development begins in the embryo with dorsal ectodermal cell proliferation to form the neural plate, and, with its closure, the neural tube, followed by the rapid division of pluripotential cells, their migration to the periphery of the neural tube, and differentiation into neural or glial cells. During the latter stages, cells form special structures such as nuclei, ganglia, cerebral cortical layers, and they also develop a network with their cytoplasmic extensions, neurites. Many more cells and connections are generated in fetal life than are found in the mature organism. This excessive production of some cell groups and neurites may compensate for tissue loss due to various injuries, and their selective elimination also constitutes an efficient way to organize the architecture of the CNS. This elimination is believed to be accomplished by apoptosis. The cells' intrinsic program for development includes the expression of various genes at different times. Environmental influences, such as extracellular matrix (ECM) molecules that attract or repel cells, afferent inputs, and target-derived diffusible molecules modify and modulate cellular behavior. IGF-I is among the molecules which affect several steps involved in development.