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Mammalian Central Nervous System (mammalian + central_nervous_system)
Kinds of Mammalian Central Nervous System Selected AbstractsRetinoic acid, a regeneration-inducing moleculeDEVELOPMENTAL DYNAMICS, Issue 2 2003Malcolm Maden Abstract Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the "super-regeneration" of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR,2, is not up-regulated. When RAR,2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate. Developmental Dynamics 226:237,244, 2003.© 2003 Wiley-Liss, Inc. [source] Combinatorial treatments for promoting axon regeneration in the CNS: Strategies for overcoming inhibitory signals and activating neurons' intrinsic growth stateDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2007Larry I. Benowitz Abstract In general, neurons in the mature mammalian central nervous system (CNS) are unable to regenerate injured axons, and neurons that remain uninjured are unable to form novel connections that might compensate for ones that have been lost. As a result of this, victims of CNS injury, stroke, or certain neurodegenerative diseases are unable to fully recover sensory, motor, cognitive, or autonomic functions. Regenerative failure is related to a host of inhibitory signals associated with the extracellular environment and with the generally low intrinsic potential of mature CNS neurons to regenerate. Most research to date has focused on extrinsic factors, particularly the identification of inhibitory proteins associated with myelin, the perineuronal net, glial cells, and the scar that forms at an injury site. However, attempts to overcome these inhibitors have resulted in relatively limited amounts of CNS regeneration. Using the optic nerve as a model system, we show that with appropriate stimulation, mature neurons can revert to an active growth state and that when this occurs, the effects of overcoming inhibitory signals are enhanced dramatically. Similar conclusions are emerging from studies in other systems, pointing to a need to consider combinatorial treatments in the clinical setting. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source] Induction of endogenous neural precursors in mouse models of spinal cord injury and diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2005M. F. Azari Adult neural precursor cells (NPCs) in the mammalian central nervous system (CNS) have been demonstrated to be responsive to conditions of injury and disease. Here we investigated the response of NPCs in mouse models of spinal cord disease [motor neuron disease (MND)] with and without sciatic nerve axotomy, and spinal cord injury (SCI). We found that neither axotomy, nor MND alone brought about a response by Nestin-positive NPCs. However, the combination of the two resulted in mobilization of NPCs in the spinal cord. We also found that there was an increase in the number of NPCs following SCI which was further enhanced by systemic administration of the neuregulatory cytokine, leukaemia inhibitory factor (LIF). NPCs were demonstrated to differentiate into astrocytes in axotomized MND mice. However, significant differentiation into the various neural cell phenotypes was not demonstrated at 1 or 2 weeks following SCI. These data suggest that factors inherent to injury mechanisms are required for induction of an NPC response in the mammalian spinal cord. [source] Concepts of neural nitric oxide-mediated transmissionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2008John Garthwaite Abstract As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success. [source] Doublecortin expression levels in adult brain reflect neurogenesisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005Sebastien Couillard-Despres Abstract Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions. [source] Post-lesion transcommissural growth of olivary climbing fibres creates functional synaptic microzonesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2003Izumi Sugihara Abstract In the adult mammalian central nervous system, reinnervation and recovery from trauma is limited. During development, however, postlesion plasticity may generate alternate paths, providing models to investigate reinnervating axon,target interactions. After unilateral transection of the neonatal rat olivocerebellar path, axons from the ipsilateral inferior olive grow into the denervated hemicerebellum and develop climbing fibre (CF)-like arbors on Purkinje cells (PCs). However, the synaptic function and extent of PC reinnervation remain unknown. In adult rats pedunculotomized on postnatal day 3 the morphological and electrophysiological properties of reinnervating olivocerebellar axons were studied, using axonal reconstruction and patch-clamp PC recording of CF-induced synaptic currents. Reinnervated PCs displayed normal CF currents, and the frequency of PC reinnervation decreased with increasing laterality. Reinnervating CF arbors were predominantly normal but 6% branched within the molecular layer forming smaller secondary arbors. CFs arose from transcommissural olivary axons, which branched extensively near their target PCs to produce on average 36 CFs, which is six times more than normal. Axons terminating in the hemisphere developed more CFs than those terminating in the vermis. However, the precise parasagittal microzone organization was preserved. Transcommissural axons also branched, although to a lesser extent, to the deep cerebellar nuclei and terminated in a distribution indicative of the olivo-cortico-nuclear circuit. These results show that reinnervating olivocerebellar axons are highly plastic in the cerebellum, compensating anatomically and functionally for early postnatal denervation, and that this reparation obeys precise topographic constraints although axonal plasticity is modified by target (PC or deep nuclear neurons) interactions. [source] The position of an arginine residue influences substrate affinity and K+ coupling in the human glutamate transporter, EAAT1JOURNAL OF NEUROCHEMISTRY, Issue 2 2010Renae M. Ryan J. Neurochem. (2010) 114, 565,575. Abstract Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and extracellular glutamate levels are controlled by a family of transporters known as excitatory amino acid transporters (EAATs). The EAATs transport glutamate and aspartate with similar micromolar affinities and this transport is coupled to the movement of Na+, K+, and H+. The crystal structure of a prokaryotic homologue of the EAATs, aspartate transporter from Pyrococcus horokoshii (GltPh), has yielded important insights into the architecture of this transporter family. GltPh is a Na+ -dependent transporter that has significantly higher affinity for aspartate over glutamate and is not coupled to H+ or K+. The highly conserved carboxy-terminal domains of the EAATs and GltPh contain the substrate and ion binding sites, however, there are a couple of striking differences in this region that we have investigated to better understand the transport mechanism. An arginine residue is in close proximity to the substrate binding site of both GltPh and the EAATs, but is located in transmembrane domain (TM) 8 in the EAATs and hairpin loop 1 (HP1) of GltPh. Here we report that the position of this arginine residue can explain some of the functional differences observed between the EAATs and GltPh. Moving the arginine residue from TM8 to HP1 in EAAT1 results in a transporter that has significantly increased affinity for both glutamate and aspartate and is K+ independent. Conversely, moving the arginine residue from HP1 to TM8 in GltPh results in a transporter that has reduced affinity for aspartate. [source] Chemical inducers and transcriptional markers of oligodendrocyte differentiationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2010Lara Joubert Abstract Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protection of the mammalian central nervous system. To advance our molecular understanding of differentiation by these cells, we screened libraries of pharmacologically active compounds and identified inducers of differentiation of Oli-neu, a stable cell line of mouse oligodendrocyte precursors (OPCs). We identified four broad classes of inducers, namely, forskolin/cAMP (protein kinase A activators), steroids (glucocorticoids and retinoic acid), ErbB2 inhibitors, and nucleoside analogs, and confirmed the activity of these compounds on rat primary oligodendrocyte precursors and mixed cortical cultures. We also analyzed transcriptional responses in the chemically induced mouse and rat OPC differentiation processes and compared these with earlier studies. We confirm the view that ErbB2 is a natural signaling component that is required for OPC proliferation, whereas ErbB2 inhibition or genetic knockdown results in OPC differentiation. © 2010 Wiley-Liss, Inc. [source] Activation of adenosine A1 receptor,induced neural stem cell proliferation via MEK/ERK and Akt signaling pathwaysJOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2008Hideyuki Migita Abstract Adenosine, a modulator of neuronal function in the mammalian central nervous system, exerts a neuroprotective effect via the adenosine A1 receptor; however, its effect on neural stem cells (NSCs) remains unclear. Because adenosine is released in response to pathological conditions and NSCs play a key role in neuroregeneration, we tested the hypothesis that adenosine is capable of stimulating NSC proliferation. We demonstrated that NSCs dominantly express adenosine A1 and A2B receptors. Adenosine and the adenosine A1 receptor agonist cyclopentyladenosine (CPA) increased proliferation of NSCs, and this CPA-induced cell proliferation was attenuated by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPA). CPA also induced phosphorylation of extracellular signal,regulated kinase (ERK), mitogen-activated protein kinase/ERK kinase (MEK), and Akt, and their phosphorylation was inhibited by DPCPA. In addition, CPA-induced cell proliferation was inhibited by MEK and Akt inhibitors. These results suggest that activation of adenosine A1 receptor,stimulated proliferation of NSCs occurs via MEK/ERK and Akt signaling pathways. © 2008 Wiley-Liss, Inc. [source] Heterogeneous expression of melatonin receptor MT1 mRNA in the rat intestine under control and fasting conditionsJOURNAL OF PINEAL RESEARCH, Issue 2 2006Soták Abstract:, Melatonin is found in mammalian central nervous system and various peripheral tissues including gastrointestinal tract (GIT) where it participates in the regulation of intestinal motility, blood flow, immunomodulation, ion transport, cell proliferation and scavenging of free radicals. Some of these effects are achieved via melatonin binding to specific receptors, MT1 and MT2. As no thorough study on the expression of these receptors in the GIT has yet been done, the aim of this study was to determine the MT1 mRNA expression in the rat intestine under both control and fasting conditions. Our results suggest that MT1 mRNA is present in epithelial as well as subepithelial layer, with higher expression in the latter in all intestinal segments studied. The highest signal of the MT1 transcript along the rostro,caudal intestinal axis was found both in epithelial and subepithelial layers of the duodenum. Nevertheless, duodenal MT1 mRNA expression did not reach the level found in pituitary gland. In a 12:12-hr light:dark cycle a MT1 receptor expression in the subepithelial layer of rat distal colon did not manifest a significant diurnal rhythm. Short-term fasting increased the expression of MT1 transcript in the subepithelial layer of both the small and large intestine. During long-term fasting the increase persisted only in distal colon while a return to control levels was observed in small intestinal segments. In conclusion we demonstrated heterogeneous expression of MT1 receptor in the rat intestine and showed that its expression is up-regulated by nutritional deprivation. [source] Glutamate-Dopamine Cotransmission and Reward Processing in AddictionALCOHOLISM, Issue 9 2006Christopher C. Lapish While Dale's principle of "one neuron, one neurotransmitter" has undergone revisions to incorporate evidence of the corelease of atypical neurotransmitters such as neuropeptides, the corelease of classical neurotransmitters has only recently been realized. Surprisingly, numerous studies now indicate that the corelease of neurotransmitters in the mammalian central nervous system is not an obscure and rare phenomenon but is widespread and involves most classical neurotransmitters systems. However, the suggestion that glutamate can be coreleased with dopamine (DA) has remained controversial. Furthermore, glutamate-DA cotransmission has not yet been seriously considered in the context of the neurocircuitry of addiction. If glutamate is in fact coreleased with DA as some evidence now suggests, this may have significant implications for advancing our understanding of the interactive role that these 2 neurotransmitters play in cognitive and reward processes. In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamate-DA corelease in addiction. In particular, we describe a recently proposed model in which coreleased glutamate transmits a temporally precise prediction error signal of reward described by Schultz et al., whereas the function of coreleased DA is to exert prolonged modulatory influences on neuronal activity. In addition, we suggest that as alcohol consumption transitions from recreational use to addiction, there is a corresponding transition in the reward valence signal from better than predicted to worse than predicted. [source] Neural Stem Cells and AlcoholALCOHOLISM, Issue 2 2003F. T. Crews This article summarizes the proceedings of a symposium held at the 2002 Research Society on Alcoholism Meeting in San Francisco, California. The aim of this symposium was to review research on the effects of ethanol on neural stems cells and neurogenesis. Ethanol is known to alter neurogenesis during development; however, recent studies indicate that the brain forms new neurons from stem cells throughout life. Furthermore, stem cells can be transplanted into the brain, creating exciting new possibilities to study brain function. The symposium covered these research areas. Dr. Michael W. Miller reviewed knowledge on the effects of ethanol on stem cell proliferation and differentiation during development. Dr. Wu Ma described studies in culture indicating that (1) neural stem cells express functional muscarinic acetylcholine receptors (mAchR), (2) mAchR-mediated proliferation involves Ca2+ signaling and mitogen-activated protein kinase phosphorylation, and (3) phosphoinositol-3 kinase is a downstream effector for mAchR-mediated cell proliferation via activation of Akt. Drs. Kim Nixon and Fulton T. Crews followed with in vivo studies on ethanol's effects on adult neural stem cell proliferation and differentiation. Dr. W. Michael Zawada described studies directed at dopamine neuron cell transplants into mammalian central nervous system. These studies clearly establish that ethanol has significant effects on stem cells. [source] Subtype selective kainic acid receptor agonists: Discovery and approaches to rational designMEDICINAL RESEARCH REVIEWS, Issue 1 2009Lennart Bunch Abstract (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all,to our knowledge,published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 1, 3,28, 2009 [source] Competitive AMPA receptor antagonistsMEDICINAL RESEARCH REVIEWS, Issue 2 2007Daniela Catarzi Abstract Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) where it is involved in the physiological regulation of different processes. It has been well established that excessive endogenous Glu is associated with many acute and chronic neurodegenerative disorders such as cerebral ischaemia, epilepsy, amiotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease. These data have consequently added great impetus to the research in this field. In fact, many Glu receptor antagonists acting at the N -methyl- D -aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), and/or kainic acid (KA) receptors have been developed as research tools and potential therapeutic agents. Ligands showing competitive antagonistic action at the AMPA type of Glu receptors were first reported in 1988, and the systemically active 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline (NBQX) was first shown to have useful therapeutic effects in animal models of neurological disease in 1990. Since then, the quinoxaline template has represented the backbone of various competitive AMPA receptor antagonists belonging to different classes which had been developed in order to increase potency, selectivity and water solubility, but also to prolong the "in vivo" action. Compounds that present better pharmacokinetic properties and less serious adverse effects with respect to the others previously developed are undergoing clinical evaluation. In the near future, the most important clinical application for the AMPA receptor antagonists will probably be as neuroprotectant in neurodegenerative diseases, such as epilepsy, for the treatment of patients not responding to current therapies. The present review reports the history of competitive AMPA receptor antagonists from 1988 up to today, providing a systematic coverage of both the open and patent literature. © 2006 Wiley Periodicals, Inc. [source] The GABAergic-like system in the marine demosponge Chondrilla nuculaMICROSCOPY RESEARCH AND TECHNIQUE, Issue 11 2007Paola Ramoino Abstract Gamma-amino butyric acid (GABA) is believed to be the principal inhibitory neurotransmitter in the mammalian central nervous system, a function that has been extended to a number of invertebrate systems. The presence of GABA in the marine demosponge Chondrilla nucula was verified using immunofluorescence detection and high-pressure liquid chromatography. A strong GABA-like immunoreactivity (IR) was found associated with choanocytes, exopinacocytes, endopinacocytes lining inhalant, and exhalant canals, as well as in archaeocytes scattered in the mesohyl. The capacity to synthesize GABA from glutamate and to transport it into the vesicles was confirmed by the presence in C. nucula of glutamate decarboxylase (GAD) and vesicular GABA transporters (vGATs), respectively. GAD-like and vGAT-like IR show the same distribution as GABA-like IR. Supporting the similarity between sponge and mammalian proteins, bands with an apparent molecular weight of about 65,67 kDa and 57 kDa were detected using antibodies raised against mammalian GAD and vGAT, respectively. A functional metabotropic GABAB -like receptor is also present in C. nucula. Indeed, both GABAB R1 and R2 isoforms were detected by immunoblot and immunofluorescence. Also in this case, IR was found in choanocytes, exopinacocytes, and endopinacocytes. The content of GABA in C. nucula amounts to 1225.75 ± 79 pmol/mg proteins and GABA is released into the medium when sponge cells are depolarized. In conclusion, this study is the first indication of the existence of the GABA biosynthetic enzyme GAD and of the GABA transporter vGAT in sponges, as well as the first demonstration that the neurotransmitter GABA is released extracellularly. Microsc. Res. Tech., 2007. © 2007 Wiley-Liss, Inc. [source] Cytokines and neurotrophic factors fail to affect Nogo-A mRNA expression in differentiated human neurones: implications for inflammation-related axonal regeneration in the central nervous systemNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2002J.-I. Satoh Nogo is a novel myelin-associated inhibitor of neurite outgrowth which regulates stable neuronal connections during axonal regeneration following injury in the adult mammalian central nervous system (CNS). Because cytokines and neurotrophic factors play a key role in inflammation-related axonal regeneration, we investigated: (i) the constitutive expression of Nogo and the Nogo receptor (NgR) mRNA in human neural cell lines; (ii) Nogo and NgR mRNA levels in the NTera2 human teratocarcinoma cell line during retinoic acid (RA)-induced neuronal differentiation; and (iii) their regulation in NTera2-derived differentiated neurones (NTera2-N) after exposure to a battery of cytokines and growth factors potentially produced by activated glial cells at post-traumatic inflammatory lesions in the CNS. By reverse transcriptase-polymerase chain reaction analysis, the constitutive expression of Nogo-A, the longest isoform of three distinct Nogo transcripts and NgR mRNA was identified in a wide variety of human neural and non-neural cell lines. By Northern blot analysis, the levels of Nogo-A mRNA were elevated markedly in NTera2 cells following RA-induced neuronal differentiation, accompanied by an increased expression of the neurite growth-associated protein GAP-43 mRNA. In contrast, Nogo-A, Nogo-B, NgR and GAP-43 mRNA levels were unaltered in NTera2-N cells by exposure to basic fibroblast growth factor, brain-derived neurotrophic factor, glia-derived neurotrophic factor, tumour necrosis factor-,, interleukin-1,, dibutyryl cyclic AMP or phorbol 12-myristate 13-acetate. These results indicate that both Nogo-A and NgR mRNA are coexpressed in various human cell types, including differentiated neurones, where their expression is unaffected by exposure to a panel of cytokines and neurotrophic factors which might be involved in inflammation-related axonal regeneration in the CNS. [source] The Developmental Remodeling of Eye-Specific Afferents in the Ferret Dorsal Lateral Geniculate NucleusTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 1 2010Colenso M. Speer Abstract Eye-specific projections to the dorsal lateral geniculate nucleus (dLGN) serve as a model for exploring how precise patterns of circuitry form during development in the mammalian central nervous system. Using a combination of dual-label anterograde retinogeniculate tracing and Nissl-staining, we studied the patterns of eye-specific afferents and cellular laminae in the dLGN of the pigmented sable ferret at eight developmental timepoints between birth and adulthood. Each time point was investigated in the three standard orthogonal planes of section, allowing us to generate a complete anatomical map of eye-specific development in this species. We find that eye-specific retinal ganglion cell axon segregation varies according to location in the dLGN, with the principle contralateral (A) and ipsilateral layers (A1) maturing first, followed by the contralateral and ipsilateral C laminae. Cytoarchitectural lamination lags behind eye-specific segregation, except in the C laminae where underlying cellular layers never develop to accompany eye-specific afferent domains. The emergence of On/Off sublaminae occurs following eye-specific segregation in this species. On the basis of these findings, we constructed a three-dimensional map of eye-specific channels in the developing and mature ferret dLGN. Anat Rec, 293:1,24, 2010. © 2010 Wiley-Liss, Inc. [source] Generalized arousal of mammalian central nervous systemTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 1 2005Donald Pfaff Abstract A fundamental capacity of the mammalian CNS is becoming amenable to study with the techniques of functional genomics. Emphasized in this review are ascending connections from the medullary reticular formation and descending connections from the paraventricular nucleus of the hypothalamus. In particular, sex hormone effects on neurons allow us to relate generalized arousal to a specific form of arousal which is required for reproductive behaviors. J. Comp. Neurol. 493:86,91, 2005. © 2005 Wiley-Liss, Inc. [source] Direct Stimulation of Adult Neural Stem Cells In Vitro and Neurogenesis In Vivo by Vascular Endothelial Growth FactorBRAIN PATHOLOGY, Issue 3 2004Anne Schänzer Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia-inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR-2/Flk-1 are expressed in clonally-derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR-2/Flk-1-kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR-2/Flk-1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system. These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases. [source] | |||||||||||||