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  • Blackwell Science Ltd  (63,715)
  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Notes: The past is littered with seemingly robust organisations disappearing into oblivion. But corporate extinction rarely happens by chance. Helga Drummond offers an alternative universe to show how a prosperous business can decline if companies fail to innovate.
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Notes: Like problem children, if they're not handled well corporate ventures can cause their parents financial heartache and make them wish they'd never been born. But they can bring rich rewards if gently nurtured to their best ability. Julian Birkinshaw offers advice on practical corporate parenting.
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 11
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 12
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 13
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 14
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 15
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 16
    Electronic Resource
    Electronic Resource
    Oxford, UK and Boston, USA : Blackwell Science Ltd
    Business strategy review 16 (2005), S. 0 
    ISSN: 1467-8616
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Economics
    Type of Medium: Electronic Resource
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  • 17
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 18
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: Dean Zimmerman focuses on the debate between a serious-tenser B-theorist and an eternalist A-theorist concerning truth and truth-conditions of tensed propositions. According to Zimmerman, the only way for the A-theorist to distinguish herself from the B-theorist is to argue for the non-relative (temporary monadic) truth of tensed propositions denying some aspects of the doctrine of temporal parts. I claim instead that the A-theorist can argue for the non-relative truth of tensed propositions adopting tensed truth-conditions incompatible with the B-theorist's hypotheses.
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  • 19
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: The paper has two parts: First, I describe a relatively popular thesis in the philosophy of propositional attitudes, worthy of the name ‘taking tense seriously’; and I distinguish it from a family of views in the metaphysics of time, namely, the A-theories (or what are sometimes called ‘tensed theories of time’). Once the distinction is in focus, a skeptical worry arises. Some A-theorists maintain that the difference between past, present, and future, is to be drawn in terms of what exists: growing-block theorists eschew ontological commitment to future entities; presentists, to future and past entities. Others think of themselves as A-theorists but exclude no past or future things from their ontology. The metaphysical skeptic suspects that their attempt to articulate an ‘eternalist’ version of the A-theory collapses into merely ‘taking tense seriously’– a thesis that does not imply the A-theory. The second half of the paper is the search for a stable eternalist A-theory. It includes discussion of temporary intrinsics, temporal parts, and truth.
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  • 20
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: The purpose of this article is to provide a non-contradictory interpretation of sentences such as “Smith's murderer might not have murdered Smith”. An anti-actualist, two-dimensional framework including partial functions provides the basis for my solution. I argue for two claims. (1) The modal profile of the proposition (truth-condition) expressed by “The F might not have been an F” (where “F” is an empirical predicate) is complex: at any world where there is a unique F the proposition is true; at any world without a unique F the proposition has no truth-value; hence, at no world is it false. It remains an open semantic and epistemological question which of the first two kinds of world the actual world is. (2) The semantic method should be based on explicit intensionalization in lieu of actualism. Actualism accords a privileged role to the actual world. Explicit intensionalization places all possible worlds, including the actual one, on an equal footing. Syntactically, a lambda-bound world variable replaces the (explicit or implicit) actual-world constant or operator, while the other world variable is existentially bound.
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  • 21
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 22
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: I attempt to explain Frege's handling of the Julius Caesar issue in terms of his more general philosophical commitments. These only became fully explicit in his middle-period writings, but his earlier moves are best explained, I suggest, if we suppose them to be implicit in his earlier thinking. These commitments conditionally justify Frege in rejecting Hume's Principle as either a definition or axiom but in accepting Axiom V. However, the general epistemological picture they constitute has serious problems in accounting for how knowledge is possible at all of such propositions as that Julius Caesar is not a number.
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  • 23
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: A feature of Frege's philosophy of arithmetic that has elicited a great deal of attention in the recent secondary literature is his contention that numbers are ‘self-subsistent’ objects. The considerable interest in this thesis among the contemporary philosophy of mathematics community stands in marked contrast to Kreisel's folk-lore observation that the central problem in the philosophy of mathematics is not the existence of mathematical objects, but the objectivity of mathematics. Although Frege was undoubtedly concerned with both questions, a goal of the present paper is to argue that his success in securing the objectivity of arithmetic depends on a less contentious commitment to numbers as objects than either he or his critics have supposed. As such, this paper is an articulation and defense of both Frege's analysis of arithmetic and Kreisel's observation.
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  • 24
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: The issues surrounding the Caesar problem are assumed to be inert as far as ongoing mathematics is concerned. This paper aims to correct this impression by spelling out the ways that, in their historical context, Frege's remarks would have had considerable resonance with work that other mathematicians such as Riemann and Dedekind were doing. The search for presentation-independent characterizations of objects and global definitions was seen as bound up with fundamental methodological questions in complex analysis and number theory.
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  • 25
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 26
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 27
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
    Notes: The Generality Problem for process reliabilism is to outline a procedure for determining when two beliefs are produced by the same process, in such a way as to avoid, on the one hand, individuating process types so narrowly that each type is instantiated only once, or, on the other hand, individuating them so broadly that beliefs that have different epistemic statuses are subsumed under the same process type. In this paper, I offer a solution to the problem which takes belief-independent processes to be functions that take as inputs information about distal states of affairs, and produce beliefs as outputs. Processes are individuated narrowly, so as to avoid the latter aspect of the Generality problem, but, by holding process tokens to be of the same type when they take perceptually equivalent scenes as inputs, and produce beliefs of the same kind as outputs, the former aspect of the problem is avoided too. Having argued that this method of typing process tokens solves the Generality Problem, I then argue that my solution does not fall prey to objections that have been, or might be, raised for similar proposals.
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  • 28
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 29
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 30
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 31
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 32
    Electronic Resource
    Electronic Resource
    Oxford, UK and Malden, USA : Blackwell Science Ltd
    Dialectica 59 (2005), S. 0 
    ISSN: 1746-8361
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Philosophy
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  • 33
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Asymmetric photic stimulation during embryonic or post-hatch development induces a functional lateralization of the pigeon's visual system, which is accompanied by left–right differences in tectal cell sizes. The intracellular membrane-anchored GTPase Ras can be activated by a number of upstream mechanisms including binding of brain-derived neurotrophic factor to its specific TrkB receptor. Ras activity plays an important morphogenetic role in neurons and therefore might also be involved in the asymmetric differentiation of tectal cells. To investigate the role of Ras, we determined the relative levels of activated Ras and of signalling active phospho-TrkB in tecta of light- and dark-incubated pigeons and combined this with an immunohistochemical detection of Ras-GTP and TrkB receptors. While Ras activation levels did not differ between light- and dark-incubated pigeons during embryonic development, directly after hatching Ras activity was significantly decreased in the stronger stimulated left tectum of light-incubated animals. This was accompanied by lower levels of TrkB phosphorylation. Immunohistochemical staining revealed Ras-GTP-positive cell bodies within the efferent cell layer. These cells were TrkB-positive and developed enlarged soma sizes within the right tectum during the first week after hatching. This association suggests asymmetric Ras activation to be involved in the asymmetric differentiation of the efferent cells as a result of asymmetric TrkB signalling. Because asymmetric light exposure occurs only during embryonic development, the observed transient asymmetric inhibition of TrkB/Ras activity after hatching may reflect differential embryonic maturation of tectal inhibitory circuits leading to a functional superiority of the right eye in the adult organism.
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  • 34
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aims of this study were: first, to investigate the effects of anaesthesia on phosphorylated extracellular signal-regulated kinase (p-ERK)1/2-immunoreactivity (-ir) in the brainstem; second, to choose the best anaesthetic for p-ERK1/2 studies; and third, to determine the effect of short-term hypotension on p-ERK1/2-ir in the brainstem. Rats were anaesthetized with halothane, sodium pentobarbital or 100% CO2 narcosis, or were cervically dislocated and within 5 min perfused and the brains processed immunohistochemically for pERK1/2-ir. p-ERK1/2-ir was primarily observed in regions associated with cardiovascular and/or respiratory control. Several regions consistently showed dense p-ERK1/2 labelling, including a restricted region of the ventrolateral medulla (VLM). In contrast, other regions showed differential labelling depending on the mode of death. Cervical dislocation showed the least VLM labelling, limited to a discrete area approximately 0.6–1.4 mm caudal to the facial nucleus. Anaesthetics induced labelling throughout the VLM, with halothane inducing the most. Many p-ERK1/2-ir VLM neurons were catecholaminergic following halothane or sodium pentobarbital anaesthesia, but no double labelling was seen following cervical dislocation. Of the anaesthetics, sodium pentobarbital induced the least labelling and was used subsequently. Intravenous hydralazine was used to induce a 20-min period of hypotension, whereas arterial pressure did not change in vehicle-treated animals. Hydralazine evoked more pERK-ir neurons in specific regions, including the VLM, nucleus tractus solitarius (NTS), parabrachial nuclei, Kolliker-Fuse nucleus and locus coeruleus. Approximately twice as many p-ERK1/2-positive neurons were seen in the intermediate NTS and rostral VLM following hydralazine compared with the vehicle. In conclusion, p-ERK1/2-ir identifies neurons in central autonomic regions, and their number and distribution are markedly affected by anaesthetics, and are increased in some regions by short-term hypotension.
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  • 35
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: It is widely accepted that learning first involves generating new memories and then consolidating them into long-term memory. Thus learning is generally viewed as a single continuous process with two sequential stages; acquisition and consolidation. Here, we tested an alternative hypothesis proposing that acquisition and consolidation take place, at least partly, in parallel. Human subjects learned two visuomotor tasks. One task required moving a cursor under visuomotor rotation and the other required arbitrary association of colour to direction of movement. Subjects learned the two tasks in sequence, and were tested for acquisition of the second immediately after learning the first, and for retention of the first on the following day. The results show that learning one task led to proactive interference to acquisition of the second. However, this interference was not accompanied by retroactive interference to consolidation of the first task, indicating that acquisition and consolidation can be uncoupled.
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  • 36
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In decerebrate newborn rats, serotonin (5-HT) is a respiratory depressant via activation of 5-HT2 receptors, whereas it evokes respiratory stimulant effects when applied to the isolated brainstem obtained from the newborn rat. This discrepancy could be due to deafferentation in the in vitro preparation. The aim of our study was to analyse the role of vagal afferents in the modulation of central respiratory effects of 5-HT. In decerebrate cervically or abdominally bivagotomized newborn rats aged between 0 and 3 days, we recorded electrical activity from the diaphragm and from a hypoglossally innervated tongue muscle, as well as cardiac frequency (Fc), before and after application of 5-HT to the floor of the IVth ventricle. The effects of related agents (a 5-HT1A agonist, 8-OH DPAT, and a 5-HT2 agonist, DOI) were studied in cervically bivagotomized animals. For comparison, and to assess the spontaneous variability in inspiratory frequency (Fi) and Fc, sham groups were studied. Each group comprised ten newborn rats. In cervically bivagotomized newborn rats, 5-HT induces a significant increase in Fi, which is the opposite to that observed in decerebrate newborn rats with intact vagi. This respiratory effect is mediated in particular, via activation of 5-HT1A. By contrast, in abdominally bivagotomized newborn rats, a decrease in Fi was observed in response to 5-HT (as previously described in decerebrate animals with intact vagi). We conclude that pulmonary vagal afferents modulate the central respiratory action of 5-HT in decerebrate newborn rats, explaining the conflicting results between in vivo and in vitro experiments.
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  • 37
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The formation of neuronal synapses is thought to depend on trans-synaptic interactions between cell adhesion molecules (CAMs) on the surface of axons and dendrites. Synapses are highly asymmetric structures. Pre- and post-synaptic domains might therefore be assembled around heterophilic CAMs which are polarized to axons vs. dendrites. We here investigated the targeting of neuroligin (NLG)-1, a heterophilic CAM, which promotes synapse formation through interaction with its receptor β-neurexin in axons. We demonstrate that NLG-1 is highly polarized to the dendritic plasma membrane. Dendritic targeting relies on a cytoplasmic amino acid motif. By expressing chimeras of NLG-1 and CD8, an unpolarized protein, we show that the cytoplasmic domain of NLG-1 is necessary and sufficient for dendritic targeting. Furthermore, by truncation analysis we isolated a 32-amino-acid targeting motif. When appended to CD8 this cytoplasmic sequence is sufficient to direct exclusively dendritic localization of the protein. Analysis of yellow fluorescent protein-tagged NLG-1 revealed that vesicular structures containing NLG-1 are excluded from the axon indicating that polarized distribution may be achieved by direct dendritic transport. We propose that the strict polarity of NLG-1 contributes to the directional assembly of synapses during development of the central nervous system.
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  • 38
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    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The major impediments to axonal regeneration in the central nervous system are growth-inhibitory proteins present in the myelin sheath, and Nogo-A is one of the most potent inhibitors synthesized by oligodendrocytes. However, neuronal expression of Nogo-A during development suggests that it may have an additional role. The spatio-temporal regulation of both Nogo-A mRNA and protein expression was examined by in situ hybridization and immunohistochemistry in the developing rat olfactory system. During embryonic and postnatal development (from E13 to P6), Nogo-A mRNA and protein were strongly expressed by differentiating neurons in the olfactory epithelium and in the olfactory bulb. From the second postnatal week, a progressive down-regulation of both Nogo-A mRNA and protein occurred, such that only a weak expression persisted in the adult olfactory system. Using double-immunostainings in the adult olfactory epithelium, we determined that Nogo-A was preferentially expressed by immature olfactory receptor neurons extending axonal processes toward the olfactory bulb. At all developmental stages, Nogo-A protein was preferentially targeted in olfactory axons emerging from the olfactory epithelium. Using an in vitro model of olfactory axon growth, we demonstrated that, in addition to its presence along the entire axon length, Nogo-A accumulated in axonal growth cone and at axonal branching points, with a distribution similar to that of microtubule-associated proteins. Moreover, Nogo-A was transiently expressed in dendritic processes in the postnatal olfactory bulb. Together, our data suggest that, in non-pathological conditions, Nogo-A may be involved in the processes of axonal growth and dendritic modeling through the regulation of microtubule dynamics.
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  • 39
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To determine whether members of the Netrin-1 and Slit families and their receptors are expressed after central nervous system (CNS) injury, we performed in situ hybridization for netrin-1, slit-1, 2 and 3, and their receptors (dcc, unc5h-1, 2 and 3, robo-1, 2 and 3) 8 days, 2–3 months and 12–18 months after traumatic lesions of rat cerebellum. The expression pattern of these molecules was unchanged in axotomized Purkinje cells, whereas unc5h3 expression was upregulated in deafferented granule cells. Cells expressing slit-2 or dcc were never detected at the lesion site. By contrast, cells expressing netrin-1, slit-1 and slit-3, unc5h-1, 2 and 3, and robo-1, 2 and 3 (rig-1) could be detected at the cerebellar lesion site as soon as 8 days after injury. Expression of unc5h-2, robo-1, robo-2, slit-1 and slit-3 at the lesion site was maintained until 3 months, and up to 12–18 months for unc5h-1 and 3 and robo-3. Likewise, in the mouse spinal cord, netrin-1, slit-1 and slit-3 were also expressed at the lesion site 8 days after injury. Most of the cells expressing these mRNAs were located at the centre of the lesions, suggesting that they are macrophages/activated microglial cells (macrophagic cells) or meningeal fibroblastic cells. The macrophagic nature of most Netrin-1-positive cells and the macrophagic or fibroblastic nature of Robo-1-positive cells were corroborated by double staining. Thus, Netrin-1, Slits and their receptors may contribute to the regenerative failure of axons in the adult CNS by inhibiting axon outgrowth or by participating in the formation of the CNS scar.
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We reported previously that 96 h of sleep deprivation (SD) reduced cell proliferation in the dentate gyrus (DG) of the hippocampus in adult rats. We now report that SD reduces the number of new cells expressing a mature neuronal marker, neuronal nuclear antigen (NeuN). Rats were sleep-deprived for 96 h, using an intermittent treadmill system. Total sleep time was reduced to 6.9% by this method in SD animals, but total treadmill movement was equated in SD and treadmill control (CT) groups. Rats were allowed to survive for 3 weeks after 5-bromo-2-deoxyuridine (BrdU) injection. The phenotype of BrdU-positive cells in the DG was assessed by immunofluorescence and confocal microscopy. After 3 weeks the number of BrdU-positive cells was reduced by 39.6% in the SD group compared with the CT. The percentage of cells that co-localized BrdU and NeuN was also lower in the SD group (SD: 46.6 ± 1.8% vs. CT: 71.9 ± 2.1, P 〈 0.001). The percentages of BrdU-labeled cells co-expressing markers of immature neuronal (DCX) or glial (S100-β) cells were not different in SD and CT groups. Thus, SD reduces neurogenesis in the DG by affecting both total proliferation and the percentage of cells expressing a mature neuronal phenotype. We hypothesize that sleep provides anabolic or signaling support for proliferation and cell fate determination.
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  • 41
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Programmed cell death is an important mechanism during brain development in order to control neuronal cell numbers and to correctly form neuronal circuitries. Programmed cell death is also present in neurogenic regions of the adult brain, and a significant portion of the adult-born cells is eliminated during the first months of maturation. We here address the question whether overexpression of the anti-apoptotic protein Bcl-2 would improve the survival of neural progenitor cells and, as a consequence, increase neurogenesis in the adult hippocampus. Transgenic animals, which express human Bcl-2 under the neuron-specific enolase promoter (NSE-huBcl-2), show a significant reduction of apoptotic cells in the hippocampal granule cell layer to about half of the wild-type level. These apoptotic cells are almost exclusively found in the zone of hippocampal progenitor activity and frequently co-label with the neuronal progenitor marker doublecortin (DCX). The rate of adult neurogenesis is doubled in the dentate gyrus of Bcl-2-overexpressing mice as demonstrated by quantification of progenitor cells using DCX and new neurons using bromodeoxyuridine (BrdU)/neuronal nuclei antigen (NeuN) double-labelling. The effect of Bcl-2 is limited to the late phase of progenitor maturation, as proliferation and early-phase progenitor cells were not affected. The increased level of neurogenesis leads to a significantly higher total number of granule cells in the dentate gyrus. These results underline the importance of developmental cell death during neurogenesis in the adult brain.
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  • 42
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Hypothalamic luteinizing hormone-releasing hormone neurons (LHRH) form the final pathway for the central control of reproduction through the release of LHRH into the pituitary-hypothalamic system. We previously found that LHRH-producing GT1-7 cells respond to acetylcholine (ACh) with an increase in intracellular calcium ([Ca2+]i) through activation of muscarinic receptors. This effect is acutely modulated by 17β-estradiol in a manner compatible with specific membrane binding sites. Because increasing evidence suggests that second messengers are involved in the rapid action of estradiol, the aim of the present study was to identify the pathway underlying estrogen actions on ACh-induced Ca2+ signals. 8-Bromoguanosine 3′,5′-cyclic monophosphate (10 µm) and C-type natriuretic peptide (10 µm) mimicked the effect of estradiol. On the contrary, neither dibutyryl cAMP (100 µm), forskolin (100 nm or 10 µm), or sodium nitroprusside (10 µm) induced any modification of [Ca2+]i in response to ACh. The effect of estradiol on calcium transients was totally blocked by two different cGMP-dependent protein kinase (PKG) inhibitors. In addition, phosphorylation of inositol 1,4,5-triphosphate (IP3) receptor was rapidly induced by estradiol but totally blocked when the cells were pretreated with a PKG inhibitor. We conclude that physiological concentrations of estradiol reduce ACh-induced Ca2+ transients via a mechanism involving a membrane-associated guanylate cyclase, which finally induces a PKG-dependent IP3 receptor phosphorylation that modifies calcium release from the endoplasmic reticulum.
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  • 43
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Relapse to drug taking is triggered by stimuli previously associated with consumption of drugs of misuse (cues) and involves brain systems controlling motivated behaviour towards natural reinforcers. In this study, we aimed to identify and compare neuronal pathways in corticostriatal systems that control conditioned heroin or natural reward (sucrose) seeking. To that end, rats were trained to self-administer heroin or sucrose in association with an identical compound cue. After more than 3 weeks of abstinence during extinction training, cue exposure robustly reinstated heroin and sucrose seeking, but induced distinct and even opposing changes in the expression of the neuronal activation marker zif268 in the prelimbic cortex and striatal complex, respectively. Because in the prelimbic area zif268 expression was enhanced during cue-induced heroin seeking but unaffected during sucrose seeking, a pharmacological intervention was aimed at this prefrontal region. Injection of a GABA agonist mixture within the prelimbic area enhanced conditioned heroin seeking, but had no effect on conditioned sucrose seeking. Our findings suggest a differential role of the prelimbic area and the striatum in the persistence of heroin vs. sucrose seeking following long-term extinction.
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  • 44
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We studied receptive field organization of motion-sensitive neurons in macaque middle temporal cortical area (MT), by mapping direction selectivity in space and in time. Stimuli consisted of pseudorandom sequences of single motion steps presented simultaneously at many different receptive field locations. Spatio-temporal receptive field profiles were constructed by cross-correlating stimuli and spikes. The resulting spike-triggered averages revealed centre-surround organization. The temporal dynamics of the receptive fields were generally biphasic with increased probability for the preferred direction at short latency (50–70 ms) and decreased probability at longer latency (80–100 ms). The response latency of the receptive field surround was on average 16 ms longer than that of the centre. Our results show that surround input and biphasic behaviour reflect two different mechanisms, which make MT cells specifically sensitive to motion contrast in space and time.
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  • 45
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cellular responses after spinal cord injury include activation of astrocytes, degeneration of neurons and oligodendrocytes, and reactions of the ependymal layer and meningeal cells. Because it has been suggested that tissue repair partially recapitulates morphogenesis, we have investigated the expression of several developmentally prominent molecules after spinal cord injury of adult mice where neurogenesis does not occur after injury. Cell fate determinants Numb, Notch-1, Shh and BMPs are abundantly expressed during development but mostly decline in the adult. In the present study, we investigated whether these genes are triggered by spinal cord injury as a sign of attempted recapitulation of development. Expression of Numb, Notch, Shh, BMP2/4 and Msx1/2 was analysed in the adult mouse spinal cord after compression injury by in situ hybridization up to 1 month after injury. The mRNA expression levels of Notch-1, Numb, Shh, BMP4 and Msx2 increased in the grey matter and/or white matter and in the ependyma rostral and caudal to the lesion site after injury. However, BMP2 and Msx1 were not up-regulated. Combining immunohistochemistry of cell type-specific markers with in situ hybridization we found that all the up-regulated genes were expressed in neurons. Moreover, Numb, BMP4 and Msx2 were also expressed by GFAP-positive astrocytes, while Shh was expressed by MBP-positive oligodendrocytes. In conclusion, the cell fate determinants Notch-1, Numb, Shh, BMP4 and Msx2 are expressed in neurons and/or glial cells after injury in a time-dependent manner, suggesting that these genes reflect to some extent an endogenous self-repair potential by recapitulating some features of development.
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  • 46
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.
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  • 47
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We showed recently that behavioural and striatal dopaminergic (DA) responses obtained in latent inhibition are crucially dependent on the parahippocampal region, the entorhinal cortex. In the present study, we investigated the influence exerted by the hippocampal ventral subicular region (SUB) on the DA responses in the anterior part of the dorsal striatum using in vivo voltammetry in freely moving rats and the same latent inhibition paradigm. To that end, the left SUB was temporarily blocked with tetrodotoxin (TTX) during pre-exposure to a new olfactory stimulus (banana odour). During the second session the animals were aversively conditioned to banana odour. With respect to the results obtained during the test session (third presentation of banana odour), similar changes in behaviour and DA levels were obtained in control and conditioned rats microinjected with the solvent, phosphate-buffered saline (PBS), in the SUB, consistently with a latent inhibition phenomenon. In contrast, after reversible inactivation of the SUB during the pre-exposure session, TTX-pre-exposed conditioned animals displayed aversive behaviour in the test session, and anterior striatal DA variations in these animals differed significantly from those obtained in pre-exposed rats injected locally with PBS. Striatal DA variations obtained in conditioned animals microinjected with TTX were also significantly different from those observed in conditioned non-pre-exposed animals. The present data suggest that, in parallel to the entorhinal cortex, the SUB regulates the latent inhibition-related behavioural and DA responses in the anterior part of the dorsal striatum. These data may provide new insight into the pathophysiology of schizophrenic psychoses.
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  • 48
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) results in time-dependent changes in neuronal activity, structure and connectivity in the contralateral motor cortex of adult rats. These changes have been linked to facilitation of motor skill learning in the less-affected/ipsilesional forelimb, which is likely to promote its use in the development of behavioral compensation. The goal of this study was to determine whether an early post-lesion-sensitive time period exists for this enhanced learning and whether it is linked to synaptogenesis in the contralesional motor cortex. Rats were trained for 21 days on a skilled reaching task with the ipsilesional forelimb beginning 4 or 25 days after unilateral ischemic (endothelin-1-induced) FLsmc lesions or sham operations. As found previously, reaching performance was significantly enhanced in rats trained early post-lesion compared with sham-operates. In rats trained later post-lesion, performance was neither significantly different from time-matched sham-operates nor strikingly different from animals trained earlier post-lesion. In layer V of the contralesional motor cortex, stereological methods for light and electron microscopy revealed significantly more total, multisynaptic bouton and perforated synapses per neuron compared with sham-operates, but there were no significant differences between early- and late-trained lesion groups. Thus, there appears to be a sensitive time window for the maximal expression of the enhanced learning capacity of the less-affected forelimb but this window is broadly, rather than sharply, defined. These results indicate that relatively long-lasting lesion-induced neuronal changes are likely to underlie the facilitation of learning with the less-affected forelimb.
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  • 49
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The purpose of this study was to examine the functional interaction between endogenous opioid and cannabinoid receptor systems in the caudate putamen and nucleus accumbens. We therefore examined by autoradiography the functional activity and density of µ-, κ- and δ-opioid receptors in both brain regions of cannabinoid CB1 receptor knockout mice. Functional activity was estimated by measuring agonist-stimulated [35S]GTPγS binding. Results showed that deletion of the CB1 cannabinoid receptor markedly increased κ-opioid (50%) and δ-opioid (42%) receptor activities whereas no differences were found in µ-opioid receptor in the caudate putamen. In contrast, binding autoradiography showed a similar density of µ-, κ- and δ-opioid receptors between mutant and wild-type mice. No differences were found in densities or activities of µ-, κ- and δ-opioid receptors between mutant and wild-type mice in the nucleus accumbens. Taken together, our results revealed that deletion of CB1 cannabinoid receptors produced a pronounced increase in the activity of κ- and δ-opioid receptors in the caudate putamen. This endogenous interaction between opioid and cannabinoid receptors may be relevant to further understand a variety of neuroadaptative processes involving the participation of opioid receptors, such as motor behaviour, emotional responses and drug dependence.
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  • 50
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Complexin II is reduced in Huntington's disease (HD) patients and in the R6/2 mouse model of HD. Mice lacking complexin II (Cplx2–/– mice) show selective cognitive deficits that reflect those seen in R6/2 mice. To determine whether or not there is a common mechanism that might underlie the cognitive deficits, long-term potentiation (LTP) was examined in the CA3 region of hippocampal slices from R6/2 mice and Cplx2–/– mice. While associational/commissural (A/C) LTP was not significantly different, mossy fibre (MF) LTP was significantly reduced in slices from R6/2 mice and Cplx2–/– mice compared with wild-type (WT) and Cplx2+/+ control mice. MF field excitatory postsynaptic potentials (fEPSPs) in response to paired stimuli were not significantly different between control mice and R6/2 or Cplx2–/– mice, suggesting that MF basal glutamate release is unaffected. Forskolin (30 µm) caused an increase in glutamate release at MF synapses in slices from R6/2 mice and from Cplx2–/– mice that was not significantly different from that seen in control mice, indicating that the capacity for increased glutamate release is not diminished. Thus, R6/2 mice and Cplx2–/– mice have a common selective impairment of MF LTP in the CA3 region. Together, these data suggest that complexin II is required for MF LTP, and that depletion of complexin II causes a selective impairment in MF LTP in the CA3 region. This impairment in MF LTP could contribute to spatial learning deficits observed in R6/2 and Cplx2–/– mice.
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  • 51
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To elucidate the central mechanisms of sound segregation, we compared responses to a harmonic sound and a mistuned sound using a whole-head magnetoencephalography system. The harmonic sound was composed of a 200-Hz tone and its 2nd to 12th harmonics. The mistuned sound had, instead of the 600-Hz harmonic, a 696-Hz tone. In the right hemisphere, the amplitude of N100m responses evoked by the mistuned sound was significantly larger and the peak latency significantly longer than that evoked by the harmonic sound, suggesting that the right hemisphere plays a more important role than the left in detecting mistuned partials.
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  • 52
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Thyroid hormone (TH) has a profound effect on astrocyte differentiation and maturation. Astrocytes cultured under TH-deficient conditions fail to transform from flat polygonal morphology to mature, process-bearing, stellate cells. Supplementation of physiological concentrations of TH initiate gradual transformation of the cells and the process takes ≈ 48 h to complete. The signal transduction pathways associated with TH-mediated maturation of astrocytes have been investigated. TH treatment caused an initial activation of protein kinase A (PKA), with a peak activity at 2 h which fell back to basal level there after. Although there was no visible change in morphology of the cells during the observed activation of PKA, it was sufficient to drive the process of transformation to completion, suggesting the involvement of downstream regulators of PKA. PKA inhibitors as well as the MEK inhibitor PD098059 attenuated the TH-induced morphological transformation. Further studies showed that TH treatment resulted in a biphasic response on the cellular phospho-MAP kinase (p-MAPK or p-ERK) level: an initial decline in the p-ERK level followed by an induction at 18–24 h, both of which could be blocked by a PKA inhibitor. Such sustained activation of p-ERK levels by TH at this later stage coincided with initiation of morphological differentiation of the astrocytes and appeared to be critical for the transformation of astrocytes. The nitric oxide synthase (NOS) inhibitor 7-NI inhibited this induction of p-ERK activity. Moreover, the induction was accompanied by a parallel increase in phospho-CREB activity which, however, persisted at the end of the transformation of the astroglial cells.
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  • 53
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Co-localization of dopamine D1 and D3 receptors in striatal neurons suggests that these two receptors interact at a cellular level in mediating dopaminergic function including psychostimulant-induced behaviour. To study D1 and D3 receptor interactions in cocaine-mediated effects, cocaine-induced locomotion and reward in mice lacking either D1, D3 or both receptors were analysed. Spontaneous locomotor activity was increased in D1–/– and D1–/–D3–/– mice and D1–/–D3–/– mice did not exhibit habituation of spontaneous rearing activity. Cocaine (20 mg/kg) increased locomotor activity in wild-type and D3–/– mice, failed to stimulate activity in D1–/– mice and reduced activity in D1–/–D3–/– mice. In the conditioned place preference, all groups exhibited reward at 5, 10 and 20 mg/kg of cocaine. D1–/–D3–/– mice did not demonstrate preference at 2.5 mg/kg of cocaine although preference was observed in wild-type, D1–/– and D3–/– mice. The transcription factor cAMP-responsive element binding protein (CREB) is activated by phosphorylation in striatal regions following dopamine receptor activation. Striatal pCREB levels following acute cocaine were increased in wild-type and D3–/– mice and decreased in D1–/– and D1–/–D3–/– mice. After repeated administration of 2.5 mg/kg of cocaine, D1–/– mice had lower pCREB levels in caudate–putamen and nucleus accumbens. Our findings suggest that, although spontaneous and cocaine-induced horizontal activity depended mainly on the presence of the D1 receptor, there may be crosstalk between D1 and D3 receptors in rearing habituation and the perception of cocaine reward at low doses of the drug. Furthermore, alterations in pCREB levels were associated with changes in cocaine-induced locomotor activity but not reward.
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  • 54
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Insulin-like growth factor-I (IGF-I) has multiple effects within the developing nervous system but its role in neurogenesis in the adult nervous system is less clear. The adult olfactory mucosa is a site of continuing neurogenesis that expresses IGF-I, its receptor and its binding proteins. The aim of the present study was to investigate the roles of IGF-I in regulating proliferation and differentiation in the olfactory mucosa. The action of IGF-I was assayed in serum-free culture combined with bromodeoxyuridine-labelling of proliferating cells and immunochemistry for specific cell types. IGF-I and its receptor were expressed by globose basal cells (the neuronal precursor) and by olfactory neurons. IGF-I reduced the numbers of proliferating neuronal precursors, induced their differentiation into neurons and promoted morphological differentiation of neurons. The evidence suggests that IGF-I is an autocrine and/or paracrine signal that induces neuronal precursors to differentiate into olfactory sensory neurons. These effects appear to be similar to the cellular effects of IGF-I in the developing nervous system.
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  • 55
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We have made use of a reporter mouse line in which enhanced green fluorescence protein (GFP) is inserted into the Sox1 locus. We show that the GFP reporter is coexpressed with the Sox1 protein as well as with other known markers for neural stem and progenitor cells, and can be used to identify and isolate these cells by fluorescence-activated cell sorting (FACS) from the developing or adult brain and from neurosphere cultures. All neurosphere-forming cells with the capacity for multipotency and self-renewal reside in the Sox1–GFP-expressing population. Thus, the Sox1–GFP reporter system is highly useful for identification, isolation and characterization of neural stem and progenitor cells, as well as for the validation of alternative means for isolating neural stem and progenitor cells. Further, transplantation experiments show that Sox1–GFP cells isolated from the foetal brain give rise to neurons and glia in vivo, and that many of the neurons display phenotypic characteristics appropriate for the developing brain region from which the Sox1–GFP precursors were derived. On the other hand, Sox1–GFP cells isolated from the adult subventricular zone or expanded neurosphere cultures gave rise almost exclusively to glial cells following transplantation. Thus, not all Sox1–GFP cells possess the same capacity for neuronal differentiation in vivo.
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  • 56
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Serum and potassium deprivation-induced neuronal death on the primary culture of rat cerebellar granule neurons is being widely used as an in vitro model of neurodegeneration and neuronal apoptosis. In our experiments, serum and potassium deprivation for 12 h induced neuronal death in ≈ 20% of cerebellar granule neurons as demonstrated by Trypan Blue assay. Neuronal death was accompanied by a transient increase in the intralysosomal cathepsin L activity, which preceded neuronal death. During this time, the lysosomal membrane integrity remained preserved and no leakage of cathepsin L into the cytosol was seen. Ultrastructural analysis revealed the appearance of multiple vacuoles and autophagosomes in the cytoplasmatic compartment of serum- and potassium-deprived granule neurons. Addition of selective cathepsin L inhibitors or of the autophagy inhibitor 3-methyladenine provided partial protection against serum and potassium deprivation-induced death. Our data also show that combining cathepsin L inhibitors and caspase-3 inhibitors leads to a synergistic neuroprotective effect against serum and potassium deprivation. The results of the current study suggest that activation of the autophagosomal–lysosomal compartment plays an important role in neuronal death induced by serum and potassium deprivation in cultured cerebellar granule cells.
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  • 57
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Vascular inflammation is well known for its ability to compromise the function of the blood–brain barrier (BBB). Whether inflammation on the parenchymal side of the barrier, such as that associated with Parkinson's-like dopamine (DA) neuron lesions, similarly disrupts BBB function, is unknown. We assessed BBB integrity by examining the leakage of FITC-labeled albumin or horseradish peroxidase from the vasculature into parenchyma in animals exposed to the DA neurotoxin 6-hydroxydopamine (6OHDA). Unilateral injections of 6OHDA into the striatum or the medial forebrain bundle produced increased leakage in the ipsilateral substantia nigra and striatum 10 and 34 days following 6OHDA. Microglia were markedly activated and DA neurons were reduced by the lesions. The areas of BBB leakage were associated with increased expression of P-glycoprotein and β3-integrin expression suggesting, respectively, a compensatory response to inflammation and possible angiogenesis. Behavioural studies revealed that domperidone, a DA antagonist that normally does not cross the BBB, attenuated apomorphine-induced stereotypic behaviour in animals with 6OHDA lesions. This suggests that drugs which normally have no effect in brain can enter following Parkinson-like lesions. These data suggest that the events associated with DA neuron loss compromise BBB function.
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  • 58
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neuropathic pain from nerve injury by trauma, disease or surgery often causes prolonged suffering. To explore the molecular mechanisms that underlie neuropathic pain, we used mRNA from the L4–5 segments of the lumbar spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain, and differentially screened a cDNA library from the rat brain. A novel gene, termed RSEP1 (Rat Spinal cord Expression Protein 1), was identified. Northern blots revealed that RSEP1 was expressed mainly in the central nervous system including the cerebral cortex, hippocampus, brainstem and spinal cord, as well as in the kidney and ovary. In situ hybridization showed a high level of RSEP1 expression in the CA1, CA3 and dentate gyrus regions of the hippocampus and the small sensory neurons in the dorsal horn, as well as the large neurons in the ventral horn of the spinal cord. Intrathecal injection of RSEP1 antisense oligonucleotide into the spinal cord lumbar enlargement attenuated neuropathic pain behaviours in CCI rats, suggesting a functional involvement of RSEP1 in neuropathic pain.
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  • 59
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Voltage-gated K+ channel α subunits Kv4.2 and Kv4.3 are the major contributors of somatodendritic A-type K+ currents in many CNS neurons. A recent hypothesis suggests that Kv4 subunits may be involved in pain modulation in dorsal horn neurons. However, whether Kv4 subunits are expressed in dorsal horn neurons remains unknown. Using immunohistochemistry, we found that Kv4.2 and Kv4.3 immunoreactivity was concentrated in the superficial dorsal horn, mainly in lamina II. Both Kv4.2 and Kv4.3 appeared on many rostrocaudally orientated dendrites, whereas Kv4.3 could be also detected from certain neuronal somata. Kv4.3(+) neurons were a subset of excitatory inerneurons with calretinin(+)/calbindin(–)/PKCγ(–) markers, and a fraction of them expressed µ-opioid receptors. Kv4.3(+) neurons also expressed ERK2 and mGluR5, which are molecules related to the induction of central sensitization, a mechanism mediating nociceptive plasticity. Together with the expression of Kv4.3 in VR1(+) DRG neurons, our data suggest that Kv4 subunits could be involved in pain modulation.
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  • 60
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Static changes of the shoulder joint from 30° adduction (ANT) to 30° abduction (POST) in the horizontal plane reduce the gain of the input–output relationship of the corticospinal pathway to the abductor digiti minimi (ADM) muscle [F. Ginanneschi et al. (2005)Exp. Brain Res., 161, 374–382]. The present study examined force estimation under conditions in which the input–output relationship of the corticospinal innervation to ADM was modified by changing shoulder position as above. The input–output relationship was studied using transcranial magnetic stimulation. Estimates of force were assessed using a matching procedure; subjects first matched a target level (10–40% of maximum) on a screen by applying a reference (Ref) isometric contraction of ADM and then they reproduced the same level of force without visual feedback by a test contraction (Test). When Ref and Test contractions were performed at either ANT or POST (i.e. the same input–output), the respective force levels were closely matched. In contrast, when the Test and Ref were performed in POST and ANT, respectively (i.e. different input–output), subjects exerted more force than required. Errors were in the opposite direction when the Test and Ref were in ANT and POST, respectively. The present results suggest that the process of force estimation is based on the effort : tension ratio which is a direct function of the corticomotoneuronal input–output relationship. This notion may contribute to explaining the pathophysiology of central fatigue.
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  • 61
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Stress and stress hormones affect a variety of behaviors and cognitive abilities. The influences of stress and glucocorticoids on motor function, however, have not been characterized although the presence of glucocorticoid receptors in the motor system has been documented. Here we demonstrate that stress and the stress hormone corticosterone influence motor system function in rats. Groups of adult female Long-Evans rats underwent either a daily stress-inducing procedure (immobilization or swimming in cold water) or oral corticosterone treatment. While these treatments continued, animals were tested in skilled reaching and skilled walking tasks for a period of 2 weeks. Both acute (day 1) and chronic (day 14) stress and corticosterone treatment reduced skilled movement accuracy in reaching and walking and increased performance speed. Furthermore, both chronic stress and chronic corticosterone treatment altered skilled movement patterns in the reaching task. These findings indicate that stress modulates motor system function and that these effects are partially mediated by glucocorticoids. To examine whether stress-induced changes might also derive from enhanced emotionality, rats were treated with the benzodiazepine diazepam. Based on an inverted U-shaped dose–response relationship, a moderate dose of diazepam significantly improved reaching success while at the same time reducing corticosterone levels. Thus, stress-associated emotional responses such as anxiety might account for diminished movement accuracy. These results suggest that stress affects the motor system both directly via hormonal changes and indirectly via changes in emotionality. These findings are discussed with respect to the role of stress in motor system function and movement disorders.
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  • 62
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To elucidate the mechanisms underlying sensorimotor integration, we investigated modulation in the primary (SI) and secondary (SII) somatosensory cortices during the preparatory period of a self-initiated finger extension. Electrical stimulation of the right median nerve was applied continuously, while the subjects performed a self-initiated finger extension and were instructed not to pay attention to the stimulation. The preparatory period was divided into five sub-periods from the onset of the electromyogram to 3000 ms before movement and the magnetoencephalogram signals following stimulation in each sub-period were averaged. Multiple source analysis indicated that the equivalent current dipoles (ECDs) were located in SI and bilateral SII. Although the ECD moment for N20m (the upward deflection peaking at around 20 ms) was not significantly changed, that for P30m (the downward deflection peaking at around 30 m) was significantly smaller in the 0- to −500-ms sub-period than the −2000- to −3000-ms sub-period. As for SII, the ECD moment for the SII ipsilateral to movement showed no significant change, while that for the contralateral SII was significantly larger in the 0- to −500-ms sub-period than the −1500- to −2000-ms or −2000- to −3000-ms sub-period. The opposite effects of movement on SI and SII cortices indicated that these cortical areas play a different role in the function of the sensorimotor integration and are affected differently by the centrifugal process.
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  • 63
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Increasing evidence implicates glutamate-mediated excitotoxicity as a contributory factor in dopaminergic cell death in the substantia nigra pars compacta (SNc) in Parkinson's disease (PD). Previous studies have suggested that metabotropic glutamate receptor (mGluR) ligands are neuroprotective against excitotoxicity in vitro. In the present study, the neurotoxin 6-hydroxydopamine (6-OHDA) produced a significant loss (61.2 ± 8.9%; P 〈 0.01) of tyrosine hydroxylase-immunopositive (TH+) cells in both the SNc and striatal dopamine (58.02 ± 1.27%; P 〈 0.05) in control male Sprague–Dawley rats. Both losses were significantly attenuated by sub-chronic (7 day) treatment with the Group I mGluR antagonists, 2-methyl-6(phenylethynyl)-pyridine (MPEP) or (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385); the Group II mGluR agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC); or the Group III mGluR agonist, l(+)-2-amino-4-phosphonobutyric acid (L-AP4). These data demonstrate a neuroprotective action of mGluR ligands in vivo against 6-OHDA toxicity that has important implications for the treatment of PD.
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  • 64
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The nucleus accumbens, as the main input structure of the ventral basal ganglia loop, is described as a limbic–motor interface. Dopamine input to nucleus accumbens modulates processing of concurrent glutamate input from limbic structures carrying motor and motivational information. There is evidence that these dopamine/glutamate interactions are fundamentally involved in response selection processes. However, the pedunculopontine tegmental nucleus (PPTg) in the brainstem is connected with limbic structures as well as dopaminergic midbrain areas, which also project to the nucleus accumbens. Furthermore, behavioral studies implicate the PPTg in complex, motivated behavior. Thus, the PPTg might be involved in motivated behavior by influencing response selection processes in the nucleus accumbens. In this study we used in vivo microdialysis in freely moving rats in order to inhibit (100, 200, 300 and 400 µm baclofen) or stimulate [5, 12.5, 25 or 50 µmα-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)] the PPTg in animals that are performing an operant discrimination task for food reward. The behavioral consequences were correlated with dopamine and glutamate levels in nucleus accumbens and PPTg, respectively. PPTg inhibition by local GABAB receptors impaired the response rate and accuracy of performance in the operant discrimination task. PPTg stimulation by local AMPA receptors exclusively impaired the response rate. Both treatments blocked the performance-driven dopamine signal in nucleus accumbens, whereas glutamate in PPTg was enhanced after AMPA administration only. The data indicate that the PPTg functionally participates in a network of subcortical and cortical structures, which is responsible for the execution of motivated behavior and response selection processes.
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  • 65
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The involvement of matrix metalloproteinases (MMPs) in cerebral ischemia-induced apoptosis was investigated in a model of transient focal cerebral ischemia in rats treated intracerebroventricularly (i.c.v.) with 4-((3-(4-phenoxylphenoxy)propylsulfonyl)methyl)-tetrahydropyran-4-carboxylic acid N-hydroxy amide, a broad spectrum non-peptidic hydroxamic acid MMP inhibitor, and in MMP-9-deficient mice. Our results showed that MMP inhibition reduced DNA fragmentation by 51% (P 〈 0.001) and cerebral infarct by 60% (P 〈 0.05) after ischemia. This protection was concomitant with a 29% reduction of cytochrome c release into the cytosol (P 〈 0.005) and a 54% reduction of calpain-related α-spectrin degradation (P 〈 0.05), as well as with an 84% increase in the immunoreactive signal of the native form of poly(ADP) ribose polymerase (P 〈 0.01). By contrast, specific targeting of the mmp9 gene in mice did reduce cerebral damage by 34% (P 〈 0.05) but did not modify the apoptotic response after cerebral ischemia. However, i.c.v. injection of MMP-9-deficient mice with the same broad-spectrum inhibitor used in rats significantly reduced DNA degradation by 32% (P 〈 0.05) and contributed even further to the protection of the ischemic brain. Together, our pharmacological and genetic results indicate that MMPs other than MMP-9 are actively involved in cerebral ischemia-induced apoptosis.
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  • 66
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Song behavior in songbirds induces the expression of activity-dependent genes in brain areas involved in perceptual processing, production and learning of song. This genomic response is thought to represent a link between neuronal activation and long-term changes in song-processing circuits of the songbird brain. Here we demonstrate that Arc, an activity-regulated gene whose product has dendritic localization and is associated with synaptic plasticity, is rapidly induced by song in the brain of zebra finches. We show that, in the context of song auditory stimulation, Arc expression is induced in several telencephalic auditory areas, most prominently the caudomedial nidopallium and mesopallium, whereas in the context of singing, Arc is also induced in song control areas, namely nucleus HVC, used as a proper name, the robust nucleus of the arcopallium and the interface nucleus of the nidopallium. We also show that song-induced Arc expression co-localizes at the cellular level with those of the transcriptional regulators zenk and c-fos, and that the song induction of these three genes is dependent on activation of the mitogen-activated protein kinase signaling pathway. These findings provide evidence for an involvement of Arc in the brain's response to birdsong. They also demonstrate that genes representing distinct genomic and cellular regulatory programs, namely early effectors and transcription factors, are co-activated in the same neuronal cells by a naturally learned stimulus.
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  • 67
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The go/nogo task is a useful paradigm for recording event-related potentials (ERPs) to investigate the neural mechanisms of response inhibition. In nogo trials, a negative deflection at around 140–300 ms (N2), which has been called the ‘nogo potential’, is elicited at the frontocentral electrodes, compared with ERPs recorded in go trials. In the present study, we investigated the generators of nogo potentials by recording ERPs and by using magnetoencephalography (MEG) simultaneously during somatosensory go/nogo tasks to elucidate the regions involved in generating nogo potentials. ERP data revealed that the amplitude of the nogo-N140 component, which peaked at about 155 ms from frontocentral electrodes, was significantly more negative than that of go-N140. MEG data revealed that a long-latency response peaking at approximately 160 ms, termed nogo-M140 and corresponding to nogo-N140, was recorded in only nogo trials. The equivalent current dipole of nogo-M140 was estimated to lie around the posterior part of the inferior frontal sulci in the prefrontal cortex. These results revealed that both nogo-N140 and nogo-M140 evoked by somatosensory go/nogo tasks were related to the neural activity generated from the prefrontal cortex. Our findings combining MEG and ERPs clarified the spatial and temporal processing related to somato-motor inhibition caused in the posterior part of the inferior frontal sulci in the prefrontal cortex in humans.
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  • 68
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The scaffold protein family Homer/Vesl serves to couple surface receptors or channels with endoplasmic calcium release channels. Homer 1a/Vesl-1S is regarded as regulating such coupling in an activity-dependent manner. The present calcium photometry and electrophysiological measurement revealed that Homer 1a up-regulates voltage-dependent calcium channels (VDCCs), depending on inositol-1,4,5-trisphosphate (IP3) receptors (IP3Rs). In rat neocortex pyramidal cells, intracellular injection by diffusion from the patch pipette (referred to as ‘infusion’) of Homer 1a protein enhanced spike-induced calcium increase, depending on both the protein concentration and spike frequency. Induction of this enhancement was disrupted by blockers of key molecules of the mGluR–IP3 signalling pathway, including metabotropic glutamate receptors (mGluRs), phospholipase C and IP3Rs. However, infusion of IP3 failed to mimic the effect of Homer 1a, suggesting requirement for a second Homer 1a-mediated signalling as well as the mGluR–IP3 signalling. In contrast to the induction, maintenance of this enhancement was independent of the mGluR–IP3 signalling, taking the form of augmented calcium influx via L-type VDCCs. Presumably due to the VDCC up-regulation, threshold currents for calcium spikes were reduced. Given that Homer 1a induction is thought to down-regulate neural excitability and hence somatic spike firing, this facilitation of calcium spikes concomitant with such attenuated firing may well have a critical impact on bi-directional synaptic plasticity.
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  • 69
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A considerable body of evidence reveals that consolidated memories, recalled by a reminder, enter into a new vulnerability phase during which they are susceptible to disruption again. Consistently, reconsolidation was shown by the amnesic effects induced by administration of consolidation blockers after memory labilization. To shed light on the functional value of reconsolidation, we explored whether an endogenous process activated during a concurrent real-life experience improved this memory phase. Reconsolidation of long-term contextual memory has been well documented in the crab Chasmagnathus. Previously we showed that angiotensin II facilitates memory consolidation. Moreover, water deprivation increases brain angiotensin and improves memory consolidation and retrieval through angiotensin II receptors. Here, we tested whether concurrent water deprivation improves reconsolidation via endogenous angiotensin and therefore strengthens memory. We show that memory reconsolidation, induced by training context re-exposure, is facilitated by a concurrent episode of water deprivation, which induces a raise in endogenous brain angiotensin II. Positive modulation is expressed by full memory retention, despite a weak training, 24 or 72 but not 4 h after memory reactivation. This is the first evidence that memory can be positively modulated during reconsolidation through an identified endogenous process triggered during a real-life episode. We propose that the functional value for reconsolidation would be to make possible a change in memory strength by the influence of a concurrent experience. Reconsolidation improvement would lead to memory re-evaluation, not by altering memory content but by modifying the behaviour as an outcome of changing the hierarchy of the memories that control it.
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  • 70
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Despite abundant evidence implicating the importance of N-methyl-d-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
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  • 71
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Central serotonin [5-hydroxytryptamine (5-HT)] is involved in the aetiology of numerous disease states, including depression and anxiety disorders. Studies have shown that exposure of rats to animal tests of anxiety increases extracellular 5-HT in the cortex or hippocampus determined by in vivo microdialysis. To discriminate whether this increase is caused by the aversive conditions of an animal test for anxiety or by an unconditioned stressor evoking mainly arousal, the present study investigates the effects of an unconditioned acoustic stimulus and exposure to the elevated plus maze (X-maze), respectively, on the release of 5-HT in the ventral hippocampus compared with hippocampal 5-HT release in the home cage and in a non-aversive unfamiliar environment in freely moving rats. Our results showed a distinct pattern of 5-HT release in the ventral hippocampus depending on the stimulus used. Exposure to the X-maze for 20 min was accompanied by an ‘anxious’ behaviour in the rats and increased extracellular 5-HT to 165% of basal release, whereas exposure to a less aversive ‘deactivated’ plus maze (115 ± 6%) or to white noise for 20 min in the familiar surroundings of the home cage (98 ± 6%) did not change hippocampal 5-HT release significantly, despite similar behavioural activation indicated by increased locomotor activity. While both the X-maze and white noise may model anxiety and stress to a certain extent, it seems that the X-maze is more aversive. The results suggest a close relationship between anxiety-related behaviour, but not arousal/non-specific behavioural activation, and 5-HT release in the ventral hippocampus.
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  • 72
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Functional recovery after peripheral nerve injury is often poor. Comprehension of cellular and molecular mechanisms limiting or promoting restoration of function and design of efficient therapeutic approaches remain serious challenges for neuroscience and medicine. Progress has been restricted by the lack of reliable methods for evaluation of motor functions in laboratory animals. We describe a novel approach for assessment of muscle function in mice after femoral nerve damage, an injury causing impairment of knee extension. The functional deficit can be precisely estimated by angle and distance measurements on single video frames recorded during movements of the animals with or without body weight support. Using this method we describe here the precise time-course and degree of functional recovery after femoral nerve crush and transection. In addition, we show that restoration of function is considerably impaired in mice with a reduced expression level of the tyrosine kinase receptor B, a cognate receptor for the neurotrophin brain-derived neurotrophic factor. This finding is consistent with known functions of brain-derived neurotrophic factor and tyrosine kinase receptor B and demonstrates the potential of the method. The principles of the approach are highly relevant for the development of novel functional assays in other peripheral and, in particular, central nervous system injury paradigms.
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  • 73
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The auditory cortex (AC) is the major origin of descending auditory projections and is one of the targets of the cholinergic basal forebrain, nucleus basalis (NB). In the big brown bat, cortical activation evokes frequency-specific plasticity in the inferior colliculus and the NB augments this collicular plasticity. To examine whether cortical descending function and NB contributions to collicular plasticity are different between the bat and mouse and to extend the findings in the bat, we induced plasticity in the central nucleus of the mouse inferior colliculus by a tone paired with electrical stimulation of the NB (hereafter referred to as tone-ESNB). We show here that tone-ESNB shifted collicular best frequencies (BFs) towards the frequency of the tone paired with ESNB when collicular BFs were different from tone frequency. The shift in collicular BF was linearly correlated to the difference between collicular BFs and tone frequencies. The changes in collicular BFs after tone-ESNB were similar to those found in the big brown bat. Compared with cortical plasticity evoked by tone-ESNB, the pattern of collicular BF shifts was identical but the shifting range of collicular BFs was narrower. A GABAA agonist (muscimol) or a muscarinic acetylcholine receptor antagonist (atropine) applied to the AC completely abolished the collicular plasticity evoked by tone-ESNB. Therefore, our findings strongly suggest that the AC plays a critical role in experience-dependent auditory plasticity through descending projections.
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  • 74
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Calbindin is a fast Ca2+-binding protein expressed by Purkinje cells and involved in their firing regulation. Its deletion produced ∼160-Hz oscillation sustained by synchronous, rhythmic Purkinje cells in the cerebellar cortex of mice. Parvalbumin is a slow-onset Ca2+-binding protein expressed in Purkinje cells and interneurons. In order to assess its function in Purkinje cell firing regulation, we studied the firing behavior of Purkinje cells in alert mice lacking parvalbumin (PV–/–), calbindin (CB–/–) or both (PV–/–CB–/–) and in wild-type controls. The absence of either protein resulted in Purkinje cell firing alterations (decreased complex spike duration and pause, increased simple spike firing rate) that were more pronounced in CB–/– than in PV–/– mice. Cumulative effects were found in complex spike alterations in PV–/–CB–/– mice. PV–/– and CB–/– mice manifested ∼160-Hz oscillation that was sustained by Purkinje cells firing rhythmically and synchronously along the parallel fiber axis. This oscillation was dependent on GABAA, N-methyl-d-aspartate and gap junction transmission. PV–/–CB–/– mice exhibited a dual-frequency (110 and 240 Hz) oscillation. The instantaneous spectral densities of both components were inversely correlated. Simple and complex spikes of Purkinje cells were phase-locked to one of the two oscillation frequencies. Mono- and dual-frequency oscillations presented similar pharmacological properties. These results demonstrate that the absence of the Ca2+ buffers parvalbumin and calbindin disrupts the regulation of Purkinje cell firing rate and rhythmicity in vivo and suggest that precise Ca2+ transient control is required to maintain the normal spontaneous arrhythmic and asynchronous firing pattern of the Purkinje cells.
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  • 75
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: New neurons are produced continually in the dentate gyrus of the hippocampus. Numerous factors modulate the rate of neuron production. One of the most important is the adrenal-derived corticoids. Raised levels of corticoids suppress proliferation of progenitor cells, while removal of corticoids by adrenalectomy reverses this. The exact mechanisms by which corticoids mediate such regulation are unknown, but corticoids are believed to act through the receptors for mineralocorticoids (MR) and glucocorticoids (GR). Previous reports regarding the roles of these receptors in regulating cell proliferation came to contrasting conclusions. Here we use both agonists and antagonists to these receptors in adult male rats to investigate and clarify their roles. Blockade of MR with spironolactone in adrenalectomised male rats implanted with a corticosterone pellet to reproduce basal levels enhanced proliferation, whereas treatment with the GR antagonist mifepristone had no effect. However, mifepristone reversed the suppressive effect of additional corticosterone in intact rats. Both aldosterone and RU362, agonists of MR and GR, respectively, reduced proliferation in adrenalectomised rats, and combined treatment with both agonists had an additional suppressive action. These results clearly show that occupancies of both receptors act in the same direction on progenitor proliferation. The existence of two receptors with different affinities for corticoids may ensure that proliferation of progenitor cells in the adult dentate gyrus is regulated across the range of adrenal corticoid activity, including both basal and stressful contexts. Although a small proportion of newly formed cells may express GR and MR, corticosterone probably regulates proliferation indirectly through other local cells.
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  • 76
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Temporal organization of the molecular clockwork and behavioral output were investigated in nocturnal rats housed in constant darkness and synchronized to nonphotic cues (daily normocaloric or hypocaloric feeding and melatonin infusion) or light (light–dark cycle and daily 1-h light exposure). Clock gene (Per1, Per2 and Bmal1) and clock-controlled gene (Vasopressin) expression in the suprachiasmatic nuclei was assessed over 24 h. Light and exogenous melatonin synchronized the molecular clock, signaling, respectively, ‘daytime’ and ‘nighttime’, without affecting temporal organization of behavioral output (rest/activity rhythm). By contrast, synchronization to hypocaloric feeding led to a striking temporal change between gene expression in the suprachiasmatic clock and waveform of locomotor activity rhythm, rats then becoming active during the subjective day (diurnal-like temporal organization). When the time of feeding coincided with activity offset, normocaloric feeding also synchronized the locomotor activity rhythm with no apparent switch in temporal organization. Peak of Per2 expression in the piriform cortex occurred between the beginning and the middle of the activity/feeding period, depending on the synchronizer. These data demonstrate that even though the suprachiasmatic clockwork can be synchronized to nonphotic cues, hypocaloric feeding likely acts downstream from clock gene oscillations in the suprachiasmatic nuclei to yield a stable yet opposite organization of the rest/activity cycle.
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  • 77
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    Oxford, UK : Blackwell Science Ltd
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Both tetrodotoxin-sensitive (TTX-S) and TTX-resistant (TTX-R) voltage-dependent Na+ channels are expressed in the human neuroblastoma cell line NB-1, but a gene encoding the TTX-R Na+ channel has not been identified. In this study, we have cloned cDNA encoding the α subunit of the TTX-R Na+ channel in NB-1 cells and designated it hNbR1. The longest open reading frame of hNbR1 (accession no. 〈accessionId ref="info:ddbj-embl-genbank/AB158469"〉AB158469) encodes 2016 amino acid residues. Sequence analysis has indicated that hNbR1 is highly homologous with human cardiac Nav1.5/SCN5A with 〉 99% amino acid identity. The presence of a cysteine residue (Cys373) in the pore-loop region of domain I is consistent with the supposition that hNbR1 is resistant to TTX. Analysis of the genomic sequence of SCN5A revealed a new exon encoding S3 and S4 of domain I (exon 6A). In addition, an alternative splicing variant, lacking exon 18, that encodes 54 amino acids in the intracellular loop