bluuebunny/crossref_metadata_2025 huggingface dataset:
Including the Assessment of Nontraditional Factors in Pharmacy School Admissions
Authors: Latif David A
Published: March 2005

OBJECTIVE:

To review the relevant literature regarding the predictive ability of cognitive measures (ie, Pharmacy College Admissions Test [PCAT] scores and prepharmacy grade point average [GPA]) on both academic and clinical performance and discuss the inclusion of nontraditional assessment during the admissions process.

DATA SOURCES:

Articles were identified through searches of International Pharmaceutical Abstracts (1970–April 2004), MEDLINE (1966–January 2004), and ERIC (1966–April 2004) using the key words admissions variables, predictors of success, Pharmacy College Admissions Test, grade point average, cognitive variables, and noncognitive variables.

STUDY SELECTION AND DATA EXTRACTION:

Cross-sectional, longitudinal, and retrospective studies, as well as reviews, regarding pharmacy school and other higher education admissions' variables were included in this review.

DATA SYNTHESIS:

Many pharmacy school admissions committees give a majority weight to the traditional cognitive markers of prepharmacy GPA and PCAT scores when selecting viable applicants. Doing so may be problematic due to the magnitude of the relationship between traditional cognitive predictors and pharmacy school performance.

CONCLUSIONS:

Based on this review, a cogent argument is advanced for the need to examine, in addition to PCAT scores and GPAs, such nontraditional factors as empathy, citizenship, and ethical behavior. This may increase the predictive ability of preadmission factors on pharmacy school didactic and clinical performance. Schools of pharmacy can do this through questionnaires and interviews designed to assess nontraditional variables.
Interventions to Improve Treatment of Respiratory Infections in Ambulatory Managed-Care Patients
Authors: Raebel Marsha A
Published: March 2005

OBJECTIVE:

To review the literature on managed-care initiatives to improve antimicrobial use in respiratory tract infections (RTIs) and examine whether efforts were successful in decreasing antibiotic prescribing when an antibiotic was not indicated or in increasing the frequency with which a preferred antimicrobial agent was chosen when an antibiotic was appropriate.

DATA SOURCES:

A computerized search of Ovid MEDLINE was conducted for research articles published between 1966 and September 2004 using a key word search of MeSH subject headings and titles. Search terms included managed care or health maintenance organization and antibacterial agents or antibiotic or antimicrobial.

STUDY SELECTION AND DATA EXTRACTION:

Studies evaluating initiatives in ambulatory managed-care environments and the effects of managed care on treatment of RTIs were chosen. Articles addressing both population and individual level tools were included.

DATA SYNTHESIS:

Initiatives have been attempted in a variety of managed-care models. In some studies, multidimensional educational interventions were effective in decreasing antimicrobial prescribing rates for RTIs. However, in other studies, no decrease in antimicrobial prescribing after implementation of an evidence-based guideline or initiation of an educational intervention was observed. In one successful study, patient satisfaction was similar between groups. Each study had limitations in design or generalizability. Several studies had strengths, including using randomized groups or offering multidimensional educational efforts.

CONCLUSIONS:

Randomized prospective studies of interventions to improve antimicrobial prescribing for RTIs in managed care have been variably successful. Because the topic is one of ongoing importance, it will continue to be an area of research.
Single zinc-finger extension: enhancing transcriptional activity and specificity of three-zinc-finger proteins
Authors: Smith Alexander E.F. , Farzaneh Farzin , Ford Kevin G.
Published: March 2005

In order to demonstrate that an existing zinc-finger protein can be simply modified to enhance DNA binding and sequence discrimination in both episomal and chromatin contexts using existing zinc-finger DNA recognition code data, and without recourse to phage display and selection strategies, we have examined the consequences of a single zinc-finger extension to a synthetic three-zinc-finger VP16 fusion protein, on transcriptional activation from model target promoters harbouring the zinc-finger binding sequences. We report a nearly 10-fold enhanced transcriptional activation by the four-zinc-finger VP16 fusion protein relative to the progenitor three-finger VP16 protein in transient assays and a greater than five-fold enhancement in stable reporter-gene expression assays. A marked decrease in transcriptional activation was evident for the four-zinc-finger derivative from mutated regulatory regions compared to the progenitor protein, as a result of recognition site-size extension. This discriminatory effect was shown to be protein concentration-dependent. These observations suggest that four-zinc-finger proteins are stable functional motifs that can be a significant improvement over the progenitor three-zinc-finger protein, both in terms of specificity and the ability to target transcriptional function to promoters, and that single zinc-finger extension can therefore have a significant impact on DNA zinc-finger protein interactions. This is a simple route for modifying or enhancing the binding properties of existing synthetic zinc-finger-based transcription factors and may be particularly suited for the modification of endogenous zinc-finger transcription factors for promoter biasing applications.
Pre-steady-state kinetic analysis of riboflavin synthase using a pentacyclic reaction intermediate as substrate
Authors: Illarionov Boris , Haase Ilka , Fischer Markus , Bacher Adelbert , Schramek Nicholas
Published: March 2005

Riboflavin synthase catalyses a mechanistically complex dismutation affording riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione from 6,7-dimethyl-8-ribityllumazine. A pentacyclic adduct (compound2) of two substrate molecules was used as substrate for pre-steady-state kinetic analysis. Whereas the wild-type enzyme catalyses the decomposition of compound2into a mixture of riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, as well as into two equivalents of 6,7-dimethyl-8-ribityllumazine, a H102Q mutant enzyme predominantly catalyses the former reaction. Stopped-flow experiments with this mutant enzyme failed to identify a reaction intermediate between compound2and riboflavin. However, the apparent rate constants for the formation of riboflavin as observed by stopped-flow and quenched-flow experiments were significantly different, thus suggesting that the reaction proceeds via a significantly populated intermediate, the absorbance of which is similar to that of compound2. An F2A mutant enzyme converts compound2predominantly into 6,7-dimethyl-8-ribityllumazine. Stopped-flow experiments using compound2as substrate indicated a slight and rapid initial increase in absorbance at 310 nm, followed by a slower decrease. This finding, in conjunction with different apparent rates for the formation of 6,7-dimethyl-8-ribityllumazine, suggests the involvement of a significantly populated intermediate in the transition between compound2and 6,7-dimethyl-8-ribityllumazine, the optical spectrum of which is similar to that of compound1.
Lactoferrampin, an antimicrobial peptide of bovine lactoferrin, exerts its candidacidal activity by a cluster of positively charged residues at the C-terminus in combination with a helix-facilitating N-terminal part
Authors: van der Kraan Marieke I.A. , Nazmi Kamran , Teeken Afke , Groenink Jasper , van 't Hof Wim , Veerman Enno C.I. , Bolscher Jan G.M. , Nieuw Amerongen Arie V.
Published: March 2005

The antimicrobial activity of bovine lactoferrin (bLF) is attributed to lactoferricin, which is situated in the N1-domain of bLF. Recently, another antimicrobial domain consisting of residues 268–284, designated lactoferrampin (LFampin), has been identified in the N1-domain of bLF, which exhibited antimicrobial activity againstCandida albicansand several bacteria. In the present study, the candidacidal activity of a series of peptides spanning this antimicrobial domain was investigated in relation to the charge and the capacity to form a helical conformation in hydrophobic environments. C-Terminal truncation of LFampin resulted in a drastic decrease in candidacidal activity. Positively charged residues clustered at the C-terminal side of the LFampin domain appeared to be crucial for the candidacidal activity. The ability to adopt helical conformations did not change when LFampin was truncated at the C-terminal side. N-Terminally truncated LFampin peptides, truncated up to the sequence 270–284, were more reluctant to adopt a helical conformation. Therefore, we conclude that the C-terminal part of LFampin 265–284, which is the most active peptide, is crucial for its candidacidal activity, due to the presence of clustered positive charges, and that the N-terminal part is essential for activity as it facilitates helix formation.
Ceramides induce programmed cell death in Arabidopsis cells in a calcium-dependent manner
Authors: Townley Helen E. , McDonald Kerrie , Jenkins Gareth I. , Knight Marc R. , Leaver Christopher J.
Published: March 2005

While the role of C2-ceramide in the induction of programmed cell death (PCD) in animal systems has been well documented, little is known of its role in plant cells. Here we show that C2-ceramide induces PCD inArabidopsissuspension cultures, which is preceded by the generation of a calcium transient and an increase in reactive oxygen species (ROS). Inhibition of the calcium transient prevented cell death, whereas inhibition of ROS had no effect on cell survival. These observations suggest that calcium signalling plays a role in ceramide-induced PCD but is independent of the generation of ROS.
A Small True Triaxial Apparatus with Wave Velocity Measurement
Authors: Ismail MA , Sharma SS , Fahey M
Published: March 2005

This paper describes a new cubical, true triaxial apparatus recently developed at the University of Western Australia (UWA). The apparatus is a stand-alone unit of the rigid type, where three pairs of pistons can be pressurized to impose three independent, rectilinear stresses on a sample of 250 mm side length. The sample can be tested either dry or saturated. Both drained and undrained shearing can be carried out with maximum pressure of about 1.5 MPa and maximum linear strain of about 8% in any of the three principal directions. A wave velocity measurement system is incorporated so that both elastic shear (Vs) and compression (VF) wave velocities can be measured, with the wave travelling between any two opposite faces of the device, or along skew paths. The elastic waves are generated and detected using “in house” manufactured wave transducers, which can access the sample externally. This feature enables the shear transducers to be rotated 90° degrees to change the polarization direction, enabling Vs to be measured in inclined planes. Additionally, the device enables accurate measurement of Ko. The paper presents results obtained from a silica sand to show the capability of the new device.
Reduced Nerve Injury-Induced Neuropathic Pain in Kinin B1Receptor Knock-Out Mice
Authors: Ferreira Juliano , Beirith Alessandra , Mori Marcelo A. S. , Araújo Ronaldo C. , Bader Michael , Pesquero João B. , Calixto João B.
Published: March 2005

Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B1receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B1receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. In the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B1receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B1receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B1selective receptor antagonist des-Arg9-[Leu8]-bradykinin reduced the established mechanical allodynia observed 7-28 d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B1receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B1receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B1receptor antagonist might have therapeutic potential in the management of chronic pain.
Compartment-Resolved Imaging of Activity-Dependent Dynamics of Cortical Blood Volume and Oximetry
Authors: Vanzetta Ivo , Hildesheim Rina , Grinvald Amiram
Published: March 2005

Optical imaging, positron emission tomography, and functional magnetic resonance imaging (fMRI) all rely on vascular responses to image neuronal activity. Although these imaging techniques are used successfully for functional brain mapping, the detailed spatiotemporal dynamics of hemodynamic events in the various microvascular compartments have remained unknown. Here we used high-resolution optical imaging in area 18 of anesthetized cats to selectively explore sensory-evoked cerebral blood-volume (CBV) changes in the various cortical microvascular compartments. To avoid the confounding effects of hematocrit and oximetry changes, we developed and used a new fluorescent blood plasma tracer and combined these measurements with optical imaging of intrinsic signals at a near-isosbestic wavelength for hemoglobin (565 nm). The vascular response began at the arteriolar level, rapidly spreading toward capillaries and venules. Larger veins lagged behind. Capillaries exhibited clear blood-volume changes. Arterioles and arteries had the largest response, whereas the venous response was smallest. Information about compartment-specific oxygen tension dynamics was obtained in imaging sessions using 605 nm illumination, a wavelength known to reflect primarily oximetric changes, thus being more directly related to electrical activity than CBV changes. Those images were radically different: the response began at the parenchyma level, followed only later by the other microvascular compartments. These results have implications for the modeling of fMRI responses (e.g., the balloon model). Furthermore, functional maps obtained by imaging the capillary CBV response were similar but not identical to those obtained using the early oximetric signal, suggesting the presence of different regulatory mechanisms underlying these two hemodynamic processes.
Noradrenaline and Dopamine Elevations in the Rat Prefrontal Cortex in Spatial Working Memory
Authors: Rossetti Zvani L. , Carboni Sonia
Published: March 2005

The role of prefrontal cortical dopamine (DA) in the modulation of working memory functions is well documented, but substantial evidence indicates that the locus ceruleus noradrenergic system also modulates working memory via actions within the prefrontal cortex (PFC). This study shows that PFC noradrenaline (NA) and DA dialysate levels phasically increase when rats perform correctly in a delayed alternation task in a T-maze, a test of spatial working memory. However, NA levels were markedly enhanced in animals trained to alternate compared with rats that acquired the spatial information about the location of food in the maze but were untrained to make a choice to obtain the reward. In contrast, PFC DA elevations occurred independently of whether the animal had acquired the trial-specific information for correct task execution. The contribution of anticipatory responses to catecholamine efflux was also evaluated by exposing rats to an environment signaling the presence of the reward in the successive alternation task. No conditioned NA efflux was observed in either group. In contrast, in both groups, DA efflux increased in the anticipatory phase of the test to the same levels of those reached during the task. These data provide the first direct evidence for a selective activation of PFC NA transmission during a spatial working memory task. We propose that, in the working memory task, DA is primarily associated with reward expectancy, whereas NA is involved in the active maintenance of the information about a goal and the rules to achieve it.
Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited
Authors: Lazarov Orly , Morfini Gerardo A. , Lee Edward B. , Farah Mohamed H. , Szodorai Anita , DeBoer Scott R. , Koliatsos Vassilis E. , Kins Stefan , Lee Virginia M.-Y. , Wong Philip C. , Price Donald L. , Brady Scott T. , Sisodia Sangram S.
Published: March 2005

The sequential enzymatic actions of β-APP cleaving enzyme 1 (BACE1), presenilins (PS), and other proteins of the γ-secretase complex liberate β-amyloid (Aβ) peptides from larger integral membrane proteins, termed β-amyloid precursor proteins (APPs). Relatively little is known about the normal function(s) of APP or the neuronal compartment(s) in which APP undergoes proteolytic processing. Recent studies have been interpreted as consistent with the idea that APP serves as a kinesin-1 cargo receptor and that PS and BACE1 are associated with the APP-resident membranous cargos that undergo rapid axonal transport. In this report, derived from a collaboration among several independent laboratories, we examined the potential associations of APP and kinesin-1 using glutathioneS-transferase pull-down and coimmunoprecipitation assays. In addition, we assessed the trafficking of membrane proteins in the sciatic nerves of transgenic mice with heterozygous or homozygous deletions ofAPP. In contrast to previous reports, we were unable to find evidence for direct interactions between APP and kinesin-1. Furthermore, the transport of kinesin-1 and tyrosine kinase receptors, previously reported to require APP, was unchanged in axons ofAPP-deficient mice. Finally, we show that two components of the APP proteolytic machinery, i.e., PS1 and BACE1, are not cotransported with APP in the sciatic nerves of mice. These findings suggest that the hypothesis that APP serves as a kinesin-1 receptor and that the proteolytic processing machinery responsible for generating Aβ is transported in the same vesicular compartment in axons of peripheral nerves requires revision.
Degradation of Head Direction Cell Activity during Inverted Locomotion
Authors: Calton Jeffrey L. , Taube Jeffrey S.
Published: March 2005

Head direction (HD) cells in the rat limbic system carry information about the direction the head is pointing in the horizontal plane. Most previous studies of HD functioning have used animals locomoting in an upright position or ascending/descending a vertical wall. In the present study, we recorded HD cell activity from the anterodorsal thalamic nucleus while the animal was locomoting in an upside-down orientation. Rats performed a shuttle-box task requiring them to climb a vertical wall and locomote across the ceiling of the apparatus while inverted to reach an adjoining wall before ascending into the reward compartment. The apparatus was oriented toward the preferred direction of the recorded cell, or the 180° opposite direction. When the animal was traversing the vertical walls of the apparatus, the HD cells remained directionally tuned as if the walls were an extension of the floor. When the animal was locomoting inverted on the ceiling, however, cells showed a dramatic change in activity. Nearly one-half (47%) of the recorded cells exhibited no directional specificity during inverted locomotion, despite showing robust directional tuning on the walls before and after inversion. The remaining cells showed significantly degraded measures of directional tuning and random shifts of the preferred direction relative to the floor condition while the animal was inverted. It has previously been suggested that the HD system uses head angular velocity signals from the vestibular system to maintain a consistent representation of allocentric direction. These findings suggest that being in an inverted position causes a distortion of the vestibular signal controlling the HD system.
The Multiple Functions of Cysteine-String Protein Analyzed atDrosophilaNerve Terminals
Authors: Bronk Peter , Nie Zhiping , Klose Markus K. , Dawson-Scully Ken , Zhang Jinhui , Robertson R. Meldrum , Atwood Harold L. , Zinsmaier Konrad E.
Published: March 2005

The synaptic vesicle-associated cysteine-string protein (CSP) is important for synaptic transmission. Previous studies revealed multiple defects at neuromuscular junctions (NMJs) ofcspnull-mutantDrosophila, but whether these defects are independent of each other or mechanistically linked through J domain mediated-interactions with heat-shock cognate protein 70 (Hsc70) has not been established. To resolve this issue, we genetically dissected the individual functions of CSP by anin vivostructure/function analysis. Expression of mutant CSP lacking the J domain atcspnull-mutant NMJs fully restored normal thermo-tolerance of evoked transmitter release but did not completely restore evoked release at room temperature and failed to reverse the abnormal intraterminal Ca2+levels. This suggests that J domain-mediated functions are essential for the regulation of intraterminal Ca2+levels but only partially required for regulating evoked release and not required for protecting evoked release against thermal stress. Hence, CSP can also act as an Hsc70-independent chaperone protecting evoked release from thermal stress. Expression of mutant CSP lacking the L domain restored neurotransmission and partially reversed the abnormal intraterminal Ca2+levels, suggesting that the L domain is important, although not essential, for the role of CSP in regulating intraterminal Ca2+levels. We detected no effects ofcspmutations on individual presynaptic Ca2+signals triggered by action potentials, suggesting that presynaptic Ca2+entry is not primarily impaired. Both the J and L domains were also required for the role of CSP in synaptic growth. Together, these results suggest that CSP has several independent synaptic functions, affecting synaptic growth, evoked release, thermal protection of evoked release, and intraterminal Ca2+levels at rest and during stimulation.
Neurosteroid-Induced Plasticity of Immature Synapses via Retrograde Modulation of Presynaptic NMDA Receptors
Authors: Mameli Manuel , Carta Mario , Partridge L. Donald , Valenzuela C. Fernando
Published: March 2005

Neurosteroids are producedde novoin neuronal and glial cells, which begin to express steroidogenic enzymes early in development. Studies suggest that neurosteroids may play important roles in neuronal circuit maturation via autocrine and/or paracrine actions. However, the mechanism of action of these agents is not fully understood. We report here that the excitatory neurosteroid pregnenolone sulfate induces a long-lasting strengthening of AMPA receptor-mediated synaptic transmission in rat hippocampal neurons during a restricted developmental period. Using the acute hippocampal slice preparation and patch-clamp electrophysiological techniques, we found that pregnenolone sulfate increases the frequency of AMPA-mediated miniature excitatory postsynaptic currents in CA1 pyramidal neurons. This effect could not be observed in slices from rats older than postnatal day 5. The mechanism of action of pregnenolone sulfate involved a short-term increase in the probability of glutamate release, and this effect is likely mediated by presynaptic NMDA receptors containing the NR2D subunit, which is transiently expressed in the hippocampus. The increase in glutamate release triggered a long-term enhancement of AMPA receptor function that requires activation of postsynaptic NMDA receptors containing NR2B subunits. Importantly, synaptic strengthening could also be triggered by postsynaptic neuron depolarization, and an anti-pregnenolone sulfate antibody scavenger blocked this effect. This finding indicates that a pregnenolone sulfate-like neurosteroid is a previously unrecognized retrograde messenger that is released in an activity-dependent manner during development.
Beyond Memory, Navigation, and Inhibition: Behavioral Evidence for Hippocampus-Dependent Cognitive Coordination in the Rat
Authors: Wesierska Malgorzata , Dockery Colleen , Fenton André A.
Published: March 2005

Injecting tetrodotoxin (TTX) into one hippocampus impaired avoidance of a place defined by distal cues while rats were on a slowly rotating arena. The impairment could be explained by a deficit in memory, navigation, or behavioral inhibition. Here, we show that the TTX injection abolished the ability of rats to organize place-avoidance behavior specifically when distal room and local arena cues were continuously dissociated. The results provide evidence that injecting TTX into one hippocampus specifically impaired the coordination of representations that support organized behavior because of the following: (1) rats normally coordinate separate room and arena avoidance memories; (2) the TTX injection spared spatial, relational, and representational memory, navigation, and behavioral inhibition; and (3) the TTX-induced impairment of place avoidance depended on the need to coordinate representations of local and distal stimuli.
Properties of Synaptically Evoked Astrocyte Calcium Signal Reveal Synaptic Information Processing by Astrocytes
Authors: Perea Gertrudis , Araque Alfonso
Published: March 2005

The synaptic control of the astrocytic intracellular Ca2+is crucial in the reciprocal astrocyte-neuron communication. Using electrophysiological and Ca2+imaging techniques in rat hippocampal slices, we investigated the astrocytic Ca2+signal modulation induced by synaptic terminals that use glutamate and acetylcholine. Ca2+elevations were evoked by glutamate released from Schaffer collaterals and by acetylcholine, but not glutamate, released by alveus stimulation, indicating that astrocytes discriminate the activity of different synapses belonging to different axon pathways. The Ca2+signal was modulated bidirectionally by simultaneous activation of both pathways, being depressed at high stimulation frequencies and enhanced at low frequencies. The Ca2+modulation was attributable to astrocytic intrinsic properties, occurred at discrete regions of the processes, and controlled the intracellular expansion of the Ca2+signal. In turn, astrocyte Ca2+signal elicited NMDA receptor-mediated currents in pyramidal neurons. Therefore, because astrocytes discriminate and integrate synaptic information, we propose that they can be considered as cellular elements involved in the information processing by the nervous system.
Insulin-Like Growth Factor-1 Inhibits Adult Supraoptic Neurons via Complementary Modulation of Mechanoreceptors and Glycine Receptors
Authors: Ster Jeanne , Colomer Claude , Monzo Cécile , Duvoid-Guillou Anne , Moos Françoise , Alonso Gérard , Hussy Nicolas
Published: March 2005

In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons.In vivoapplication of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl-currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.
Impaired Outcome-Specific Devaluation of Instrumental Responding in Mice with a Targeted Deletion of the AMPA Receptor Glutamate Receptor 1 Subunit
Authors: Johnson Alexander W. , Bannerman David M. , Rawlins Nicholas P. , Sprengel Rolf , Good Mark A.
Published: March 2005

The present study evaluated the proposal that mice with a targeted deletion of the glutamate receptor 1 (GluR1) subunit of the AMPA receptor are impaired in using an instrumental or pavlovian signal to gain access to a representation of the sensory-specific motivational properties of a primary reward. In experiment 1, mice were trained to approach two goal boxes in a plus-maze; each goal box contained a different reward (sucrose solution vs food pellet). After acquisition, one of the rewards was devalued by an outcome-specific satiety procedure. Subsequent test trials performed in extinction showed an increase in the latency to enter the devalued goal arm, relative to the nondevalued goal arm in control but not GluR1-/-mice. In experiment 2, a similar outcome-specific satiety procedure was used to examine the effects of reward devaluation on an instrumental nose-poke response. During testing, control but not GluR1-/-mice decreased their rate of responding on a nose poke associated with a devalued reward. A subsequent choice test showed that GluR1-/-mice were able to discriminate between the devalued and nondevalued outcomes used in both experiments. These deficits mirror those seen after lesions of the basolateral amygdala and suggests that GluR1-mediated neurotransmission in this region contributes to encoding the relationship between sensory-specific aspects of reward and their incentive value.
Neural Substrates for Behaviorally Conditioned Immunosuppression in the Rat
Authors: Pacheco-López Gustavo , Niemi Maj-Britt , Kou Wei , Härting Margarete , Fandrey Joachim , Schedlowski Manfred
Published: March 2005

We have previously demonstrated behaviorally conditioned immunosuppression using cyclosporin A as an unconditioned stimulus and saccharin as a conditioned stimulus. In the current study, we examined the central processing of this phenomenon generating excitotoxic lesions before and after acquisition to discriminate between learning and memory processes. Three different brain areas were analyzed: insular cortex (IC), amygdala (Am), and ventromedial nucleus of the hypothalamus (VMH). The results demonstrate that IC lesions performed before and after acquisition disrupted the behavioral component of the conditioned response (taste aversion). In contrast, Am and VMH lesions did not affect conditioned taste aversion. The behaviorally conditioned suppression of splenocyte proliferation and cytokine production (interleukin-2 and interferon-γ) was differentially affected by the excitotoxic lesions, showing that the IC is essential to acquire and evoke this conditioned response of the immune system. In contrast, the Am seems to mediate the input of visceral information necessary at the acquisition time, whereas the VMH appears to participate within the output pathway to the immune system necessary to evoke the behavioral conditioned immune response. The present data reveal relevant neural mechanisms underlying the learning and memory processes of behaviorally conditioned immunosuppression.
Ethanol-Responsive Brain Region Expression Networks: Implications for Behavioral Responses to Acute Ethanol in DBA/2J versus C57BL/6J Mice
Authors: Kerns Robnet T. , Ravindranathan Ajay , Hassan Sajida , Cage Mary P. , York Tim , Sikela James M. , Williams Robert W. , Miles Michael F.
Published: March 2005

Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factorBdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.
Shal and Shaker Differential Contribution to the K+Currents in theDrosophilaMushroom Body Neurons
Authors: Gasque Gabriel , Labarca Pedro , Reynaud Enrique , Darszon Alberto
Published: March 2005

Shaker, a voltage-dependent K+channel, is enriched in the mushroom bodies (MBs), the locus of olfactory learning inDrosophila. Mutations in theshakerlocus are known to alter excitability, neurotransmitter release, synaptic plasticity, and olfactory learning. However, a direct link of Shaker channels to MB intrinsic neuron (MBN) physiology has not been documented. We found that transcripts forshab,shaw,shaker, andshal, among which only Shaker and Shal have been reported to code for A-type currents, are present in the MBs. The electrophysiological data showed that the absence of functional Shaker channels modifies the distribution of half-inactivation voltages (Vi1/2) in the MBNs, indicating a segregation of Shaker channels to only a subset (∼28%) of their somata. In harmony with this notion, we found that approximately one-fifth of MBNs lacking functional Shaker channels displayed dramatically slowed-down outward current inactivation times and reduced peak-current amplitudes. Furthermore, whereas all MBNs were sensitive to 4-aminopyridine, a nonspecific A-type current blocker, a subset of neurons (∼24%) displayed little sensitivity to a Shal-specific toxin. This subset of neurons displaying toxin-insensitive outward currents had more depolarizedVi1/2values attributable to Shaker channels. Our findings provide the first direct evidence that altered Shaker channel function disrupts MBN physiology inDrosophila. To our surprise, the experimental data also indicate that Shaker channels segregate to a minor fraction of MB neuronal somata (20-30%), and that Shal channels contribute the somatic A-type current in the majority of MBNs.
Coxsackievirus Targets Proliferating Neuronal Progenitor Cells in the Neonatal CNS
Authors: Feuer Ralph , Pagarigan Robb R. , Harkins Stephanie , Liu Fei , Hunziker Isabelle P. , Whitton J. Lindsay
Published: March 2005

Type B coxsackieviruses (CVB) frequently infect the CNS and, together with other enteroviruses, are the most common cause of viral meningitis in humans. Newborn infants are particularly vulnerable, and CVB also can infect the fetus, leading to mortality, or to neurodevelopmental defects in surviving infants. Using a mouse model of neonatal CVB infection, we previously demonstrated that coxsackievirus B3 (CVB3) could infect neuronal progenitor cells in the subventricular zone (SVZ). Here we extend these findings, and we show that CVB3 targets actively proliferating (bromodeoxyuridine+, Ki67+) cells in the SVZ, including type B and type A stem cells. However, infected cells exiting the SVZ have lost their proliferative capacity, in contrast to their uninfected companions. Despite being proliferation deficient, the infected neuronal precursors could migrate along the rostral migratory stream and radial glia, to reach their final destinations in the olfactory bulb or cerebral cortex. Furthermore, infection did not prevent cell differentiation, as determined by cellular morphology and the expression of maturation markers. These data lead us to propose a model of CVB infection of the developing CNS, which may explain the neurodevelopmental defects that result from fetal infection.
Constitutional Aneuploidy in the Normal Human Brain
Authors: Rehen Stevens K. , Yung Yun C. , McCreight Matthew P. , Kaushal Dhruv , Yang Amy H. , Almeida Beatriz S. V. , Kingsbury Marcy A. , Cabral Kátia M. S. , McConnell Michael J. , Anliker Brigitte , Fontanoz Marisa , Chun Jerold
Published: March 2005

The mouse brain contains genetically distinct cells that differ with respect to chromosome number manifested as aneuploidy (Rehen et al., 2001); however, the relevance to humans is not known. Here, using double-label fluorescencein situhybridization for the autosome chromosome 21 (chromosome 21 point probes combined with chromosome 21 “paint” probes), along with immunocytochemistry and cell sorting, we present evidence for chromosome gain and loss in the human brain. Chromosome 21 aneuploid cells constitute ∼4% of the estimated one trillion cells in the human brain and include non-neuronal cells and postmitotic neurons identified by the neuronspecific nuclear protein marker. In comparison, human interphase lymphocytes present chromosome 21 aneuploidy rates of 0.6%. Together, these data demonstrate that human brain cells (both neurons and non-neuronal cells) can be aneuploid and that the resulting genetic mosaicism is a normal feature of the human CNS.
Trafficking of a Ligand-Receptor Complex on the Growth Cones as an Essential Step for the Uptake of Nerve Growth Factor at the Distal End of the Axon: A Single-Molecule Analysis
Authors: Tani Tomomi , Miyamoto Yoshikazu , Fujimori Kazuhiro E. , Taguchi Takahisa , Yanagida Toshio , Sako Yasushi , Harada Yoshie
Published: March 2005

The behavior of single molecules of neurotrophins on growth cones was observed by the use of the fluorescent conjugate of nerve growth factor (NGF), Cy3-NGF. After the application of 0.4 nmCy3-NGF, chick dorsal root ganglion growth cones responded within 1 min of adding the stimulus by expanding their lamellipodia. Only 40 molecules of Cy3-NGF, which occupied <5% of the estimated total binding sites on a single growth cone, were required to initiate the motile responses. After binding to the high-affinity receptor, Cy3-NGF displayed lateral diffusion on the membrane of the growth cones with a diffusion constant of 0.3 μm2s-1. The behavior of Cy3-NGF was shifted to a one-directional rearward movement toward the central region of the growth cone. The one-directional movement of Cy3-NGF displayed the same rate as the rearward flow of actin, ∼4 μm/min. This movement could be stopped by the application of the potent inhibitor of actin polymerization, latrunculin B. Molecules of Cy3-NGF were suggested to be internalized in the vicinity of the central region of the growth cone during this rearward trafficking, because Cy3-NGF remained in the growth cone after the growth cones had been exposed to an acidic surrounding medium: acidic medium causes the complete dissociation of Cy3-NGF from the receptors on the surface of growth cones. These results suggested that actin-driven trafficking of the NGF receptor complex is an essential step for the accumulation and endocytosis of NGF at the growth cone and for the retrograde transport of NGF toward the cell body.
Glutamate Receptor Trafficking: Endoplasmic Reticulum Quality Control Involves Ligand Binding and Receptor Function
Authors: Mah Stephanie J. , Cornell Elizabeth , Mitchell Nicholas A. , Fleck Mark W.
Published: March 2005

The glutamate receptor (GluR) agonist-binding site consists of amino acid residues in the extracellular S1 and S2 domains in the N-terminal and M3-M4 loop regions, respectively. In the present study, we sought to confirm that the conserved ligand-binding residues identified in the AMPA receptor S1S2 domains also participate in ligand binding of GluR6 kainate receptors. Amino acid substitutions were made in the GluR6 parent at R523, T690, and E738 to alter their potential interactions with ligand. Mutant receptors were expressed in human embryonic kidney 293 cells, confirmed by Western blot analysis, and tested by [3H]kainate binding and patch-clamp recording. Each of the binding site mutations was sufficient to reduce [3H]kainate binding to undetectable levels and eliminate functional responses to glutamate or kainate. As with our studies of other nonfunctional mutants (Fleck et al., 2003), immunocytochemical staining and cell-surface biotinylation studies showed that the mutant receptors were retained intracellularly and did not traffic to the cell surface. Endoglycosidase-H digests and colocalization with endoplasmic reticulum (ER) markers demonstrated that the mutant receptors are immaturely glycosylated and retained in the ER. Immunoprecipitation, native PAGE, and functional studies confirmed that the GluR6-binding site mutants are capable of multimeric assembly, indicating their retention in the ER does not result from a gross protein folding error. Together, these results confirm the role of R523, T690, and E738 directly in ligand binding to GluR6 and further support our previous report that nonfunctional GluRs are retained intracellularly by a functional checkpoint in ER quality control.
Role of the Primary Motor and Dorsal Premotor Cortices in the Anticipation of Forces during Object Lifting
Authors: Chouinard Philippe A. , Leonard Gabriel , Paus Tomáš
Published: March 2005

When lifting small objects, people apply forces that match the expected weight of the object. This expectation relies in part on information acquired during a previous lift and on associating a certain weight with a particular object. Our study examined the role of the primary motor and dorsal premotor cortices in predicting weight based either on information acquired during a previous lift (no-cue experiment) or on arbitrary color cues associated with a particular weight (cue experiment). In the two experiments, subjects used precision grip to lift two different weights in a series of trials both before and after we applied low-frequency repetitive transcranial magnetic stimulation over the primary motor and dorsal premotor cortices. In the no-cue experiment, subjects did not receive any previous information about which of two weights they would have to lift. In the cue experiment, a color cue provided information about which of the two weights subjects would have to lift. Our results demonstrate a double dissociation in the effects induced by repetitive stimulation. When applied over the primary motor cortex, repetitive stimulation disrupted the scaling of forces based on information acquired during a previous lift. In contrast, when applied over the dorsal premotor cortex, repetitive stimulation disrupted the scaling of forces based on arbitrary color cues. We conclude that the primary motor and dorsal premotor cortices have unique roles during the anticipatory scaling of forces associated with the lifting of different weights.
Spike-Frequency Adaptation Separates Transient Communication Signals from Background Oscillations
Authors: Benda Jan , Longtin André , Maler Len
Published: March 2005

Spike-frequency adaptation is a prominent feature of many neurons. However, little is known about its computational role in processing behaviorally relevant natural stimuli beyond filtering out slow changes in stimulus intensity. Here, we present a more complex example in which we demonstrate how spike-frequency adaptation plays a key role in separating transient signals from slower oscillatory signals. We recordedin vivofrom very rapidly adapting electroreceptor afferents of the weakly electric fishApteronotus leptorhynchus. The firing-frequency response of electroreceptors to fast communication stimuli (“small chirps”) is strongly enhanced compared with the response to slower oscillations (“beats”) arising from interactions of same-sex conspecifics. We are able to accurately predict the electroreceptor afferent response to chirps and beats, using a recently proposed general model for spike-frequency adaptation. The parameters of the model are determined for each neuron individually from the responses to step stimuli. We conclude that the dynamics of the rapid spike-frequency adaptation is sufficient to explain the data. Analysis of additional data from step responses demonstrates that spike-frequency adaptation acts subtractively rather than divisively as expected from depressing synapses. Therefore, the adaptation dynamics is linear and creates a high-pass filter with a cutoff frequency of 23 Hz that separates fast signals from slower changes in input. A similar critical frequency is seen in behavioral data on the probability of a fish emitting chirps as a function of beat frequency. These results demonstrate how spike-frequency adaptation in general can facilitate extraction of signals of different time scales, specifically high-frequency signals embedded in slower oscillations.