bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stabilization of mutant Cu/Zn superoxide dismutase (SOD1) protein by coexpressed wild SOD1 protein accelerates the disease progression in familial amyotrophic lateral sclerosis mice
Authors: Fukada Kei , Nagano Seiichi , Satoh Masahiko , Tohyama Chiharu , Nakanishi Toyofumi , Shimizu Akira , Yanagihara Takehiko , Sakoda Saburo 
Published: March 2003

AbstractTransgenic mice carrying familial amyotrophic lateral sclerosis (FALS)‐linked mutant Cu/Zn superoxide dismutase (SOD1) genes such as G93A (G93A‐mice) and G85R (G85R‐mice) genes develop limb paresis. Introduction of human wild type SOD1 (hWT‐SOD1) gene, which does not cause motor impairment by itself, into different FALS mice resulted in different effects on their clinical courses, from no effect in G85R‐mice to acceleration of disease progression in G93A‐mice. However, the molecular mechanism which causes the observed difference, has not been clarified. We hypothesized that the difference might be caused by the stability of mutant SOD1 proteins. Using a combination of mass spectrometry and enzyme‐linked immunosorbent assay, we found that the concentration of G93A‐SOD1 protein was markedly elevated in tissues of transgenic mice carrying both G93A‐ and hWT‐SOD1 genes (G93A/hWT‐mice) compared to that in G93A‐mice, and also found that the concentration of G93A‐SOD1 protein had a close relation to the disease duration. The concentration of metallothionein‐I/II in the spinal cord, reflecting the degree of copper‐mediated oxidative stress, was highest in G93A/hWT‐mice, second in G93A‐mice, and normal in the mice carrying hWT‐SOD1 gene. These results indicated that the increase of G93A‐SOD1 protein was responsible for the increase of oxidative stress and disease acceleration in G93A/hWT‐mice. We speculate that coexpression of hWT‐SOD1 protein is deleterious to transgenic mice carrying a stable mutant such as G93A‐SOD1, because this mutant protein is stabilized by hWT‐SOD1 protein, but not to transgenic mice carrying an unstable mutant such as G85R‐SOD1, because this mutant protein is not stabilized by hWT‐SOD1.
Substance P in the descending cholinergic projection to REM sleep‐induction regions of the rat pontine reticular formation: anatomical and electrophysiological analyses
Authors: Kohlmeier Kristi A. , Burns Joan , Reiner Peter B. , Semba Kazue 
Published: March 2003

AbstractRelease of acetylcholine within the pontine reticular formation (PRF) from the axon terminals of mesopontine cholinergic neurons has long been hypothesized to play an important role in rapid eye movement (REM) sleep generation. As some of these cholinergic neurons are known to contain substance P (SP), we used anatomical, electrophysiological and pharmacological techniques to characterize this projection in the rat. Double immunofluorescence demonstrated that 16% of all cholinergic neurons within the mesopontine tegmentum contained SP; this percentage increased to 27% in its caudal regions. When double immunofluorescence was combined with retrograde tracing techniques, it was observed that up to 11% of all SP‐containing cholinergic neurons project to the PRF. Whole‐cell patch‐clamp recordings from in vitro brainstem slices revealed that SP administration depolarized or evoked an inward current in a dose‐dependent manner in all PRF neurons examined, and that these effects were antagonized by a SP antagonist. The amplitude of the SP‐induced inward current varied with changes in the Na+ concentration, did not reverse at the calculated K+ or Cl– equilibrium potentials, and was not attenuated in the presence of tetrodotoxin, low Ca2+ concentration or caesium ions. These data suggest that activation of a tetrodotoxin‐insensitive cation channel(s) permeable to Na+ is responsible for a SP‐induced inward current at resting membrane potentials. The depolarizing actions of SP appeared to be primarily due to activation of the adenylate cyclase pathway, and were additive with cholinergic receptor activation even at maximal concentrations. These data indicate that SP is colocalized in a subpopulation of mesopontine tegmental cholinergic neurons projecting to REM sleep‐induction regions of the PRF, and that actions of these two neuroactive substances on PRF neurons are additive. If SP is coreleased with acetylcholine, the additive actions of the two neurotransmitters might heighten the excitability of postsynaptic PRF neurons and ensure the initiation and maintenance of REM sleep.
The neural substrate of orientation short‐term memory and resistance to distractor items
Authors: Cornette L. , Dupont P. , Orban G. A. 
Published: March 2003

AbstractWe used Positron Emission Tomography to map the neural substrate of human short‐term memory for orientation, defined as retaining a single orientation in memory over a long delay, by comparing a successive discrimination task with a 6‐s delay to the same task with a brief 0.3 s delay and to an identification control task. Short‐term memory engaged the superior parietal lobe bilaterally, the middle occipital gyrus bilaterally and the left dorsolateral prefrontal cortex. In addition, we studied the resistance to a distractor item by comparing the successive discrimination task with long delay, with and without an intervening distractor stimulus. This manipulative process engaged left ventral premotor cortex and left dorsolateral prefrontal cortex. The activation of left dorsolateral prefrontal cortex is interpreted as reflecting co‐ordination between task components. These results, combined with those of two previous studies using an identical reduction strategy, underscore the functional heterogeneity in the prefrontal cortex during short‐term and working memory.
Clonidine injections into the lateral nucleus of the amygdala block acquisition and expression of fear‐potentiated startle
Authors: Schulz Brigitte , Fendt Markus , Schnitzler Hans‐Ulrich 
Published: March 2003

AbstractNumerous studies of aversive learning with different animal models have shown that the noradrenergic system has an important role in the acquisition, consolidation and expression of aversive learning. We used intracerebral clonidine injections to investigate the role of the noradrenergic amygdaloid system in the fear‐potentiated startle paradigm. Clonidine is a noradrenergic α2‐receptor agonist which can decrease noradrenergic transmission by stimulating presynaptic α2‐receptors. Rats received injections of 0, 2.5, 5 and 10 nmol clonidine into the lateral amygdala (i) before fear‐conditioning, (ii) immediately after fear‐conditioning, (iii) before testing and (iv) before both fear‐conditioning and the testing of conditioned fear. Clonidine injections blocked the acquisition and expression of conditioned fear. The effect on acquisition was not caused by state‐dependency or possible side‐effects of clonidine on consolidation. Given that clonidine decreases amygdaloid noradrenaline release, these results show a crucial role of noradrenergic transmission within the amygdala in classical fear‐conditioning. Surprisingly, both the acquisition and the expression of conditioned fear were blocked after amygdaloid injections of clonidine, suggesting that amygdaloid noradrenaline is necessary to induce both unconditioned and conditioned fear.
Hippocampal granule neuron production and population size are regulated by levels of bFGF
Authors: Cheng Yinghong , Black Ira B. , DiCicco‐Bloom Emanuel 
Published: March 2003

AbstractNumerous studies of the proliferative effects of basic fibroblast growth factor (bFGF) in culture, including neonatal and adult hippocampal precursors, suggest that the factor plays a ubiquitous and life‐long role in neurogenesis. In contrast, in vivo, bFGF is devoid of effects on neurons in mature hippocampus, raising the possibility that bFGF exhibits developmental stage‐specific activity in the complex animal environment. To define neurogenetic effects in the newborn, a single subcutaneous injection of bFGF (20 ng/gm) was administered to postnatal day 1 (P1) rats, and hippocampal DNA content was quantified: bFGF elicited an increase in total DNA throughout adulthood, by 48% at P4, 25% at P22, and 17% at P180, suggesting that bFGF increases hippocampal cell number. To define mechanisms, bromodeoxyuridine (BrdU) was injected at P1 and mitotically labelled cells were assessed at P22: there was a twofold increase in BrdU‐positive cells in the dentate granule cell layer (GCL), indicating that bFGF enhanced the generation of neurons, or neuronogenesis, from a cohort of precursors. Moreover, enhanced mitosis and survival led to a 33% increase in absolute GCL neuron number, suggesting that neuron production depends on environmental levels of bFGF. To evaluate this possibility, bFGF‐knockout mice were analyzed: hippocampal DNA content was decreased at all ages examined (P3, −42%; P21, −28%; P360, −18%), and total GCL neuron and glial fibrillary acidic protein (GFAP)‐positive cell number were decreased by 30%, indicating that bFGF is necessary for normal hippocampal neurogenesis. We conclude that environmental levels of bFGF regulate neonatal hippocampal neurogenesis. As adult hippocampal neuronogenesis was unresponsive to bFGF manipulation in our previous study [Wagner, J.P., Black, I.B. & DiCicco‐Bloom, E. (1999) J. Neurosci., 19, 6006], these observations suggest distinct, stage‐specific roles of bFGF in the dentate gyrus granule cell lineage.
Participation of the homing pigeon thalamofugal visual pathway in sun‐compass associative learning
Authors: Budzynski Cheri A. , Gagliardo Anna , Ioalé Paolo , Bingman Verner P. 
Published: March 2003

AbstractThe ascending thalamofugal visual pathway in pigeons (Columba livia) terminates in the telencephalic wulst. Characterizing the role of this pathway in visually guided behaviour has remained a challenge. To determine whether this pathway, and in particular the wulst, may participate in sun‐compass‐guided behaviour in homing pigeons, intact, ectostriatum‐lesioned or wulst‐lesioned pigeons were trained to use their sun compass to locate the direction of a food reward in an outdoor, octagonal arena. Control and ectostriatum‐lesioned pigeons learned the task well, and orientated appropriately during the first trial of the last three training sessions and after a phase‐shift manipulation. In contrast, the wulst‐lesioned pigeons learned the task but they took more sessions to learn, and their directional choices were more scattered during the first trial of the last three training sessions and after the phase‐shift manipulation. A subsequent regression analysis indicated that deeper layers of the wulst might have made more of a contribution to the observed behavioural impairments. The data indicate that the homing pigeon wulst participates in visually guided behaviour when the sun compass is used to learn the directional location of a goal.
Macrophage‐stimulating protein is a neurotrophic factor for embryonic chicken hypoglossal motoneurons
Authors: Schmidt Oliver , Doxakis Epaminondas , Davies Alun M. 
Published: March 2003

AbstractMacrophage‐stimulating protein (MSP) exerts a variety of biological actions on many cell types, but has no known functions in the brain. MSP is structurally related to hepatocyte growth factor (HGF), another pleiotropic factor whose many functions include promoting neuronal survival and growth. To investigate whether MSP is also capable of acting as a neurotrophic factor, we purified hypoglossal motoneurons from the embryonic chicken hindbrain because these neurons are known to express the MSP receptor tyrosine kinase RON. MSP promoted the in vitro survival of these neurons during the period of naturally occurring neuronal death and enhanced the growth of neurites from these neurons. MSP mRNA was detected in the developing tongue whose musculature is innervated by hypoglossal neurons. Our study demonstrates that MSP is a neurotrophic factor for a population of developing motoneurons.
Characterization of retinal guanylate cyclase‐activating protein 3 (GCAP3) from zebrafish to man
Authors: Imanishi Yoshikazu , Li Ning , Sokal Izabela , Sowa Mathew E. , Lichtarge Olivier , Wensel Theodore G. , Saperstein David A. , Baehr Wolfgang , Palczewski Krzysztof 
Published: March 2003

AbstractCalmodulin‐like neuronal Ca2+‐binding proteins (NCBPs) are expressed primarily in neurons and contain a combination of four functional and nonfunctional EF‐hand Ca2+‐binding motifs. The guanylate cyclase‐activating proteins 1–3 (GCAP1–3), the best characterized subgroup of NCBPs, function in the regulation of transmembrane guanylate cyclases 1–2 (GC1–2). The pairing of GCAPs and GCs in vivo depends on cell expression. Therefore, we investigated the expression of these genes in retina using in situ hybridization and immunocytochemistry. Our results demonstrate that GCAP1, GCAP2, GC1 and GC2 are expressed in human rod and cone photoreceptors, while GCAP3 is expressed exclusively in cones. As a consequence of extensive modification, the GCAP3 gene is not expressed in mouse retina. However, this lack of evolutionary conservation appears to be restricted to only some species as we cloned all three GCAPs from teleost (zebrafish) retina and localized them to rod cells, short single cones (GCAP1–2), and all subtypes of cones (GCAP3). Furthermore, sequence comparisons and evolutionary trace analysis coupled with functional testing of the different GCAPs allowed us to identify the key conserved residues that are critical for GCAP structure and function, and to define class‐specific residues for the NCBP subfamilies.
Characterizing CGI‐94 (comparative gene identification‐94) which is down‐regulated in the hippocampus of early stage Alzheimer's disease brain
Authors: Heese Klaus , Nakayama Takahiro , Hata Ryuji , Masumura Makoto , Akatsu Hiroyasu , Li Feng , Nagai Yasuo , Yamamoto Takayuki , Kosaka Kenji , Suemoto Takahiro , Sawada Tohru 
Published: March 2003

AbstractThe treatment of Alzheimer's disease (AD) remains a major challenge because of the incomplete understanding of the triggering events that lead to the selective neurodegeneration characteristic of AD brains. Here we describe a new protein, CGI‐94, that is down‐regulated at the mRNA level in the hippocampus of early stage AD brain. Transfection experiments with CGI‐94 as a green fluorescent protein (GFP)‐fusion‐protein show that this protein is translocated into the nucleus of the cell. The finding that this protein, which has a bipartite nuclear localization signal, is also observed in the cytoplasm and extracellular space points to a multifunctional protein. Immunohistochemical analyses reveal that CGI‐94 is mainly expressed in neurons of the hippocampal formation and the cortex but not in the cerebellar nucleus. In conclusion, the expression of the nucleolar phosphoprotein CGI‐94 appears to be disturbed in early processes of neuronal degeneration.
Transgenic mice expressing a pH and Cl– sensing yellow‐fluorescent protein under the control of a potassium channel promoter
Authors: Metzger Friedrich , Repunte‐Canonigo Vez , Matsushita Shinichi , Akemann Walther , Diez‐Garcia Javier , Ho Chi Shun , Iwasato Takuji , Grandes Pedro , Itohara Shigeyoshi , Joho Rolf H. , Knöpfel Thomas 
Published: March 2003

AbstractDuring the last few years a variety of genetically encodable optical probes that monitor physiological parameters such as local pH, Ca2+, Cl–, or transmembrane voltage have been developed. These sensors are based on variants of green‐fluorescent protein (GFP) and can be synthesized by mammalian cells after transfection with cDNA. To use these sensor proteins in intact brain tissue, specific promoters are needed that drive protein expression at a sufficiently high expression level in distinct neuronal subpopulations. Here we investigated whether the promoter sequence of a particular potassium channel may be useful for this purpose. We produced transgenic mouse lines carrying the gene for enhanced yellow‐fluorescent protein (EYFP), a yellow‐green pH‐ and Cl– sensitive variant of GFP, under control of the Kv3.1 K+ channel promoter (pKv3.1). Transgenic mouse lines displayed high levels of EYFP expression, identified by confocal microscopy, in adult cerebellar granule cells, interneurons of the cerebral cortex, and in neurons of hippocampus and thalamus. Furthermore, using living cerebellar slices we demonstrate that expression levels of EYFP are sufficient to report intracellular pH and Cl– concentration using imaging techniques and conditions analogous to those used with conventional ion‐sensitive dyes. We conclude that transgenic mice expressing GFP‐derived sensors under the control of cell‐type specific promoters, provide a unique opportunity for functional characterization of defined subsets of neurons.
Gelatinase B and TIMP‐1 are regulated in a cell‐ and time‐dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia
Authors: Rivera Santiago , Ogier Crystel , Jourquin Jérôme , Timsit Serge , Szklarczyk Arkadius W. , Miller Karen , Gearing Andrew J. H. , Kaczmarek Leszek , Khrestchatisky Michel 
Published: March 2003

AbstractMatrix metalloproteinases (MMPs) belong to a large family of endopeptidases that regulate the pericellular environment through the cleavage of protein components of the extracellular matrix, membrane receptors and cytokines. MMP activity is controlled by the multifunctional tissue inhibitors of metalloproteinases (TIMPs). Proteases and their inhibitors are critically involved in developmental and pathological processes in numerous organs, including the brain. Global transient cerebral ischemia induces selective delayed neuronal death and neuroinflammation. We compared, in discrete vulnerable and resistant areas of the ischemic rat hippocampus, the kinetics and cellular distribution of gelatinase B and its principal inhibitor TIMP‐1 and we assessed byin situzymography, the net gelatinolytic activity at the cellular level. We show that gelatinases are expressed and active in neurons, suggesting that MMPs play a role in maintaining neural homeostasis. In the ischemic rat brain, expression and activity of gelatinase B, and expression of TIMP‐1 are altered in a time‐, region‐ and cell‐dependent manner. Gelatinase B is induced first in reactive microglia and subsequently in reactive astrocytes.In situ, increases in gelatinase activity accompanied the progression of neuronal death and glial reactivity. Our results suggest that MMPs and TIMPs are involved in cell viability and tissue remodelling in the ischemic brain, and reinforces the idea that the MMP/TIMP system contributes both to neuronal demise and tissue repair in the context of glial reactivity.
Neurotransmitter release from tottering mice nerve terminals with reduced expression of mutated P‐ and Q‐type Ca2+‐channels
Authors: Leenders A. G. Miriam , Van Den Maagdenberg Arn M. J. M. , Da Silva Fernando H. Lopes , Sheng Zu‐Hang , Molenaar Peter C. , Ghijsen Wim E. J. M. 
Published: March 2003

AbstractNeurotransmitter release is triggered by Ca2+‐influx through multiple sub‐types of high voltage‐activated Ca2+‐channels. Tottering mice have a mutation in the α1A pore‐forming subunit of P‐ and Q‐type Ca2+‐channels, two prominent sub‐types that regulate transmitter release from central nerve terminals. Immunoblotting analysis of purified forebrain terminals from tottering mice revealed an 85% reduction in the protein expression level of the mutated α1A subunit compared to expression of the α1A subunit in wild‐type terminals. In contrast, the expression of the α1B subunit of the N‐type Ca2+‐channels was unchanged. Release of the amino acids glutamate and GABA and of the neuropeptide cholecystokinin (CCK) induced by a short (100 ms) depolarization pulse was unchanged in the terminals of tottering mice. Studies using specific blockers of Ca2+‐channels however, revealed a reduced contribution of P‐ and Q‐type Ca2+‐channels to glutamate and cholecystokinin release, whereas a greater reliance on N‐type Ca2+‐channels for release of these transmitters was observed. In contrast, the contribution of the P‐, Q‐ and N‐type Ca2+‐channels to the release of GABA was not altered in tottering mice. These results indicate that the expression of the α1A subunit was decreased in terminals from tottering mice, and that a decreased contribution of P‐ and Q‐type Ca2+‐channels to the release of glutamate and cholecystokinin was functionally compensated by an increased contribution of N‐type Ca2+‐channels.
Dopamine D1/5 receptor stimulation induces c‐fos expression in the subthalamic nucleus: possible involvement of local D5 receptors
Authors: Svenningsson Per , Le Moine Catherine 
Published: March 2003

AbstractThe activity of neurons in the subthalamic nucleus controls various aspects of movement. The present study examined the action of dopamine receptor agonists on c‐fos gene expression in the subthalamic nucleus in normal rats. We found that systemic administration of the dopamine D1/5 receptor agonist, SKF 82958 (1 mg/kg), induces c‐fos expression in the subthalamic nucleus. In contrast, systemic administration of the dopamine D2/3 receptor agonist, quinelorane (2 mg/kg) had no effect. When combined, SKF 82958 and quinelorane induced c‐fos expression in subthalamic neurons that was similar to that found following administration of SKF 82958 alone. We also examined c‐fos expression in the substantia nigra pars reticulata, the major projection area for subthalamic neurons, and found that SKF 82958, but not quinelorane, caused an induction of c‐fos expression in this area. In order to clarify the mechanisms underlying the SKF 82958‐mediated induction of c‐fos expression in the subthalamic nucleus and substantia nigra pars reticulata, in situ hybridization for the dopamine D1, D2, D3 and D5 receptor mRNAs was performed. The only significant observation was that D5 receptor mRNA is expressed in subthalamic neurons.The present data show that dopamine, via D1/D5 receptors, upregulates c‐fos expression in subthalamic neurons, and that the high expression of D5 receptors in this area might be involved. Taken together, these data suggest that dopamine D1/5 receptors are more important for the action of dopamine in the so‐called indirect pathway of the basal ganglia circuitry than what is recognized in current models of basal ganglia organization.
Control of kinetic properties of GluR2 flop AMPA‐type channels: impact of R/G nuclear editing
Authors: Krampfl Klaus , Schlesinger Friedrich , Zörner Antje , Kappler Martin , Dengler Reinhard , Bufler Johannes 
Published: March 2003

AbstractThe GluR2 flop subunit of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA)‐type glutamate receptors greatly determines calcium permeability and kinetic properties of heteromeric AMPA subunit assemblies. Post‐transcriptional editing of this subunit at the Q/R/N site controls calcium permeability whereas editing at the R/G site is involved in the regulation of biophysical properties. We used patch‐clamp techniques with ultrafast solution exchange to examine the kinetics of recombinant human homomeric GluR2 flop channels transiently expressed in HEK293 cells [edited at the R/G site and Q/R/N site (GR), and unedited (RN) and edited (GN) at the R/G site both with asparagine (N) at the Q/R/N site]. The time constant of desensitization after application of 10 mm glutamate was 1.38 ± 0.05 ms (n = 10), 5.53 ± 0.57 ms (n = 7) and 1.33 ± 0.06 ms (n = 12) for the GluR2 flop GR, RN and GN channels, respectively. The time constant of resensitization was 75 ms for the GluR2 flop RN and 30 ms for the GN channels. The dose‐dependence of the peak current amplitude, kinetics of activation and deactivation, and peak open probability did not differ between RN and GN channels. The study shows that desensitization and resensitization kinetics of homomeric GluR2 flop channels are controlled by a single amino acid exchange (glycine by arginine) at the R/G site. Quantitative analysis by computer simulation using a circular kinetic scheme allows the prediction of the main experimental results.