bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterning the forebrain: FoxA4a/Pintallavis and Xvent2 determine the posterior limit ofXanf1expression in the neural plate
Authors: Martynova Natalia , Eroshkin Fedor , Ermakova Galina , Bayramov Andrey , Gray Jessica , Grainger Robert , Zaraisky Andrey
Published: May 2004

During early development of the nervous system in vertebrates, expression of the homeobox gene Anf/Hesx1/Rpx is restricted to the anterior neural plate subdomain corresponding to the presumptive forebrain. This expression is essential for normal forebrain development and ectopic expression of Xenopus Anf, Xanf1 (also known as Xanf-1),results in severe forebrain abnormalities. By use of transgenic embryos and a novel bi-colour reporter technique, we have identified a cis-regulatory element responsible for transcriptional repression of Xanf1 that defines its posterior expression limit within the neural plate. Using this element as the target in a yeast one-hybrid system, we identified two transcription factors, FoxA4a/Pintallavis and Xvent2 (also known as Xvent-2),which are normally expressed posterior to Xanf1. Overexpression of normal and dominant-negative versions of these factors, as well as inhibition of their mRNA translation by antisense morpholinos, show that they actually function as transcriptional repressors of Xanf1 just behind its posterior expression limit. The extremely high similarity of the identified Anf cis-regulatory sequences in Xenopus, chick and human,indicates that the mechanism restricting posterior expression of Anfin Xenopus is shared among vertebrates. Our findings support Nieuwkoop's activation-transformation model for neural patterning, according to which the entire neurectoderm is initially specified towards an anterior fate, which is later suppressed posteriorly as part of the trunk formation process.
mozregulates Hox expression and pharyngeal segmental identity in zebrafish
Authors: Miller Craig T. , Maves Lisa , Kimmel Charles B.
Published: May 2004

In vertebrate embryos, streams of cranial neural crest (CNC) cells migrate to form segmental pharyngeal arches and differentiate into segment-specific parts of the facial skeleton. To identify genes involved in specifying segmental identity in the vertebrate head, we screened for mutations affecting cartilage patterning in the zebrafish larval pharynx. We present the positional cloning and initial phenotypic characterization of a homeotic locus discovered in this screen. We show that a zebrafish ortholog of the human oncogenic histone acetyltransferase MOZ (monocytic leukemia zinc finger) is required for specifying segmental identity in the second through fourth pharyngeal arches. In moz mutant zebrafish, the second pharyngeal arch is dramatically transformed into a mirror-image duplicated jaw. This phenotype resembles a similar but stronger transformation than that seen in hox2 morpholino oligo (hox2-MO) injected animals. In addition, mild anterior homeotic transformations are seen in the third and fourth pharyngeal arches of moz mutants. moz is required for maintenance of most hox1-4 expression domains and this requirement probably at least partially accounts for the moz mutant homeotic phenotypes. Homeosis and defective Hox gene expression in moz mutants is rescued by inhibiting histone deacetylase activity with Trichostatin A.

Although we find early patterning of the moz mutant hindbrain to be normal, we find a late defect in facial motoneuron migration in moz mutants. Pharyngeal musculature is transformed late, but not early, in moz mutants. We detect relatively minor defects in arch epithelia of moz mutants. Vital labeling of arch development reveals no detectable changes in CNC generation in moz mutants, but later prechondrogenic condensations are mispositioned and misshapen.

Mirror-image hox2-dependent gene expression changes in postmigratory CNC prefigure the homeotic phenotype in moz mutants. Early second arch ventral expression of goosecoid (gsc) in moz mutants and in animals injected with hox2-MOs shifts from lateral to medial, mirroring the first arch pattern. bapx1, which is normally expressed in first arch postmigratory CNC prefiguring the jaw joint, is ectopically expressed in second arch CNC of moz mutants and hox2-MO injected animals. Reduction of bapx1 function in wild types causes loss of the jaw joint. Reduction of bapx1 function in mozmutants causes loss of both first and second arch joints, providing functional genetic evidence that bapx1 contributes to the moz-deficient homeotic pattern. Together, our results reveal an essential embryonic role and a crucial histone acetyltransferase activity for Moz in regulating Hox expression and segmental identity, and provide two early targets, bapx1 and gsc, of moz and hox2 signaling in the second pharyngeal arch.
Deletion ofVhlhin chondrocytes reduces cell proliferation and increases matrix deposition during growth plate development
Authors: Pfander David , Kobayashi Tatsuya , Knight Melissa C. , Zelzer Elazar , Chan Denise A. , Olsen Bjorn R. , Giaccia Amato J. , Johnson Randall S. , Haase Volker H. , Schipani Ernestina
Published: May 2004

The von Hippel Lindau tumor suppressor protein (pVHL) is a component of a ubiquitin ligase that promotes proteolysis of the transcription factor hypoxia-inducible-factor 1α (HIF1α), the key molecule in the hypoxic response. We have used conditional inactivation of murine VHL(Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development. Mice lacking Vhlh in cartilage are viable, but grow slower than control littermates and develop a severe dwarfism. Morphologically, Vhlh null growth plates display a significantly reduced chondrocyte proliferation rate, increased extracellular matrix, and presence of atypical large cells within the resting zone. Furthermore, stabilization of the transcription factor HIF1α leads to increased expression levels of HIF1α target genes in Vhlh null growth plates. Lastly, newborns lacking both Vhlh and Hif1agenes in growth plate chondrocytes display essentially the same phenotype as Hif1a null single mutant mice suggesting that the Vhlh null phenotype could result, at least in part, from increased activity of accumulated HIF1α. This is the first study reporting the novel and intriguing findings that pVHL has a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation in vivo.
The RhoGEF Pebble is required for cell shape changes during cell migration triggered by theDrosophilaFGF receptor Heartless
Authors: Schumacher Sabine , Gryzik Tanja , Tannebaum Sylvia , Müller H.-Arno J.
Published: May 2004

The FGF receptor Heartless (HTL) is required for mesodermal cell migration in the Drosophila gastrula. We show that mesoderm cells undergo different phases of specific cell shape changes during mesoderm migration. During the migratory phase, the cells adhere to the basal surface of the ectoderm and exhibit extensive protrusive activity. HTL is required for the protrusive activity of the mesoderm cells. Moreover, the early phenotype of htl mutants suggests that HTL is required for the adhesion of mesoderm cells to the ectoderm.

In a genetic screen we identified pebble (pbl) as a novel gene required for mesoderm migration. pbl encodes a guanyl nucleotide exchange factor (GEF) for RHO1 and is known as an essential regulator of cytokinesis. We show that the function of PBL in cell migration is independent of the function of PBL in cytokinesis. Although RHO1 acts as a substrate for PBL in cytokinesis, compromising RHO1 function in the mesoderm does not block cell migration. These data suggest that the function of PBL in cell migration might be mediated through a pathway distinct from RHO1. This idea is supported by allele-specific differences in the expressivity of the cytokinesis and cell migration phenotypes of different pbl mutants. We show that PBL is autonomously required in the mesoderm for cell migration. Like HTL, PBL is required for early cell shape changes during mesoderm migration. Expression of a constitutively active form of HTL is unable to rescue the early cellular defects in pbl mutants, suggesting that PBL is required for the ability of HTL to trigger these cell shape changes. These results provide evidence for a novel function of the Rho-GEF PBL in HTL-dependent mesodermal cell migration.
Tissue-specific G1-phase cell-cycle arrest prior to terminal differentiation inDictyostelium
Authors: Chen Guokai , Shaulsky Gad , Kuspa Adam
Published: May 2004

The cell cycle status of developing Dictyostelium cells remains unresolved because previous studies have led to conflicting interpretations. We propose a new model of cell cycle events during development. We observe mitosis of about 50% of the cells between 12 and 18 hours of development. Cellular DNA content profiles obtained by flow cytometry and quantification of extra-chromosomal and chromosomal DNA suggest that the daughter cells have half the chromosomal DNA of vegetative cells. Furthermore, little chromosomal DNA synthesis occurs during development, indicating that no S phase occurs. The DNA content in cells sorted by fluorescent tissue-specific reporters indicates that prespore cells divide before prestalk cells and later encapsulate as G1-arrested spores. Consistent with this, germinating spores have one copy of their chromosomes, as judged by fluorescence in situ hybridization and they replicate their chromosomes before mitosis of the emergent amoebae. The DNA content of mature stalk cells suggests that they also attain a G1 state prior to terminal differentiation. As prestalk cells appear to be in G2 up to 22 hours of development, our data suggest that they divide just prior to stalk formation. Our results suggest tissue-specific regulation of G1 phase cell cycle arrest prior to terminal differentiation in Dictyostelium.
Cell cycling through development
Authors: Levine Edward M.
Published: May 2004

Regardless of the species, the development of a multicellular organism requires the precise execution of essential developmental processes including patterning, growth, proliferation and differentiation. The cell cycle, in addition to its role as coordinator of DNA replication and mitosis, is also a coordinator of developmental processes, and is a target of developmental signaling pathways. Perhaps because of its central role during development,the cell cycle mechanism, its regulation and its effects on developing tissues is remarkably complex. It was in this light that the Keystone meeting on the cell cycle and development at Snowbird, Utah in January 2004 was held.
Interaction of arbitrary multiple cracks in an infinite plate
Authors: Yan X
Published: May 2004

In this article, the interaction of arbitrary multiple cracks in an infinite plate is examined by means of a boundary element method consisting of the non-singular displacement discontinuity element presented by Crouch and Starfied and the crack tip displacement discontinuity elements proposed by the present author. In the boundary element implementation, the left or the right crack tip element is placed locally at the corresponding left or right crack tip on top of the constant displacement discontinuity elements that cover the entire crack surface and the other boundaries. The present numerical results of stress intensity factors (SIFs) for some typical multiple crack problems show that the numerical approach is simple yet very accurate for analysing the interaction of arbitrary multiple cracks in an infinite plate.
Applicability of reference stress-based J estimates to semi-elliptical surface crack problems
Authors: Kim Y-J , Kim J-S , Shim D-J , Kim Y-J
Published: May 2004

This paper discusses the applicability of the reference stress method to estimate J along the semi-elliptical surface crack front. For a systematic investigation, two steps are taken in the present work. The first step involves investigation of the dependence of angular variations in normalized J (with respect to its elastic value) along the semi-elliptical surface crack front on the geometry, loading mode and loading magnitude. In the second step, the error associated with the reference stress-based J estimates is investigated. It is found that angular variations in normalized J are strongly dependent on the geometry, loading mode and loading magnitude. As the application of the reference stress approach to semi-elliptical surface cracks implies proportional increases in the normalized J, the present results pose a question on the applicability of the reference stress approach to estimate J for surface cracks. However, it is also found that the reference stress approach can still provide reasonably accurate J results from an engineering point of view, provided that the maximum J along the crack front is accurately estimated. In this respect, investigation of the error in the estimated J in the present work suggests that the reference stress approach is an effective engineering tool for estimating crack driving force along the semi-elliptical surface crack front, provided that the reference stress is properly defined.
Re-examination on thermal stresses of bonded structures
Authors: Wang W-C , Hsu J-S
Published: May 2004

To the authors' best knowledge this is the first time that the photoelastic method has been used to determine experimentally the whole-field state of thermal stresses of bonded structures. Except for the immediate vicinity of the interfacial edges, the photoelastic results were confirmed through the finite element method (FEM). Theoretical solutions provided by both Timoshenko and Suhir were then re-examined and compared with the photoelastic and FEM results. A comparison of those results indicated that the current theoretical solutions are oversimplified and need to be improved.
Effect of local induction heat treatment on the induced residual stresses in the web region of a welded rail
Authors: Mansouri H , Monshi A , Hadavinia H
Published: May 2004

Rails are often joined by welding and about 80–90 per cent of tracks are welded using the flash-butt welding method. As the result of the welding process, high tensile residual stresses are induced in the web region of the rail, at and near the welded zone. Since the main part of the welded zone is coarse grained and has porosities and inclusions, the web part of the rail is susceptible to failure. The magnitude of the induced stresses may be reduced by stress-relieving heat treatment, but in practice the heat treatment process is not used as it is very time consuming and adds to overall project costs. In this paper, microscopic studies were performed on the welded zone in the head, the web and the base parts of the rail. The effects of local induction heat treatments on the microstructure and on the resultant tensile residual stresses in the web region were studied. To do this, firstly, dilatometery specimens were prepared from the base metal of the rail. These were heat-treated under different induction heat treatment cycles and the resulting phase transformation and the changes in the length of the specimens were obtained. Secondly, the effects of local induction heat treatments on the residual stress field in the welded zone of the rail were investigated using finite element analysis. Finally, a local induction hardening and tempering heat treatment is proposed to reduce the residual stresses in the web region of a welded rail.
Relaxation of residual stresses induced by turning and shot peening on steels
Authors: Capello E , Davoli P , Filippini M , Foletti S
Published: May 2004

Experiments on the relaxation of residual stresses in steels by fatigue loading are described. This question is of interest because it is well known that compressive residual stresses are often induced by special surface treatments (such as shot peening) to improve the fatigue life of metal parts; however, if cyclic relaxation occurs, the beneficial effects can, in part, vanish during service. Two hardened and tempered steels of grade C45 and 39NiCrMo3 were used in the tests. For both materials, different specimens were given two surface treatments: simple turning without successive surface treatment, inducing on the surface a moderate tensile residual stress state, and shot peening, inducing high residual compressive stresses. The specimens were submitted to constant-amplitude tension-compression fatigue loading, and the surface residual stresses were measured after 0, 1, 10 cycles and more. Results show that relaxation occurs from the very first cycle; the amount of residual stress relaxation depends on many parameters and on the type of steel. The results are in agreement with data obtained by other researchers.
Mandibular strains induced by conventional and novel dental implants
Authors: Carvalho L , Vaz M. A , Simões J. A
Published: May 2004

This paper describes an experimental study that aimed at determining the mandibular strains provoked by impact loads on conventional and non-conventional dental implant systems. The novel implant differs from typical commercial designs because it comprises an elastomeric material barrier (stress shock absorber) interposed between the implant and an artificial crown. A dried implanted cadaveric mandible with strain gauges placed at the inner and outer surfaces in the direction of the implant axis was used. The implants were loaded dynamically and uniaxial strains recorded. Overall, the results showed that an interposing flexible material between the crown and the top surface of the implant attenuates the load, avoiding high peak loads, which can occasionally occur from non-physiological occlusion loads that can be transferred to the surrounding bone tissue.
Annular sector plates under in-plane loading: General symbolic solution and its application to the collinear compression case
Authors: Tahan N , Pavlovic M. N , Kotsovos M. D
Published: May 2004

The single Fourier series technique—made both simpler and more powerful through symbolic computation (so as to bypass the need for repetitive equation solving, thus resulting in a truly closed-form analytical solution)—and Fejér's summability are applied to the plane-stress problem of an annular circular sector plate under completely arbitrary normal and/or shear loading along the two curved edges. The approach is then used for a systematic parametric study of annular sector plates of arbitrary geometry under collinear radial compression (encompassing both point and patch loadings). This leads to the identification of key tensile and compressive stresses (in non-dimensionalized form) within the plate and enables the definition of what constitutes a ‘long’ plate to be made. Such characteristics are compared with their counterparts for rectangular plates.
Experimental investigation on contact between cylindrical conformal surfaces
Authors: Pau M , Baldi A , Orrù P F , Ginesu F
Published: May 2004

The application of an experimental technique based on ultrasonic waves to investigate contact parameters for a cylinder versus cylinder system in conformal configuration is proposed. The method analyses the ultrasonic reflection from the contact interface (or the transmission through it) and yields direct information about the size and shape of the nominal contact area; it also gives a qualitative indication of the contact pressure value, which is a parameter not explicitly related to the characteristics of the reflected wave.

In order to assess the reliability of the technique as regards its ability to give a good reproduction of contact areas, the processed ultrasonic data, which can be easily represented as ‘contact maps’, were compared with the results of the application of a commercial pressure-sensitive film (Fuji Prescale HS). At the same time, a finite element model of the tested contact configuration supplied a further comparison term useful in assessing the effectiveness of the ultrasonic technique as a tool in estimating contact pressure distribution.
A review of object individuation in infancy
Authors: Krøjgaard Peter
Published: May 2004

The present review of object individuation in infancy is divided into five sections. The first section is a brief history of the field and an outline of the development of efficient methods for studying object individuation among infants. Sections 2 and 3 are structured around the empirical evidence obtained by using two different kinds of basic and widely used experiments: infants' responses to (apparently) disappearing objects (Section 2), and infants' responses to objects that (apparently) change into other objects (Section 3). In the fourth section, theories of object individuation are presented and discussed. The final section takes a look ahead to the future and proposes a few experiments that may help in resolving some of the most important disputes regarding object individuation in infancy.
The role of the counterfactually satisfied desire in the lag between false‐belief and false‐emotion attributions in children aged 4–7
Authors: Bradmetz Joël , Schneider Roland
Published: May 2004

A robust lag was evidenced between the attribution to an individual of a false belief about the world and the attribution of the false emotion associated with this false belief (Bradmetz & Schneider, 1999). This lag was unexpected in the frame of current theories of mind which consider that emotion has a rational cognitive basis. The present paper refers to the theory of appraisal which links emotion to the belief about desire satisfaction rather than the belief concerning the state of the world. The authors claim that, even if counterfactual belief is understood, the associated emotion and belief about counterfactual satisfaction of desire are not automatically understood because they depend on the success of an action. Two experiments conducted on happiness, fear, and anger confirmed this view: Attributing false belief about counterfactual desire satisfaction is much more difficult than attributing false belief about a current state of affairs, and the emotion attributed to the individual is more closely linked to a belief about desire than to a belief about the world. A four‐step developmental sequence is proposed, and the link between action and realist bias is discussed.
A lag between understanding false belief and emotion attribution in young children: Relationships with linguistic ability and mothers' mental‐state language
Authors: de Rosnay Marc , Pons Francisco , Harris Paul L. , Morrell Julian M. B.
Published: May 2004

This study examines the contribution of children's linguistic ability and mothers' use of mental‐state language to young children's understanding of false belief and their subsequent ability to make belief‐based emotion attributions. In Experiment 1, children (N = 51) were given three belief‐based emotion‐attribution tasks. A standard task in which the protagonist was a story character and the emotional outcomes were imagined, and two videos in which the story protagonist was a real infant and the emotional outcomes were observable (high and low expressed emotion conditions). Children's verbal ability (semantic competence) was also measured. In Experiment 2, children (N = 75) were given two belief‐based emotion tasks: the standard story task and the high expressed emotion video. In addition, children's verbal ability (syntactic competence) and mothers' use of mental‐state attributes when describing their children were also measured. The results showed that: (1) the lag between understanding false belief and emotion attribution was a stable feature of children's reasoning across the three tests; and (2) children who were more linguistically advanced and whose mothers' described them in more mentalistic terms were more likely to understand the association between false belief and emotion. The findings underline the continuing importance of verbal ability and linguistic input for children's developing theory‐of‐mind understanding, even after they display an understanding of false belief.
Social interaction and cognitive growth: An examination through the role‐taking skills of deaf and hearing children
Authors: Howley Mary , Howe Christine
Published: May 2004

Recent research using theory‐of‐mind tasks has rekindled interest in the possibility that social interaction makes a significant contribution to cognitive development. It is proposed here that this contribution may be most pronounced with phenomena that, like belief or affective states, are internal and abstract. A more modest contribution is envisaged with phenomena that are overt and perceptible. The proposal is explored via comparison of deaf and hearing children's ability to engage in affective and perceptual role‐taking, since the aspects of social interaction that have been implicated in cognitive development are known to be problematic for deaf children. Therefore, the proposal of more marked consequences for internal and abstract phenomena leads to the hypothesis that deaf children should lag behind hearing children on affective role‐taking, while showing little or no difference on perceptual role‐taking. The hypothesis was tested in two studies, one involving 10 deaf children and 10 hearing children aged 6.94– 8.93 years and the other involving 25 deaf children and 20 hearing children aged 5.08– 11.58 years. In both studies, affective role‐taking was examined using a task developed from Chandler (1973), while perceptual role‐taking was examined via an extension of Hughes and Donaldson's (1979) hiding task. The results provide consistent support for the hypothesis, and patterns of correlation between age, affective performance and perceptual performance give clues to the relevant developmental mechanisms.
Is early attachment security carried forward into relationships with preschool peers?
Authors: Wood Jeffrey J. , Emmerson Natasha A. , Cowan Philip A.
Published: May 2004

The association between early parent‐child attachment security and peer rejection among preschool children was examined. Children in three preschool classrooms (N = 37) participated. Mothers rated their children's attachment security at age 3 years on the Attachment Q‐Set (Waters, 1987). Sociometric ratings were collected from classmates at age 4 years through individual picture interviews. Teachers rated externalizing and internalizing behaviour exhibited at preschool. Lower attachment security was associated with greater subsequent peer rejection and higher externalizing and internalizing behaviour scores. An exploratory path model suggested that the linkage between early insecure attachment and later peer rejection may be mediated by externalizing behaviour.
Evidence of more immanent justice responding in adults than children: A challenge to traditional developmental theories
Authors: Raman Lakshmi , Winer Gerald A.
Published: May 2004

Three studies investigated developmental changes in immanent justice responding by asking participants to respond to vignettes in which a person's bad behaviour was followed by a negative consequence. Study 1 consisted of 152 sixth graders and 128 college students and presented participants with a vignette that examined the notion of bad people deserving to get ill. Study 2 consisted of 185 sixth graders and 154 college students and examined whether children and adults reasoned that that bad behaviour would actually cause the illness. Study 3 consisted of 96 third graders, 115 fifth graders, and 114 college students, and presented participants with vignettes that examined negative behaviours and consequences. Contrary to expectations based on traditional and contemporary developmental theories, all three studies demonstrated more evidence of immanent justice responding among adults than among elementary school children. These results call into question the comprehensiveness of traditional and contemporary developmental theories, and suggest the need to examine cognitive reasoning in adulthood when constructing developmental theories.
Implicit and explicit memory performance in children with attention deficit/hyperactivity disorder
Authors: Aloisi Bruno A. , McKone Elinor , Heubeck Bernd G.
Published: May 2004

The present investigation examined implicit and explicit memory in 20 children diagnosed with attention deficit/hyperactivity disorder (AD/HD) and 20 matched controls. Consistent with previous research, children with AD/HD performed more poorly than controls on an explicit test of long‐term memory for pictures. New results were that (a) there was no deficit on an implicit memory test for equivalent material and that (b) the observed deficit in explicit memory operated over and above any effects of depression/anxiety. Another finding to emerge was that AD/HD children had greater difficulty than controls in identifying pictures of objects that were presented in an unusual form, either rotated or degraded. Overall, the pattern of results is interpreted in terms of deficient effortful/resource‐intensive processes in AD/HD but intact automatic processes.
Do monsters dream? Young children's understanding of the fantasy/reality distinction
Authors: Sharon Tanya , Woolley Jacqueline D.
Published: May 2004

Young children are often thought to confuse fantasy and reality. This study took a second look at preschoolers' fantasy/reality differentiation. We employed a new measure of fantasy/reality differentiation—a property attribution task—in which children were questioned regarding the properties of both real and fantastical entities. We also modified the standard forced‐choice categorization task (into real/fantastical) to include a ‘not sure’ option, thus allowing children to express uncertainty. Finally, we assessed the relation between individual levels of fantasy orientation and fantasy/reality differentiation. Results suggest that children have a more developed appreciation of the boundary between fantasy and reality than is often supposed.
Behavioral Context and Coherent Oscillations in the Supplementary Motor Area
Authors: Lee Daeyeol
Published: May 2004

Movements with similar physical characteristics can occur in various behavioral contexts, as when they are embedded in different sequences or when the expected outcomes of movements vary. Similarly, neurons in various sensory and motor structures in the brain commonly display modulations in their activity according to contextual factors, such as expected reward. Although these contextual signals must be combined with incoming sensory inputs to generate appropriate behaviors according to the animal's motivational state, the mechanisms by which these two signals are integrated remain poorly understood. The present study examined the effects of contextual factors on the magnitude of coherent oscillations in the activity of individual neurons recorded in the supplementary motor area (SMA) of monkeys during a serial reaction time task. In this task, the animal produced a predictable sequence of hand movements repeatedly according to visual instructions. The performance of the animal was influenced by the location of the rewarded target as well as the ordinal position of the movement. In contrast, the level of coherent oscillations in the activity of SMA neurons was affected only by the rewarded target location but not by the ordinal position of the movement sequence. In addition, changes in coherent oscillations were not accounted for by systematic changes in the mean firing rates. These results are consistent with the proposal that synchronous spikes might be used to control the flow of information and suggest that coherent oscillations in the SMA might encode contextual variables, such as expected reward.
Brain-Derived Neurotrophic Factor and trkB Signaling in Parasympathetic Neurons: Relevance to Regulating α7-Containing Nicotinic Receptors and Synaptic Function
Authors: Zhou Xiangdong , Nai Qiang , Chen Min , Dittus Jason D. , Howard Marthe J. , Margiotta Joseph F.
Published: May 2004

Parasympathetic neurons do not require neurotrophins for survival and are thought to lack high-affinity neurotrophin receptors (i.e., trks). We report here, however, that mRNAs encoding both brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (trkB) are expressed in the parasympathetic chick ciliary ganglion (CG) and that BDNF-like protein is present in the ganglion and in the iris, an important peripheral target of ciliary neurons. Moreover, CG neurons express surface trkB and exogenous BDNF not only initiates trk-dependent signaling, but also alters nicotinic acetylcholine receptor (nAChR) expression and synaptic transmission. In particular, BDNF applied to CG neurons rapidly activates cAMP-dependent response element-binding protein (CREB), and over the long-term selectively upregulates expression of α7-subunit-containing, homomeric nAChRs (α7-nAChRs), increasing α7-subunit mRNA levels, α7-nAChR surface sites, and α7-nAChR-mediated whole-cell currents. At nicotinic synapses formed on CG neurons in culture, brief and long-term BDNF treatments also increase the frequency of spontaneous EPSCs, most of which are mediated by heteromeric nAChRs containing α3, α5, β4, and β2 subunits (α3*-nAChRs) with a minor contribution from α7-nAChRs. Our findings demonstrate unexpected roles for BDNF-induced, trk-dependent signaling in CG neurons, both in regulating expression of α7-nAChRs and in enhancing transmission at α3*-nAChR-mediated synapses. The presence of BDNF-like protein in CG and iris target coupled with that of functional trkB on CG neurons raise the possibility that signals generated by endogenous BDNF similarly influence α7-nAChRs and nicotinic synapsesin vivo.
Transient Receptor Potential Vanilloid 4 Is Essential in Chemotherapy-Induced Neuropathic Pain in the Rat
Authors: Alessandri-Haber Nicole , Dina Olayinka A. , Yeh Jenny J. , Parada Carlos A. , Reichling David B. , Levine Jon D.
Published: May 2004

The development of treatments for neuropathic pain has been hindered by our limited understanding of the basic mechanisms underlying abnormalities in nociceptor hyperexcitability. We recently showed that the polymodal receptor transient receptor potential vanilloid 4 (TRPV4), a member of the transient receptor potential (TRP) family of ion channels, may play a role in inflammatory pain (Alessandri-Haber et al., 2003). The present study tested whether TRVP4 also contributes to neuropathic pain, using a rat model of Taxol-induced painful peripheral neuropathy. Taxol is the most widely used drug for the treatment of a variety of tumor types, but the dose of Taxol that can be tolerated is limited by the development of a small-fiber painful peripheral neuropathy.

We found that Taxol treatment enhanced the nociceptive behavioral responses to both mechanical and hypotonic stimulation of the hind paw. Spinal administration of antisense oligodeoxynucleotides to TRPV4, which reduced the expression of TRPV4 in sensory nerve, abolished Taxol-induced mechanical hyperalgesia and attenuated hypotonic hyperalgesia by 42%. The enhancement of osmotic nociception involves sensitization of osmotransduction in primary afferents because osmotransduction was enhanced in cultured sensory neurons isolated from Taxol-treated rats. Taxol-induced TRPV4-mediated hyperalgesia and the enhanced osmotransduction in cultured nociceptors were dependent on integrin/Src tyrosine kinase signaling. These results suggest that TRPV4 plays a crucial role in a painful peripheral neuropathy, making it a very promising target for the development of a novel class of analgesics.
Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons
Authors: Chen Zhe-Yu , Patel Paresh D. , Sant Gayatree , Meng Chui-Xiang , Teng Kenneth K. , Hempstead Barbara L. , Lee Francis S.
Published: May 2004

Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in thebdnfgene, resulting in a valine to methionine substitution in the prodomain (BDNFMet), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNFMetis secreted in an activity-dependent manner. The nature of the cellular defect when both BDNFMetand wild-type BDNF (BDNFVal) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNFMeton BDNFValintracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNFMetoccurred only in neuronal and neurosecretory cells and that BDNFMetcould alter the intracellular distribution and activity-dependent secretion of BDNFVal. We determined that, when coexpressed in the same cell, ∼70% of the variant BDNF forms BDNFVal·BDNFMetheterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNFMetor the BDNFVal·BDNFMetheterodimer compared with BDNFVal. Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.
p75 Neurotrophin Receptor Signaling Regulates Growth Cone Filopodial Dynamics through Modulating RhoA Activity
Authors: Gehler Scott , Gallo Gianluca , Veien Eric , Letourneau Paul C.
Published: May 2004

The mechanisms by which neurotrophins regulate growth cone motility are unclear. We investigated the role of the p75 neurotrophin receptor (p75NTR) in mediating neurotrophin-induced increases in filopodial length. Our data demonstrate that neurotrophin binding to p75NTRis necessary and sufficient to regulate filopodial dynamics. Furthermore, retinal and dorsal root ganglion growth cones from p75 mutant mice are insensitive to neurotrophins but display enhanced filopodial lengths comparable with neurotrophin-treated wild-type growth cones. This suggests unoccupied p75NTRnegatively regulates filopodia length. Furthermore, p75NTRregulates RhoA activity to mediate filopodial dynamics. Constitutively active RhoA blocks neurotrophin-induced increases in filopodial length, whereas inhibition of RhoA enhances filopodial lengths, similar to neurotrophin treatment. BDNF treatment of retinal neurons results in reduced RhoA activity. Furthermore, p75 mutant neurons display reduced levels of activated RhoA compared with wild-type counterparts, consistent with the enhanced filopodial lengths observed on mutant growth cones. These observations suggest that neurotrophins regulate filopodial dynamics by depressing the activation of RhoA that occurs through p75NTRsignaling.
Proteinase-Activated Receptor 2-Mediated Potentiation of Transient Receptor Potential Vanilloid Subfamily 1 Activity Reveals a Mechanism for Proteinase-Induced Inflammatory Pain
Authors: Dai Yi , Moriyama Tomoko , Higashi Tomohiro , Togashi Kazuya , Kobayashi Kimiko , Yamanaka Hiroki , Tominaga Makoto , Noguchi Koichi
Published: May 2004

Proteinase-activated receptor (PAR) 2 is expressed on a subset of primary afferent neurons and involved in inflammatory nociception. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a sensory neuron-specific cation channel that responds to capsaicin, protons, or heat stimulus. Here, we show that TRPV1 is coexpressed with PAR2 but not with PAR1 or PAR3, and that TRPV1 can functionally interact with PAR2. In human embryonic kidney 293 cells expressing TRPV1 and PAR2, PAR2 agonists increased capsaicin- or proton-evoked TRPV1 currents through a PKC-dependent pathway. After application of PAR2 agonists, temperature threshold for TRPV1 activation was reduced from 42°C to well below the body temperature. PAR2-mediated Fos expression in spinal cord was decreased in TRPV1-deficient mice. The functional interaction was also observed in mouse DRG neurons and proved at a behavioral level. These represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by PAR2 activation.
Parallel Processing of Sensory Input by Bursts and Isolated Spikes
Authors: Oswald Anne-Marie M. , Chacron Maurice J. , Doiron Brent , Bastian Joseph , Maler Leonard
Published: May 2004

Burst firing is commonly observed in many sensory systems and is proposed to transmit information reliably. Although a number of biophysical burst mechanisms have been identified, the relationship between burst dynamics and information transfer is uncertain. Electrosensory pyramidal cells have a well defined backpropagation-dependent burst mechanism. We usedin vivo,in vitro, and modeling approaches to investigate pyramidal cell responses to mimics of behaviorally relevant sensory input. We found that within a given spike train, bursts are biased toward low-frequency events while isolated spikes simultaneously code for the entire frequency range. We also demonstrated that burst dynamics are essential for optimal feature detection but are not required for stimulus estimation. We conclude that burst and spike dynamics can segregate a single spike train into two parallel and complementary streams of information transfer.
Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate
Authors: Follett Pamela L. , Deng Wenbin , Dai Weimin , Talos Delia M. , Massillon Leon J. , Rosenberg Paul A. , Volpe Joseph J. , Jensen Frances E.
Published: May 2004

Periventricular leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insultin vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes eitherin vivoorin vitro. Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.
Cannabinoids Enhance Subsecond Dopamine Release in the Nucleus Accumbens of Awake Rats
Authors: Cheer Joseph F. , Wassum Kate M. , Heien Michael L. A. V. , Phillips Paul E. M. , Wightman R. Mark
Published: May 2004

Dopaminergic neurotransmission has been highly implicated in the reinforcing properties of many substances of abuse, including marijuana. Cannabinoids activate ventral tegmental area dopaminergic neurons, the main ascending projections of the mesocorticolimbic dopamine system, and change their spiking pattern by increasing the number of impulses in a burst and elevating the frequency of bursts. Although they also increase time-averaged striatal dopamine levels for extended periods of time, little is known about the temporal structure of this change. To elucidate this, fast-scan cyclic voltammetry was used to monitor extracellular dopamine in the nucleus accumbens of freely moving rats with subsecond timescale resolution. Intravenous administration of the central cannabinoid (CB1) receptor agonist,R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone mesylate, dose-dependently produced catalepsy, decreased locomotion, and reduced the amplitude of electrically evoked dopamine release while markedly increasing the frequency of detected (nonstimulated) dopamine concentration transients. The CB1receptor antagonist [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] reversed and prevented all agonist-induced effects but did not show effects on dopamine release when injected alone. These data demonstrate that doses of a cannabinoid agonist known to increase burst firing produce ongoing fluctuations in extracellular dopamine on a previously unrecognized temporal scale in the nucleus accumbens.
Learning at Different Satiation Levels Reveals Parallel Functions for the cAMP–Protein Kinase A Cascade in Formation of Long-Term Memory
Authors: Friedrich Anke , Thomas Ulf , Müller Uli
Published: May 2004

Learning and memory formation in intact animals is generally studied under defined parameters, including the control of feeding. We used associative olfactory conditioning of the proboscis extension response in honeybees to address effects of feeding status on processes of learning and memory formation. Comparing groups of animals with different but defined feeding status at the time of conditioning reveals new and characteristic features in memory formation. In animals fed 18 hr earlier, three-trial conditioning induces a stable memory that consists of different phases: a mid-term memory (MTM), translation-dependent early long-term memory (eLTM; 1–2 d), and a transcription-dependent late LTM (lLTM; ≥3 d). Additional feeding of a small amount of sucrose 4 hr before conditioning leads to a loss of all of these memory phases. Interestingly, the basal activity of the cAMP-dependent protein kinase A (PKA), a key player in LTM formation, differs in animals with different satiation levels. Pharmacological rescue of the low basal PKA activity in animals fed 4 hr before conditioning points to a specific function of cAMP–PKA cascade in mediating satiation-dependent memory formation. An increase in PKA activity during conditioning rescues only transcription-dependent lLTM; acquisition, MTM, and eLTM are still impaired. Thus, during conditioning, the cAMP–PKA cascade mediates the induction of the transcription-dependent lLTM, depending on the satiation level. This result provides the first evidence for a central and distinct function of the cAMP–PKA cascade connecting satiation level with learning.