bluuebunny/crossref_metadata_2025 huggingface dataset:
Neonatal Estrogen Exposure Disrupts Uterine Development in the Postnatal Sheep
Authors: Hayashi Kanako , Carpenter Karen D. , Spencer Thomas E.
Published: April 2004

Postnatal development of the ovine uterus between birth and postnatal day (PND) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium (LE) followed by extensive coiling and branching morphogenesis of the tubular glands. To determine the short- and long-term effects of estrogen on neonatal ovine uterine development after PND 14, neonatal sheep were randomly assigned at birth (PND 0) to be treated daily with estradiol-17β benzoate (EB; 0, 0.01, 0.1, 1, or 10 μg/kg body weight·d) during one of two developmental periods (PND 14–27 or 42–55). All ewes were hemiovariohysterectomized at the end of EB treatment on either PND 28 or 56, and the remaining uterine horn and ovary removed on PND 112. Immediate responses to EB treatment included dose- and age-dependent increases in uterine wet weight, thickness of the endometrium, myometrium, and LE, but decreases in endometrial glands on PND 28 and 56. Transient exposure to EB decreased gland number and thickness of the endometrium and LE on PND 112 but did not affect extrauterine reproductive tract structures. The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation. Real-time PCR analyses found that EB exposure disrupted normal patterns of growth factor (IGF-I, IGF-II, fibroblast growth factor-7, fibroblast growth factor-10, and hepatocyte growth factor) and receptor mRNA expression in the uterus. Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus, leading to permanent alterations in uterine structure and function.
Constitutional Rules and Fiscal Policy Outcomes
Authors: Persson Torsten , Tabellini Guido
Published: March 2004

We investigate the effect of electoral rules and forms of government on fiscal policy outcomes in a large sample of democracies. We rely on different estimation methods to address prospective problems of statistical inference, due to nonrandom selection of these constitutional rules. The findings are consistent with our theoretical priors: presidential regimes induce smaller governments than parliamentary democracies, while majoritarian elections lead to smaller governments and smaller welfare programs than proportional elections.
Bidder Discounts and Target Premia in Takeovers
Authors: Jovanovic Boyan , Braguinsky Serguey
Published: March 2004

On news of a takeover, the sum of the stock market values of the firms involved often falls, and the value of the acquirer almost always does. Does this mean that takeovers do not raise the values of the firms involved? Not necessarily. We set up a model in which the equilibrium number of takeovers is constrained efficient. Yet upon news of a takeover, a target's price rises, the bidder's price falls, and most of the time the joint value of the target and acquirer also falls.
Costly Voting
Authors: Börgers Tilman
Published: March 2004

What are good voting rules if voting is costly? We analyze this question for the case that an electorate chooses among two alternatives. In a symmetric private value model of voting we show that majority voting with voluntary participation Pareto-dominates majority voting with compulsory participation as well as random decision-making.
Factor Proportions and the Structure of Commodity Trade
Authors: Romalis John
Published: March 2004

This paper examines how factor proportions determine the structure of commodity trade. It integrates a many-country version of a Heckscher-Ohlin model with a continuum of goods with Paul R. Krugman's (1980) model of monopolistic competition and transport costs. The commodity structure of production and bilateral trade is fully determined. Two main predictions emerge. Countries capture larger shares of world production and trade of commodities that more intensively use their abundant factors. Countries that rapidly accumulate a factor see their production and export structures systematically shift towards industries that intensively use that factor. Both predictions receive support from detailed trade data.
Do We Really Know That the WTO Increases Trade?
Authors: Rose Andrew K
Published: March 2004

This paper estimates the effect on international trade of multilateral trade agreements—the World Trade Organization (WTO), its predecessor the General Agreement on Tariffs and Trade (GATT), and the Generalized System of Preferences (GSP) extended from rich countries to developing countries. I use a standard “gravity” model of bilateral merchandise trade and a large panel data set covering over 50 years and 175 countries. An extensive search reveals little evidence that countries joining or belonging to the GATT/WTO have different trade patterns from outsiders, though the GSP seems to have a strong effect.
Do Police Reduce Crime? Estimates Using the Allocation of Police Forces After a Terrorist Attack
Authors: Di Tella Rafael , Schargrodsky Ernesto
Published: March 2004

An important challenge in the crime literature is to isolate causal effects of police on crime. Following a terrorist attack on the main Jewish center in Buenos Aires, Argentina, in July 1994, all Jewish institutions received police protection. Thus, this hideous event induced a geographical allocation of police forces that can be presumed exogenous in a crime regression. Using data on the location of car thefts before and after the attack, we find a large deterrent effect of observable police on crime. The effect is local, with no appreciable impact outside the narrow area in which the police are deployed.
Dynamic Pricing in the Presence of Antidumping Policy: Theory and Evidence
Authors: Blonigen Bruce A , Park Jee-Hyeong
Published: March 2004

Antidumping (AD) trade protection policies allow government agencies to recalculate AD duties based on foreign firms' most recent pricing behavior. We examine the resulting dynamic pricing problem of a foreign firm facing such policy. We show that the expected pattern of AD duty recalculations over time crucially depends on the foreign firm's ex ante expectations of possible outcomes of AD policy enforcement. Our empirical analysis then confirms the role of ex ante expectations in explaining observed patterns of AD recalculations. Many of our model's results are applicable to other situations where enforcement of policy is tied to the subject's behavior.
The Effect of Education on Crime: Evidence from Prison Inmates, Arrests, and Self-Reports
Authors: Lochner Lance , Moretti Enrico
Published: March 2004

We estimate the effect of education on participation in criminal activity using changes in state compulsory schooling laws over time to account for the endogeneity of schooling decisions. Using Census and FBI data, we find that schooling significantly reduces the probability of incarceration and arrest. NLSY data indicate that our results are caused by changes in criminal behavior and not differences in the probability of arrest or incarceration conditional on crime. We estimate that the social savings from crime reduction associated with high school graduation (for men) is about 14–26 percent of the private return.
Testing for Indeterminacy: An Application to U.S. Monetary Policy
Authors: Lubik Thomas A , Schorfheide Frank
Published: March 2004

This paper considers a prototypical New Keynesian model, in which the equilibrium is undetermined if monetary policy is “passive.” The likelihood-based estimation of dynamic equilibrium models is extended to allow for indeterminacies and sunspot fluctuations. We construct posterior weights for the determinacy and indeterminacy region of the parameter space and estimates for the propagation of fundamental and sunspot shocks. According to the estimated model, U.S. monetary policy post-1982 is consistent with determinacy, whereas the pre-Volcker policy is not. We find that before 1979 indeterminacy substantially altered the propagation of shocks.
Internet Job Search and Unemployment Durations
Authors: Kuhn Peter , Skuterud Mikal
Published: March 2004

Using the December 1998 and August 2000 CPS Computer and Internet Supplements matched with subsequent CPS files, we ask which types of unemployed workers looked for work on line and whether Internet searchers became reemployed more quickly. In our data, Internet searchers have observed characteristics that are typically associated with shorter unemployment spells, and do spend less time unemployed. This unemployment differential is however eliminated and in some cases reversed when we hold observable characteristics constant. We conclude that either Internet job search is ineffective in reducing unemployment durations, or Internet job searchers are negatively selected on unobservables.
Pareto-Efficient International Taxation
Authors: Keen Michael , Wildasin David
Published: March 2004

This paper analyzes Pareto-efficient international tax regimes. Because every country faces its own national budget constraint, the Diamond-Mirrlees production-efficiency theorem, which underlies key tenets of policy advice in international taxation—the desirability of destination basis for commodity taxation, of the residence principle for capital income taxation, and of free trade—does not apply. The paper establishes conditions—relating to the availability of explicit or implicit devices for reallocating tax revenues across countries—under which production efficiency is nevertheless desirable, and characterizes the precise ways in which Pareto-efficient international taxation may require violation of established tenets.
Recommendations for Further Reading
Authors: Saffran Bernard
Published: April 2004

This section will list readings that may be especially useful to teachers of undergraduate economics, as well as other articles that are of broader cultural interest. In general, the articles chosen will be expository or integrative and not focus on original research. If you write or read an appropriate article, please send a copy of the article (and possibly a few sentences describing it) to Bernard Saffran, c/o Journal of Economic Perspectives, Department of Economics, Swarthmore College, Swarthmore, PA 19081.
Prices, contracts and motivations: institutional arrangements in domiciliary care
Authors: Forder Julien , Knapp Martin , Kendall Jeremy , Matosevic Tihana , Hardy Brian , Ware Patricia
Published: April 2004

English

The social care reforms of the early 1990s have had profound effects on the domiciliary care system. The adoption of markets and the ‘enabling’ role for local authorities are central features. In contrast to much of the original rhetoric that lay behind these reforms, economic theory emphasises the importance of the institutional arrangements in affecting performance. Given the discretion that local authorities have over the specific form of transactions with providers, questions about contract choices are especially pertinent. This article describes the range of arrangements being used and the different implications of contract choices. In the context of relatively competitive markets and organisations exhibiting a range of business motivations, the evidence supports the hypothesis that for otherwise equivalent providers, prices are significantly affected by contract type. In short, institutional arrangements matter.
Arthropod 5-HT2Receptors: A Neurohormonal Receptor in Decapod Crustaceans That Displays Agonist Independent Activity Resulting from an Evolutionary Alteration to the DRY Motif
Authors: Clark Merry C. , Dever Timothy E. , Dever John J. , Xu Ping , Rehder Vincent , Sosa Maria A. , Baro Deborah J.
Published: March 2004

The stomatogastric nervous system (STNS) is a premiere model for studying modulation of motor pattern generation. Whereas the cellular and network responses to monoamines have been particularly well characterized electrophysiologically, the transduction mechanisms that link the different monoaminergic signals to specific intracellular responses are presently unknown in this system. To begin to elucidate monoaminergic signal transduction in pyloric neurons, we used a bioinformatics approach to predict the existence of 18 monoamine receptors in arthropods, 9 of which have been previously cloned inDrosophilaand other insects. We then went on to use the two existing insect databases to clone and characterize the 10th putative arthropod receptor from the spiny lobster,Panulirus interruptus. This receptor is most homologous to the 5-HT2subtype and shows a dose-dependent response to 5-HT but not to any of the other monoamines present in the STNS. Through a series of pharmacological experiments, we demonstrate that this newly described receptor, 5-HT2βPan, couples with the traditional Gqpathway when expressed in HEK293 cells, but not to Gsor Gi/o. Moreover, it is constitutively active, because the highly conserved DRY motif in transmembrane region 3 has evolved into DRF. Site-directed mutagenesis that reverts the motif back to DRY abolishes this agonist-independent activity. We further demonstrate that this receptor most likely participates in the modulation of stomatogastric motor output, because it is found in neurites in the synaptic neuropil of the stomatogastric ganglion as well as in the axon terminals at identified pyloric neuromuscular junctions.
Constitutive Activity of the Serotonin2C Receptor InhibitsIn VivoDopamine Release in the Rat Striatum and Nucleus Accumbens
Authors: De Deurwaerdère Philippe , Navailles Sylvia , Berg Kelly A , Clarke William P. , Spampinato Umberto
Published: March 2004

Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, usingin vivointracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2Creceptors to identify appropriate 5-HT2Creceptor ligands, we sought to determine whether the property of 5-HT2Creceptors to spontaneously activate intracellular signaling pathwaysin vitro(constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbensin vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2Cinverse agonist. Its effect was prevented by SB 242084.In vivo, SB 206553 (1–10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1–10 mg/kg), and the 5-HT2CagonistS-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3–3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1Aagonist (±)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the firstin vivoevidence that constitutive activity of the 5-HT2Creceptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity.
Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease
Authors: Friedlich Avi L. , Lee Joo-Yong , van Groen Thomas , Cherny Robert A. , Volitakis Irene , Cole Toby B. , Palmiter Richard D. , Koh Jae-Young , Bush Ashley I.
Published: March 2004

Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal β-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular β-amyloid deposition remains unclear. Here, we identify for the first time an exchangeable pool of Zn2+in the cerebrovascular wall of normal mice. This histochemically reactive Zn2+is enriched in CAA in a transgenic mouse model of AD (Tg2576), and a dramatic reduction of CAA occurs after targeted disruption of theZnt3gene in these mice. Also, inZnt3knock-out mice, the amount of exchangeable Zn2+[detected byN-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide (TFL-Zn)] in the perivascular space was significantly decreased in the neocortex but not in peripheral organs. ZnT3 was not detected in the cerebral vessel walls or in blood components of wild-type mice. Thus, synaptic ZnT3 activity may promote CAA by indirectly raising exchangeable Zn2+concentrations in the perivascular spaces of the brain.
Methamphetamine Increases Dopamine Transporter Higher Molecular Weight Complex Formation via a Dopamine- and Hyperthermia-Associated Mechanism
Authors: Baucum Anthony J. , Rau Kristi S. , Riddle Evan L. , Hanson Glen R. , Fleckenstein Annette E.
Published: March 2004

Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (>170 kDa) DAT-associated protein complexes 24–48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor α-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent β-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formationin vivoand that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.
Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid β-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5
Authors: Wang Qinwen , Walsh Dominic M. , Rowan Michael J. , Selkoe Dennis J. , Anwyl Roger
Published: March 2004

The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid β-peptide (Aβ)1–42on the induction of long-term potentiation (LTP) were investigated in the medial perforant path to dentate granule cell synapses in hippocampal slices. Synthetic and cell-derived Aβ strongly inhibited high-frequency stimulation (HFS)-induced LTP at peak HFS and 1 hr after HFS. Cell-derived Aβ was much more potent than synthetic Aβ at inhibiting LTP induction, with threshold concentrations of ∼1 and 100–200 nm, respectively. The involvement of various kinases in Aβ-mediated inhibition of LTP induction was investigated by applying Aβ in the presence of inhibitors of these kinases. The c-Jun N-terminal kinase (JNK) inhibitor JNKI prevented the block of LTP induction by both synthetic and cell-derived Aβ. The block of LTP induced by synthetic Aβ was also prevented by the JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-one, the cyclin-dependent kinase 5 (Cdk5) inhibitors butyrolactone and roscovitine, and the p38 MAP kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole but not by the p42–p44 MAP kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene. The group I–group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid and the mGluR5 antagonist methyl-6-(phenylethynyl)pyridine prevented the block of LTP induction by Aβ. However, theα7 nicotinic ACh receptor antagonist methylcaconatine did not prevent the inhibition of LTP induction by Aβ. These studies provide evidence that the Aβ-mediated inhibition of LTP induction involves stimulation of the kinases JNK, Cdk5, and p38 MAPK after the activation of both the Aβ receptor(s) and mGluR5.
Extracellular Signal-Regulated Kinases Regulate Dendritic Growth in Rat Sympathetic Neurons
Authors: Kim In-Jung , Drahushuk Karen M. , Kim Woo-Yang , Gonsiorek Eugene A. , Lein Pamela , Andres Douglas A. , Higgins Dennis
Published: March 2004

NGF activates several signaling cascades in sympathetic neurons. We examined how activation of one of these cascades, the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase pathway, affects dendritic growth in these cells. Dendritic growth was induced by exposure to NGF and BMP-7 (bone morphogenetic protein-7). Exposure to NGF increased phosphorylation of ERK1/2. Unexpectedly, two MEK (MAP kinase kinase) inhibitors (PD 98059 and U 0126) enhanced dendritic growth, and a ligand, basic FGF, that activates the ERK pathway inhibited the growth of these processes. The enhancement of dendritic growth by PD 98059 was associated with an increase in the number of axo-dendritic synapses, and it appeared to represent a specific morphogenic effect because neither axonal growth nor cell survival was affected. In addition, increased dendritic growth was not observed after exposure to inhibitors of other signaling pathways, including the phosphatidylinositol-3-kinase inhibitor LY 294002. Dendritic growth was also increased in cells transfected with dominant-negative mutants of MEK1 and ERK2 but not with dominant-negative mutants of MEK5 and ERK5, suggesting that ERK1/2 is the primary mediator of this effect. Exposure to BMP-7 induces nuclear translocation of Smad1 (Sma- and Mad-related protein 1), and PD 98059 treatment potentiated nuclear accumulation of Smad-1 induced by BMP-7 in sympathetic neurons, suggesting a direct enhancement of BMP signaling in cells treated with an MEK inhibitor. These observations indicate that one of the signaling cascades activated by NGF can act in an antagonistic manner in sympathetic neurons and reduce the dendritic growth induced by other NGF-sensitive pathways.
Visual Feedback Control of Hand Movements
Authors: Saunders Jeffrey A. , Knill David C.
Published: March 2004

We investigated what visual information contributes to on-line control of hand movements. It has been suggested that motion information predominates early in movements but that position information predominates for endpoint control. We used a perturbation method to determine the relative contributions of motion and position information to feedback control. Subjects reached to touch targets in a dynamic virtual environment in which subjects viewed a moving virtual fingertip in place of their own finger. On some trials, we perturbed the virtual fingertip while it moved behind an occluder. Subjects responded to perturbations that selectively altered either motion or position information, indicating that both contribute to feedback control. Responses to perturbations that changed both motion and position information were consistent with superimposed motion-based and position-based control. Results were well fit by a control model that optimally integrates noisy, delayed sensory feedback about both motion and position to estimate hand state.
Representation of Angles Embedded within Contour Stimuli in Area V2 of Macaque Monkeys
Authors: Ito Minami , Komatsu Hidehiko
Published: March 2004

Angles and junctions embedded within contours are important features to represent the shape of objects. To study the neuronal basis to extract these features, we conducted extracellular recordings while two macaque monkeys performed a fixation task. Angle stimuli were the combination of two straight half-lines larger than the size of the classical receptive fields (CRFs). Each line was drawn from the center to outside the CRFs in 1 of 12 directions, so that the stimuli passed through the CRFs and formed angles at the center of the CRFs. Of 114 neurons recorded from the superficial layer of area V2, 91 neurons showed selective responses to these angle stimuli. Of these, 41 neurons (36.0%) showed selective responses to wide angles between 60° and 150° that were distinct from responses to straight lines or sharp angles (30°). Responses were highly selective to a particular angle in approximately one-fourth of neurons. When we tested the selectivity of the same neurons to individual half-lines, the preferred direction was more or less consistent with one or two components of the optimal angle stimuli. These results suggest that the selectivity of the neurons depends on both the combination of two components and the responses to individual components. Angle-selective V2 neurons are unlikely to be specific angle detectors, because the magnitude of their responses to the optimal angle was indistinguishable from that to the optimal half-lines. We suggest that the extraction of information of angles embedded within contour stimuli may start in area V2.
FoxP2Expression in Avian Vocal Learners and Non-Learners
Authors: Haesler Sebastian , Wada Kazuhiro , Nshdejan A. , Morrisey Edward E. , Lints Thierry , Jarvis Eric D. , Scharff Constance
Published: March 2004

Most vertebrates communicate acoustically, but few, among them humans, dolphins and whales, bats, and three orders of birds, learn this trait.FOXP2is the first gene linked to human speech and has been the target of positive selection during recent primate evolution. To test whether the expression pattern ofFOXP2is consistent with a role in learned vocal communication, we cloned zebra finchFoxP2and its close relativeFoxP1and compared mRNA and protein distribution in developing and adult brains of a variety of avian vocal learners and non-learners, and a crocodile. We found that the protein sequence of zebra finch FoxP2 is 98% identical with mouse and human FOXP2. In the avian and crocodilian forebrain,FoxP2was expressed predominantly in the striatum, a basal ganglia brain region affected in patients withFOXP2mutations. Strikingly, in zebra finches, the striatal nucleus Area X, necessary for vocal learning, expressed moreFoxP2than the surrounding tissue at post-hatch days 35 and 50, when vocal learning occurs. In adult canaries,FoxP2expression in Area X differed seasonally; moreFoxP2expression was associated with times when song becomes unstable. In adult chickadees, strawberry finches, song sparrows, and Bengalese finches, Area X expressedFoxP2to different degrees. Non-telencephalic regions in both vocal learning and non-learning birds, and in crocodiles, were less variable in expression and comparable with regions that expressFOXP2in human and rodent brains. We conclude that differential expression ofFoxP2in avian vocal learners might be associated with vocal plasticity.
Integration of Contour and Terminator Signals in Visual Area MT of Alert Macaque
Authors: Pack Christopher C. , Gartland Andrew J. , Born Richard T.
Published: March 2004

The integration of visual information is a critical task that is performed by neurons in the extrastriate cortex of the primate brain. For motion signals, integration is complicated by the geometry of the visual world, which renders some velocity measurements ambiguous and others incorrect. The ambiguity arises because neurons in the early stages of visual processing have small receptive fields, which can only recover the component of motion perpendicular to the orientation of a contour (the aperture problem). Unambiguous motion signals are located at end points and corners, which are referred to as terminators. However, when an object moves behind an occluding surface, motion measurements made at the terminators formed by the intersection of the object and the occluder are generally not consistent with the direction of object motion. To study how cortical neurons integrate these different motion cues, we used variations on the classic “barber pole” stimulus and measured the responses of neurons in the middle temporal area (MT or V5) of extrastriate cortex of alert macaque monkeys. Our results show that MT neurons are more strongly influenced by the unambiguous motion signals generated by terminators than to the ambiguous signals generated by contours. Furthermore, these neurons respond better to terminators that are intrinsic to a moving object than to those that are accidents of occlusion. V1 neurons show similar response patterns to local cues (contours and terminators), but for large stimuli, they do not reflect the global motion direction computed by MT neurons. These observations are consistent with psychophysical findings that show that our perception of moving objects often depends on the motion of terminators.
Common Sensory Inputs and Differential Excitability of Segmentally Homologous Reticulospinal Neurons in the Hindbrain
Authors: Nakayama Hisako , Oda Yoichi
Published: March 2004

In the hindbrain of zebrafish and goldfish, reticulospinal (RS) neurons are arranged in seven segments, with segmental homologs in adjacent segments. The Mauthner cell (M-cell) in the fourth segment (r4) is known to trigger fast escape behavior. Its serial homologs, MiD2cm in r5 and MiD3cm in r6, are predicted to contribute to this behavior, which can be evoked by head-tap stimuli. However, little is known about their input–output properties. Therefore, we studied afferent projections from the auditory posterior eighth nerve (pVIIIn) and firing properties of MiD2cm and MiD3cm for comparison with the M-cell in adult goldfish. Labeling of RS neurons and the pVIIIn afferents with fluorescent tracers showed that the pVIIIn projected to r4–r6. Tone burst and electrical stimulation of the pVIIIn evoked EPSPs in the M-cell, MiD2cm, and MiD3cm. Stepwise depolarization typically elicited a single spike at the onset in the M-cell but repetitive spiking in MiD2cm and MiD3cm. This atypical property of the M-cell was mediated by dendrotoxin-I (DTX-I)-sensitive voltage-gated potassium channels together with recurrent inhibition, because combined application of DTX-I, strychnine, and bicuculline led to continuous repetitive firing in M-cells. The M-cell but not MiD2cm or MiD3cm expressed Kv1.2, a DTX-I-sensitive potassium channel subunit. Thus, the M-cell and its segmental homologs may sense common auditory information but send different outputs to the spinal circuits to control adaptive escape behavior.
Modification of Saccades Evoked by Stimulation of Frontal Eye Field during Invisible Target Tracking
Authors: Barborica Andrei , Ferrera Vincent P.
Published: March 2004

We investigated the internal representation of invisible moving targets using electrical microstimulation in the prefrontal cortex. Monkeys were trained to make saccades to the extrapolated position of a small moving target that was rendered invisible during part of its trajectory. Although the target was invisible, involuntary saccades were evoked by electrical microstimulation of the frontal eye field. Stimulation was applied at different times relative to the disappearance of the target while the monkey fixated. When stimulation was applied immediately after target disappearance, electrically evoked saccades were biased toward the starting point of the target trajectory. When stimulation was applied later in the trial, evoked saccades were biased toward the end of the trajectory. The bias in evoked saccade direction changed continuously over time. The magnitude and statistical significance of the electrically evoked saccade deviation depended on the accuracy of the monkeys' voluntary saccades relative to the invisible target. The results suggest that covert tracking is accompanied by a continuously shifting saccade plan that moves along the target path.
Human Ability to Scale and Discriminate Forces Typical of Those Occurring during Grasp and Manipulation
Authors: Wheat Heather E. , Salo Lauren M. , Goodwin Antony W.
Published: March 2004

When humans manipulate objects, the sensorimotor system coordinates three-dimensional forces to optimize and maintain grasp stability. To do this, the CNS requires precise information about the magnitude and direction of load force (tangential to skin surface) plus feedback about grip force (normal to skin). Previous studies have shown that there is rapid, precise coordination between grip and load forces that deteriorates with digital nerve block. Obviously, mechanoreceptive afferents innervating fingerpad skin contribute essential information. We quantify human capacity to scale tangential and normal forces using only cutaneous information. Our paradigm simulated natural manipulations (a force tangential to the skin superimposed on an indenting force normal to the skin). Precisely controlled forces were applied by a custom-built stimulator to an immobilized fingerpad. Using magnitude estimation, subjects (n= 8) scaled the magnitude of tangential force (0.25–2.8 N) in two experiments (normal force, 2.5 and 4 N, respectively). Performance was unaffected by normal force magnitude and tangential force direction. Moreover, when both normal (2–4 N) and tangential forces were varied in a randomized-block factorial design, the relationship between applied and perceived tangential force remained near linear, with a minor but statistically significant nonlinearity. Our subjects could also discriminate small differences in tangential force, and this was the case for two different reference stimuli. In both cases, the Weber fraction was 0.16. Finally, scaling functions for magnitude estimates of normal force (1–5 N) were also approximately linear. These data show that the cutaneous afferents provide a wealth of precise information about both normal and tangential force.
Abnormality of G-Protein-Coupled Receptor Kinases at Prodromal and Early Stages of Alzheimer's Disease: An Association with Early β-Amyloid Accumulation
Authors: Suo Zhiming , Wu Min , Citron Bruce A. , Wong Gwendolyn T. , Festoff Barry W.
Published: March 2004

Overwhelming evidence indicates that the effects of β-amyloid (Aβ) are dose dependent bothin vitroandin vivo, which implies that Aβ is not directly detrimental to brain cells until it reaches a threshold concentration. In an effort to understand early Alzheimer's disease (AD) pathogenesis, this study focused on the effects of subthreshold soluble Aβ and the underlying molecular mechanisms in murine microglial cells and an AD transgenic mouse model. We found that there were two phases of dose-dependent Aβ effects on microglial cells: at the threshold of 5 μmand above, Aβ directly induced tumor necrosis factor-α (TNF-α) release, and at subthreshold doses, Aβ indirectly potentiated TNF-α release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold Aβ pretreatmentin vitroreduced membrane GPCR kinase-2/5 (GRK2/5), which led to retarded GPCR desensitization, prolonged GPCR signaling, and cellular hyperactivity to GPCR agonists. Temporal analysis in an early-onset AD transgenic model, CRND8 mice, revealed that the membrane (functional) GRK2/5 in brain cortices were significantly reduced. More importantly, such a GRK abnormality took place before cognitive decline and changed in a manner corresponding with the mild to moderate soluble Aβ accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold Aβ and GRK dysfunction, it also demonstrated that the GRK abnormalityin vivooccurs at prodromal and early stages of AD.
Fiber Types of the Intrinsic Whisker Muscle and Whisking Behavior
Authors: Jin Tae-Eun , Witzemann Veit , Brecht Michael
Published: March 2004

Some rodent species show rhythmic bouts of vibrissal protractions and retractions, referred to as whisking, that are among the fastest movements performed by mammals. To better understand the muscular basis of whisking, we compared (1) whisker movements of two whisking species (mouse, rat) and a non-whisking species (guinea pig), (2) the muscle fiber composition of intrinsic whisker muscles of whisking and a non-whisking species, and (3) the muscle fiber composition of intrinsic whisker muscles and of selected skeletal muscles. Using high-speed videography, we found that mice, rats, and guinea pigs can generate fast and large-amplitude whisker movements. Guinea pigs do not show bouts of fast, strictly rhythmic whisker movements, and the average speed of their whisker movements is much lower than in mice and rats. Analysis of mRNA expression of myosin heavy chain isoforms, myofibrillar ATPase staining, and antibody labeling indicate that in all three species intrinsic whisker muscles are composed predominantly of type 2B muscle fibers. Intrinsic whisker muscles of mice consisted of type 2B (≥90%) and type 2D fibers. In rats we observed, in addition to type 2B/2D fibers, ∼10% of slow type 1 fibers, and in guinea pigs we observed ∼3% of slow type 1 fibers and 20% of type 2A fibers. Type 2B fibers have high levels of anaerobic glycolytic enzymes providing a rapid source of ATP and high maximum velocity of contraction but are less fatigue resistant than other muscle fiber types. The high percentage of type 2B fibers distinguishes the intrinsic whisker musculature from skeletal muscles and may have evolved for fast scanning of the sensory environment.
Differential Distribution and Function of Hyperpolarization-Activated Channels in Sensory Neurons and Mechanosensitive Fibers
Authors: Doan Thanh N. , Stephans Kevin , Ramirez Angelina N. , Glazebrook Patricia A. , Andresen Michael C. , Kunze Diana L.
Published: March 2004

Sensory neurons express hyperpolarization-activated currents (IH) that differ in magnitude and kinetics within the populations. We investigated the structural basis for these differences and explored the functional role of theIHchannels in sensory neurons isolated from rat nodose ganglia. Immunohistochemical studies demonstrated a differential distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) protein (HCN1, HCN2, HCN4) in sensory neurons and peripheral terminals. HCN2 and HCN4 immunoreactivity was present in all nodose neurons. In contrast, only 20% of the total population expressed HCN1 immunoreactivity. HCN1 did not colocalize with IB4 (a marker for C-type neurons), and only 15% of HCN1-positive neurons colocalized with immunoreactivity for the vanilloid receptor VR1, another protein associated primarily with C-type neurons. Therefore, most HCN1-containing neurons were A-type neurons. In further support, HCN1 was present in the mechanosensitive terminals of myelinated but not unmyelinated sensory fibers, whereas HCN2 and HCN4 were present in receptor terminals of both myelinated and unmyelinated fibers. In voltage-clamp studies, cell permeant cAMP analogs shifted the activation curve forIHto depolarized potentials in C-type neurons but not A-type neurons. In current-clamp recording, CsCl, which inhibits onlyIHin nodose neurons, hyperpolarized the resting membrane potential from –63 ± 1 to –73 ± 2 mV and nearly doubled the input resistance from 1.3 to 2.2 GΩ. In addition, action potentials were initiated at lower depolarizing current injections in the presence of CsCl. At the sensory receptor terminal, CsCl decreased the threshold pressure for initiation of mechanoreceptor discharge. Therefore, elimination of theIHincreases excitability of both the soma and the peripheral sensory terminals.
A Transgenic Marker for Newly Born Granule Cells in Dentate Gyrus
Authors: Overstreet Linda S. , Hentges Shane T. , Bumaschny Viviana F. , de Souza Flavio S. J. , Smart James L. , Santangelo Andrea M. , Low Malcolm J. , Westbrook Gary L. , Rubinstein Marcelo
Published: March 2004

Neurogenesis in the dentate gyrus continues into adulthood, yet little is known about the function of newly born neurons or how they integrate into an existing network of mature neurons. We made transgenic mice that selectively and transiently express enhanced green fluorescent protein (EGFP) in newly born granule cells of the dentate gyrus under the transcriptional control of proopiomelanocortin (POMC) genomic sequences. Analysis of transgenic pedigrees with truncation or deletion mutations indicated that EGFP expression in the dentate gyrus required cryptic POMC promoter regions dispensable for arcuate hypothalamic or pituitary expression. Unlike arcuate neurons, dentate granule cells did not express the endogenous POMC gene. EGFP-positive neurons had immature properties, including short spineless dendrites and small action potentials. Colocalization with bromodeoxyuridine indicated that EGFP-labeled granule cells were ∼2 weeks postmitotic. EGFP-labeled cells expressed markers for immature granule cells but not the glial marker GFAP. The number of EGFP-labeled neurons declined with age and increased with exercise, paralleling neurogenesis. Our results indicate that POMC-EGFP marks immature granule cells and that adult-generated granule cells integrate quite slowly into the hippocampal circuitry.
High-ResolutionIn VivoImaging of Hippocampal Dendrites and Spines
Authors: Mizrahi Adi , Crowley Justin C. , Shtoyerman Eran , Katz Lawrence C.
Published: March 2004

Structural changes in hippocampal dendrites and dendritic spines are thought to be a consequence of a wide range of experience- and activity-dependent manipulations. We explored the dynamics of hippocampal dendritic spinesin vivoby developing a surgical preparation of the adult mouse brain that enabled two-photon imaging of fluorescently labeled CA1 pyramidal neurons. Dendritic trees and spines were repeatedly visualized over many hours in exquisite detail. We tested spine stability under both control conditions and during prolonged epileptic seizures. Remarkably, spines remained structurally stable after 30 min of experimental induction of epileptic seizures. Spines began to disappear only several hours after induction of epileptic activity. We thus demonstrate that this technique provides a methodology for directin vivooptical studies of the intact mammalian hippocampus.
β1-Integrins Are Critical for Cerebellar Granule Cell Precursor Proliferation
Authors: Blaess Sandra , Graus-Porta Diana , Belvindrah Richard , Radakovits Randor , Pons Sebastian , Littlewood-Evans Amanda , Senften Mathias , Guo Huailian , Li Yuqing , Miner Jeffrey H. , Reichardt Louis F. , Müller Ulrich
Published: March 2004

We have previously shown that mice with a CNS restricted knock-out of the integrin β1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adultItgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum ofItgb1-CNSko mice. In the absence of β1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely.In vitrostudies provide evidence thatβ1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin–Shh induced cell proliferation is dependent on β1 integrin expression in GCPs. Taken together, these data are consistent with a model in which β1 integrin expression in GCPs is required to recruit a laminin–Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.
Pavlovian Fear Conditioning Regulates Thr286Autophosphorylation of Ca2+/Calmodulin-Dependent Protein Kinase II at Lateral Amygdala Synapses
Authors: Rodrigues Sarina M. , Farb Claudia R. , Bauer Elizabeth P. , LeDoux Joseph E. , Schafe Glenn E.
Published: March 2004

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in synaptic plasticity and memory formation in a variety of learning systems and species. The present experiments examined the role of CaMKII in the circuitry underlying pavlovian fear conditioning. First, we reveal by immunocytochemical and tract-tracing methods that αCaMKII is postsynaptic to auditory thalamic inputs and colocalized with the NR2B subunit of the NMDA receptor. Furthermore, we show that fear conditioning results in an increase of the autophosphorylated (active) form of αCaMKII in lateral amygdala (LA) spines. Next, we demonstrate that intra-amygdala infusion of a CaMK inhibitor, 1-[NO-bis-1,5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl-4-phenylpiperazine, KN-62, dose-dependently impairs the acquisition, but not the expression, of auditory and contextual fear conditioning. Finally, in electrophysiological experiments, we demonstrate that an NMDA receptor-dependent form of long-term potentiation at thalamic input synapses to the LA is impaired by bath application of KN-62in vitro. Together, the results of these experiments provide the first comprehensive view of the role of CaMKII in the amygdala during fear conditioning.
Time Course of Information about Motion Direction in Visual Area MT of Macaque Monkeys
Authors: Osborne Leslie C. , Bialek William , Lisberger Stephen G.
Published: March 2004

We used the responses of neurons in extrastriate visual area MT to determine how well neural noise can be reduced by averaging the responses of neurons across time. For individual MT neurons, we calculated the time course of Shannon information about motion direction from sustained motion at constant velocities. Stimuli were random dot patterns moving at the preferred speed of the cell for 256 msec, in a direction chosen randomly with 15° increments. Information about motion direction calculated from cumulative spike count rose rapidly from the onset of the neural response and then saturated, reaching 80% of maximum information in the first 100 msec. Most of the early saturation of information could be attributed to correlated fluctuations in the spike counts of individual neurons on time scales in excess of 100 msec. Thus, temporal correlations limit the benefits of averaging across time, much as correlations among the responses of different neurons limit the benefits of averaging across large populations. Although information about direction was available quickly from MT neurons, the direction discrimination by individual MT neurons was poor, with mean thresholds above 30° in most neurons. We conclude that almost all available directional information could be extracted from the first few spikes of the response of the neuron, on a time scale comparable with the initiation of smooth pursuit eye movements. However, neural responses still must be pooled across the population in MT to account for the direction discrimination of the pursuit behavior.