bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms by which Dopamine Receptors May Influence Synaptic Plasticity
Authors: WOLF MARINA E. , MANGIAVACCHI SIMONA , SUN XIU
Published: January 2004

Abstract: While dopamine (DA) receptors mediate acute effects of amphetamine and cocaine, chronic drug administration produces many glutamate‐dependent adaptations, including LTP in reward‐related neuronal circuits. An important question presents itself: How do DA receptors influence glutamate‐dependent synaptic plasticity? Alterations in AMPA receptor phosphorylation and trafficking are critical for LTP. We hypothesize that D1 DA receptors modulate these processes, that chronic drug‐induced adaptations in D1 receptor signaling, therefore, trigger compensatory changes in AMPA receptor function, and that this ultimately contributes to inappropriate plasticity in addiction‐related neuronal circuits. Postnatal rat nucleus accumbens (NAc) cultures were used to study D1 receptor regulation of the AMPA receptor subunit GluR1. We found that D1 receptor stimulation enhances phosphorylation of GluR1 at the protein kinase A (PKA) site. Furthermore, D1 receptor stimulation increases GluR1 surface expression by increasing the rate of GluR1 externalization. The latter effect is prevented by the PKA inhibitors KT5720 and RpcAMPS, whereas the PKA activator SpcAMPS increases the rate of GluR1 externalization. These findings indicate that PKA phosphorylation is important in determining AMPA receptor surface expression and suggest a mechanism by which DA‐releasing drugs of abuse may directly tap into fundamental mechanisms that enable synaptic plasticity. A limitation of our current model is that there are no intrinsic glutamate neurons in the NAc and thus no glutamate synapses in NAc cultures. To address this problem, we have restored excitatory synaptic inputs to NAc neurons by co‐culturing them with prefrontal cortex (PFC) neurons. We are also studying GluR1 trafficking in PFC cultures. In both systems, synaptic AMPA receptors can be defined based on colocalization of GluR1 and the synaptic marker synaptobrevin. Preliminary results suggest that D1 receptor stimulation or PKA activation leads to increased surface GluR1 expression in PFC neurons but not to insertion into synaptic sites.
Glutamate and Depression
Authors: PAUL IAN A. , SKOLNICK PHIL
Published: January 2004

Abstract: The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N‐methyl‐d‐aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as positive modulators of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors have antidepressant‐like activity in a variety of preclinical models. Moreover, antidepressant‐like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.
Clinical Studies Implementing Glutamate Neurotransmission in Mood Disorders
Authors: SANACORA GERARD , ROTHMAN DOUGLAS L. , MASON GRAEME , KRYSTAL JOHN H.
Published: January 2004

Abstract: Emerging evidence suggests that the amino acid neurotransmitter systems are associated with the pathophysiology and treatment of mood disorders. Recent advances in the areas of molecular neurobiology, pharmacology, and magnetic resonance spectroscopy (MRS) now provide better tools to probe the function of the amino acid neurotransmitter systems and are affording us the opportunity to better investigate the relationship of these systems to mood disorders. Here we review the available literature in the field and suggest a possible pathophysiological model that may account for the many of the findings.
A Role for Noradrenergic Transmission in the Actions of Phencyclidine and the Antipsychotic and Antistress Effects of mGlu2/3 Receptor Agonists
Authors: SWANSON CHAD J. , SCHOEPP DARRYLE D.
Published: January 2004

Abstract: Evidence suggests that glutamatergic neuronal transmission is involved in psychiatric and neurological disorders and that drugs that target glutamate systems may serve as novel therapeutics in humans. For example, agonists for group II mGlu receptors (mGlu2 and mGlu3) have been shown to be anxiolytic in certain animal models and have shown promise in early human trials. mGlu2/3 receptor agonists also block the neurochemical and behavioral actions of psychotogens, such as phencyclidine and amphetamine in rodents, suggesting that they may be useful to treat psychosis in humans. Recently, we have used in vivo microdialysis and behavioral methods to further explore the potential antipsychotic and antistress actions of mGlu2/3 receptor agonists in rats. In subjects undergoing brain microdialysis of the nucleus accumbens shell, we have shown that LY379268 (3 mg/kg s.c.) (a systemically active mGlu2/3 receptor agonist) blocks PCP‐induced locomotor activations for ∼3 hours. In these animals, PCP‐induced dopamine release was reduced, but only in a transient fashion (15–75 min). PCP‐induced norepinephrine release was also reduced, but unlike dopamine, in a manner that was temporally correlated with the reduction of PCP‐induced behaviors. In separate experiments in rats not undergoing microdialysis, the α2‐adrenergic receptor agonist, clonidine, was shown to block PCP behaviors, and the norepinephrine reuptake inhibitor reboxetine was shown to exacerbate PCP‐induced ambulations. In the latter study, LY379268 pretreatment effectively reversed the PCP behaviors in both control and reboxetine‐treated animals. These data support a role for noradrenergic neurotransmission in the actions of drugs such as phencyclidine and suggest that stress pathways associated with these drugs can be normalized by mGlu2/3 receptor activation.
Glutamatergic Agents for Cocaine Dependence
Authors: DACKIS CHARLES , O'BRIEN CHARLES
Published: January 2004

Abstract: Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward‐related brain regions and evdence of cocaine‐induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate‐rich cortical regions. We review the involvement of glutamate in reward‐related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate‐enhancing agent with promise in the treatment of cocaine‐addicted individuals.
Structurally Dissimilar Antimanic Agents Modulate Synaptic Plasticity by Regulating AMPA Glutamate Receptor Subunit GluR1 Synaptic Expression
Authors: DU JING , GRAY NEIL A. , FALKE CYNTHIA , YUAN PEIXIONG , SZABO STEVEN , MANJI HUSSEINI K.
Published: January 2004

Abstract: A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse‐specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double‐immunostaining with anti‐GluR1 and anti‐synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.
Glutamate‐Mediated Plasticity in Corticostriatal Networks
Authors: KELLEY ANN E. , ANDRZEJEWSKI MATTHEW E. , BALDWIN ANNE E. , HERNANDEZ PEPE J. , PRATT WAYNE E.
Published: January 2004

Abstract:Little is known about how memories of new voluntary motor actions, also known as procedural memory, are formed at the molecular level. Our work examining acquisition of lever‐pressing for food in rats has shown that activation of glutamate NMDA receptors, within broadly distributed but interconnected regions (e.g., nucleus accumbens core, prefrontal cortex, basolateral amygdala), is critical for such learning to occur. This receptor stimulation triggers intracellular cascades that involve protein phosphorylation and new protein synthesis. In support of this idea, we have found that posttrial inhibition of protein synthesis in the ventral striatum impairs learning, whereas posttrial NMDA receptor blockade does not. More recent data show extension of this network to the central amygdala, where infusions of NMDA antagonists also impair learning. We hypothesize that activity in this distributed network (including dopaminergic activity and perhaps muscarinic cholinergic activity) computes coincident events and thus enhances the probability that temporally related actions and events (e.g., lever pressing and delivery of reward) become associated. Such basic mechanisms of plasticity within this reinforcement learning network also appear to be profoundly affected in addiction.
Evaluating Glutamatergic Transmission in Schizophrenia
Authors: TAMMINGA CAROL A. , LAHTI ADRIENNE C. , MEDOFF DEBORAH R. , GAO XUE‐MIN , HOLCOMB HENRY H.
Published: January 2004

Abstract: Our findings with schizophrenia and the glutamate system have relied on the characterization of the clinical response of patients to ketamine and their functional brain imaging response (rCBF) to the drug. Prior to the human studies reported here, we had evaluated the region activation characteristics and pharmacology of PCP and its congener MK 801 in animals. What I will report in this paper has been individually reported elsewhere but brought together here in a new synthesis.
Glutamatergic Animal Models of Schizophrenia
Authors: MOGHADDAM BITA , JACKSON MARK E.
Published: January 2004

Abstract: Several lines of evidence, including recent genetic linkage studies implicating susceptibility genes for schizophrenia, make a strong case that abnormal NMDA receptor‐mediated neurotransmission is a major locus for the pathophysiology of schizophrenia. Animal models that are relevant to putative NMDA dysfunction in schizophrenia have excellent face validity for several symptoms of schizophrenia and are important tools for the design of novel pharmacological intervention in schizophrenia. The present chapter includes a brief review of the utility of these models and the search for new medications that have the potential of normalizing glutamate neurotransmission in schizophrenia.
Anatomical Substrates for Glutamate‐Dopamine Interactions
Authors: SESACK SUSAN R. , CARR DAVID B. , OMELCHENKO NATALIA , PINTO ALINE
Published: January 2004

Abstract: For normal regulation of motor, affective, and cognitive functions, dopamine provides an essential modulation of glutamate transmission within multiple brain regions. This paper will review three principal anatomical substrates for such interactions. First, dopamine modulates the activity of glutamate neurons within the cerebral cortex. Evidence will be reviewed for dopamine regulation of pyramidal neurons in the prefrontal cortex via synaptic and extrasynaptic mechanisms and through indirect effects mediated by GABA cells. Second, glutamate neurons innervate dopamine cells within the ventral tegmental area. Evidence will be described for selective glutamate input from the prefrontal cortex or the brain stem tegmentum to different populations of dopamine cells. The third level of interaction occurs within target regions via convergent synaptic or extrasynaptic regulation of common neurons. Such convergence will be reviewed for the basal ganglia, prefrontal cortex, and amygdala. Together, these substrates for glutamate‐dopamine interactions provide several mechanisms for normal regulation of brain function. Sites of modulatory interaction between dopamine and glutamate also suggest circuit alterations that might contribute to the pathophysiology of mental health disorders and provide potential sites for therapeutic intervention in these conditions.
Physiology of the Eyelid Motor System
Authors: DELGADO‐GARCÍA JOSÉ M. , GRUART AGNÈS , TRIGO JOSÉ A.
Published: January 2004

The eyelid motor system represents an excellent experimental model for the study of reflex and learned motor responses. Eyelid responses can be recorded quantitatively with the search coil in a magnetic‐field technique. Stimuli able to evoke reflex blinks (air puffs, flashes of light, tones) can also be controlled quantitatively. Eyelid movements can be classified as spontaneous, passive (such as those following eye saccades), reflex, and acquired with classical conditioning procedures. Information is available regarding the firing activity of brainstem motoneuronal pools (abducens, accessory abducens, and facial motoneurons) involved in these types of eyelid response. In particular, facial motoneurons present different encoding properties for the generation of reflex against learned eyelid responses. In cats, accessory abducens motoneurons are involved only in reflex (but not in learned) blinks. The recent description of the complete organization of premotoneuronal pathways related to eyelid motorics opens new experimental possibilities for the study of this particular motor system.
Development of the Optokinetic Response in Macaques
Authors: DISTLER C. , HOFFMANN K.‐P.
Published: January 2004

In macaque monkeys, an optokinetic response (OKR) can be elicited monocularly both in temporonasal and, albeit weaker, in nasotemporal direction very early after birth. The further maturation of equal strengths of OKR in both directions depends on stimulus velocity: at low‐stimulus velocities (10‐20°/s) symmetry is reached at 3‐4 weeks of age, at higher‐stimulus velocities (40‐80°/s) it is reached only at 4‐5 months of age. Retinal slip neurons in the NOT‐DTN are direction selective for ipsiversive stimulus movement shortly after birth. Most of these neurons receive input from both eyes; many are dominated by the contralateral eye. Electrophysiological and neuroanatomical evidence suggests that the cortical input to the NOT‐DTN starts to become functional by postnatal day 14, at the latest. Based on these behavioral and physiological data, as well as on comparison with data from kittens and human infants, we hypothesize that the very early monocularly elicited bidirectional optokinetic response is due to the direct retinal input from both eyes to the NOT‐DTN. As the cortical projection matures, it gains more and more influence upon the response properties of retinal slip neurons in the NOT‐DTN, and the retinal influence gradually decreases.
GABAergic Neurons in the Rostral Mesencephalon of the Macaque Monkey That Control Vertical Eye Movements
Authors: HORN ANJA K.E. , HELMCHEN CHRISTOPH , WAHLE PETRA
Published: January 2004

The mesencephalic reticular formation is important for the generation of vertical eye movements, but up until now the location of inhibitory premotor neurons is not known in primates. With tract‐tracer methods combined with immunocytochemistry or in situ hybridization, we investigated the location of GABAergic premotor neurons in the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) and interstitial nucleus of Cajal (iC) in macaque monkeys. In the present work, only the premotor pathways of the downward pulling eye muscles, superior oblique (SO) and inferior rectus (IR), were studied. We found that very few, small GABAergic neurons are present in the riMLF, and none of them was found to project to the oculomotor nuclei, suggesting the presence of exclusively excitatory projections from the riMLF to the oculomotor neurons. However, in the iC, medium‐sized and large GABAergic neurons were identified projecting contralaterally to the SO and IR motoneurons, and presumably the iC of the other side. These commissural GABAergic projections are well suited to inhibit the SO and IR motoneurons and possibly premotor down‐burst‐tonic neurons during upward eye movements.
Shared Brainstem Pathways for Saccades and Smooth‐Pursuit Eye Movements
Authors: KELLER EDWARD L. , MISSAL MARCUS
Published: January 2004

A long‐standing belief holds that the saccadic and smooth‐pursuit eye movement systems are composed of largely separate premotor circuits, at least in the brainstem. One crucial prediction predicated on this belief is that the tonic discharge of omnipause neurons (OPNs), which are thought to be part of only the saccadic system, should not be modulated during pursuit eye movements. This report shows that the discharge of OPNs, in contradiction, is modulated downward during pursuit movements. In contrast to their behavior during saccades, where they pause completely for the duration of the movement, the downward modulation during pursuit did not totally silence OPNs. The depth of the downward modulation was correlated with the speed of the ongoing pursuit movement. Another type of cell, which we have named saccade/pursuit neurons, was recorded in the paramedian pontine reticular formation near the location of OPNs. This subpopulation of burst cells discharged a cascade of spikes for saccades in a preferred direction. They also displayed a lower‐frequency sustained discharge of spikes for the duration of pursuit in the same preferred direction. These data suggest a new type of combined model for the organization of the brainstem saccade/pursuit system. In this new combined model, the OPNs form a common inhibitory mechanism for both types of movements, and the saccade/pursuit neurons participate in the eye‐velocity modulation of OPN discharge or membrane polarization during either type of movement.
Mathematical Model Predicts Clinical Ocular Motor Syndromes
Authors: DIETERICH MARIANNE , GLASAUER STEFAN , BRANDT THOMAS
Published: January 2004

Clinical ocular motor syndromes were compared with ocular motor syndromes simulated by a mathematical model of the vestibuloocular reflex. The mathematical sensorimotor feedforward model of otolith control of three‐dimensional binocular eye position is based on relevant anatomical connections of the vestibuloocular reflex from the utricles to extraocular eye muscles. This is the first attempt to simulate static ocular motor syndromes for unilateral utricular or vestibular nerve failure, lesions of the vestibular nucleus, and lesions of the ascending vestibuloocular reflex pathways. Comparison of the predicted syndromes with those found in patients with unilateral disorders of the vestibular nerve (herpes zoster neuritis), the vestibular nucleus (medullary infarction), and the medial longitudinal fasciculus (pontine infarction) showed good agreement as regards the direction of horizontal, vertical, and torsional eye deviations. The ability of the model to simulate complete or incomplete failures of single elements or entire pathways allows us to pose direct clinical questions about as yet unknown ocular motor syndromes or about the localization of the damage as well as the mechanism involved in syndromes already known.
Examining the Paradoxical Relation between Number of Spikes and Gaze Amplitude in Abducens Neurons
Authors: LING L. , PHILLIPS J. O. , SIEBOLD C.
Published: January 2004

During head‐unrestrained gaze shifts, the number of spikes in the burst of abducens neurons increases with gaze amplitude, even when corrected for the component of the discharge related to the change in eye position. We examine this paradoxical dissociation between the number of spikes and eye amplitude, which occurs because eye amplitude in the head saturates for larger gaze shifts. First, we show that the extra spikes are unlikely to be due to antagonist muscle loading because the abducens neurons are completely silent during large gaze shifts when the muscle acts as an antagonist. Next, we divide the firing rate profile of abducens neurons into terms that represent signals related to eye position, velocity, and acceleration; a d.c. offset term specifying the firing associated with straight‐ahead gaze; and a slide term, which compensates for the zero of the oculomotor plant. Then we examine the contribution of each term to the number of spikes recorded. A comparison of the number of spikes with the integral of the fitted function, combining all of the terms, for the duration of the burst reveals that the simulation captures much of the actual data. However, even a model with a slide term cannot reproduce the nonlinear relationship of the number of spikes with amplitude that characterizes large gaze shifts.
Signal Processing of Semicircular Canal and Otolith Signals in the Vestibular Nuclei during Passive and Active Head Movements
Authors: McCREA ROBERT A. , LUAN HONGGE
Published: January 2004

The vestibular nerve sends signals to the brain that code the movement and position of the head in space. These signals are used by the brain for a variety of functions, including the control of reflex and voluntary movements and the construction of a sense of self‐motion. If many of these functions are to be carried out, a distinction must be made between sensory vestibular signals related to active head movements and those related to passive head movements. Current evidence is that the distinction occurs at an early stage of sensory processing in the brain, and the results are evident in the firing behavior of neurons in the vestibular nuclei that receive direct inputs from the vestibular nerve. Several specific examples of how sensory information related to passive and active head movements is transformed in the vestibular nuclei are discussed.
Role of the Dorsolateral Pontine Nucleus in Visual‐Vestibular Behavior
Authors: MUSTARI MICHAEL J. , ONO SEIJI , DAS VALLABH E. , TUSA RONALD J.
Published: January 2004

Visual‐vestibular behavior depends on signals traveling in climbing and mossy fiber pathways. Our study examined the role of the dorsolateral pontine nucleus (DLPN), a major component of the cortico‐ponto‐cerebellar mossy fiber pathway. DLPN neurons discharge in relation to smooth pursuit and during visual stimulation, indicating a potential role in visually guided motor learning in the vestibulo‐ocular reflex (VOR). We used unilateral muscimol injections to determine the potential role of the DLPN in short‐term VOR gain adaptation. Preinjection adaptation of VOR gain was achieved by sinusoidal rotation (0.2 Hz, 30°/s) for 2 h while the monkey viewed a stationary visual surround through either magnifying (×2) or minifying (×0.5) lenses. VOR gain increases (23‐32%) or decreases (22‐48%) as measured in complete darkness (VORd) were achieved. Following DLPN inactivation, initial acceleration of ipsilateral smooth‐pursuit was reduced by 35‐68%, and steady state gain was reduced by 32‐61%. Furthermore, the monkey's ability to cancel the VOR was impaired. In contrast to these significant deficits in ipsilesional smooth pursuit, the VOR during lens viewing was similar to that measured in preinjection control experiments. Similarly, following 2 h of adaptation, VORd gain adaptation was indistinguishable from control adaptation values for either ipsilesional or contralesional directions of head rotation. Our results suggest that visual error signals for short‐term adaptation of the VOR are derived from sources other than the DLPN, such as those from the accessory optic system.
Cerebellar Contribution to Saccades and Gaze Holding
Authors: GLASAUER STEFAN
Published: January 2004

The possible role of the cerebellum for the control of saccades and gaze holding is reconsidered using a computational modeling approach. As suggested by previous research, control of gaze holding is assumed to be enhanced by the floccular lobe, whereas control of the saccadic pulse is governed by the oculomotor vermis and fastigial nucleus. In the present work, a negative feedback loop via the paramedian tract neurons and the floccular lobe that contains a forward model of the oculomotor plant is supposed to enhance the time constant of the brainstem integrator. Control of saccadic amplitude is hypothesized to be achieved by a more complex network: feedforward projections from the superior colliculus via the nucleus reticularis tegmenti pontis to the oculomotor vermis and fastigial nucleus cooperate with feedback connections from excitatory burst neurons to overcome the sluggishness of the assumed local feedback loop formed via the superior colliculus and to implement inverse dynamics of downstream neural and motor processing.
Saccade Dysmetria during Functional Perturbation of the Caudal Fastigial Nucleus in the Monkey
Authors: GOFFART LAURENT , CHEN LONGTANG L. , SPARKS DAVID L.
Published: January 2004

The caudal fastigial nucleus (cFN) is the output nucleus by which the medioposterior cerebellum influences the brainstem saccade generator. In the monkey, inactivation of one cFN by local injection of muscimol impairs all saccades: ipsiversive saccades become hypermetric, contraversive saccades become hypometric, and saccades aimed at a target located in the upper or lower visual fields are biased horizontally toward the injected side. The pharmacological action of muscimol does not allow deficits that are presaccadic to be distinguished from those occurring during saccade execution. To determine the interval during which altered cFN activity affects saccade accuracy, we applied low‐frequency electrical microstimulation (100 Hz for 100‐300 ms) to the cFN of three monkeys while they were making saccades toward a flashed target. Similar to the effect of muscimol injection in cFN, low‐frequency microstimulation biased all saccades toward the ipsilateral side. When the microstimulation was applied after target flash and before saccade onset, the ipsilateral bias was absent. However, when the stimulation was applied during the ongoing movement, the saccade trajectory was biased toward the stimulated side. The muscimol‐like effect of the microstimulation suggests that the stimulation inhibits cFN activity, possibly by recruiting the inhibitory afferents from the cerebellar vermis (axons of Purkinje cells). Low‐frequency microstimulation had to be applied during the saccade to bias its trajectory. These data suggest that the ipsilateral horizontal bias observed during muscimol inactivation results from an imbalance in the intrasaccadic activity between the two caudal fastigial nuclei.
Multimodal Signal Integration in Vestibular Neurons of the Primate Fastigial Nucleus
Authors: BÜTTNER U. , GLASAUER S. , GLONTI L. , GUAN Y. , KIPIANI E. , KLEINE J. , SIEBOLD C. , TCHELIDZE T. , WILDEN A.
Published: January 2004

The rostral fastigial nucleus contains vestibular neurons, which presumably are involved in spinal mechanisms (neck, gait, posture) and which are not modulated with individual eye movements. Single‐unit recordings in the alert behaving monkey during natural stimulus conditions reveal that virtually all neurons demonstrate integration of several sensory inputs. This applies not only for canal‐canal and canal‐otolith interaction, but also for otolith‐otolith interaction. There is also some evidence that most neurons receive not only an utriculus but also a sacculus input. Furthermore, most neurons also respond to large‐field optokinetic stimulation, reflecting visual‐vestibular interaction. Neurons are also affected by the head on trunk position, which would allow these neurons to operate in a body‐centered rather than a head‐centered reference frame. These complex, multisensory features could permit fastigial nucleus neurons to rather specifically affect spinal motor functions.
Discharge Properties of Saccade‐Related Neurons in the Primate Fastigial Oculomotor Region
Authors: KLEINE J. F. , GUAN Y. , BÜTTNER U.
Published: January 2004

To clarify the mechanisms by which the cerebellar fastigial oculomotor region (FOR) contributes to the control of saccadic eye movements, we recorded saccade‐related FOR units in alert monkeys that made horizontal saccades between neighboring points of a three‐by‐three grid of target positions (16° amplitude). As in previous studies, FOR units exhibited saccade‐related bursts that occurred earlier for contralateral than for ipsilateral saccades. In addition, many FOR units reflected variations in the kinematic profiles of the saccades by exhibiting bursts with earlier onset and shorter peak latencies and higher peak discharge rates for fast as compared with slow saccades of the same amplitude. Moreover, reflecting systematic differences in saccade velocity rather than an influence of eye position itself, FOR bursts showed subtle but recurrent and, at the population level, statistically significant differences between centripetal and centrifugal saccades that closely paralleled the eye position dependency of saccadic dysmetria seen after FOR lesions. We conclude that the FOR output signal is not, as previously proposed, specifically related to the temporal properties of the saccade, but also contains information about saccade velocity. Moreover, the FOR output signal appears to change systematically depending on the actual kinematic properties of the saccade, in a way that would help to maintain saccadic accuracy.
Neurons in the Caudal Frontal Eye Fields of Monkeys Signal Three‐Dimensional Tracking
Authors: KURKIN SERGEI , TAKEICHI NORIHITO , AKAO TEPPEI , SATO FUMIE , FUKUSHIMA JUNKO , KANEKO CHRIS R.S. , FUKUSHIMA KIKURO
Published: January 2004

To maintain optimal clarity of objects moving in three dimensions, precise coordination of binocular eye movements is required in frontal‐eyed primates. Caudal parts of the frontal eye fields (FEFs) contain smooth pursuit neurons and the discharge of the majority of them is related to vergence eye movements as well. However, whether or not those pursuit neurons carry true binocular signals has not been tested critically. Using dichoptic stimuli that dissociate horizontal movements of the left and right eyes, we found that all pursuit‐related, FEF neurons tested carried binocular signals.
Prolonged Optokinetic Stimulation Generates Podokinetic after Rotation
Authors: GORDON CARLOS R. , TAL DROR , GADOTH NATAN , SHUPAK AVI
Published: January 2004

Previous studies showed that after prolonged stepping in place on the center of a rotating platform blindfolded subjects could no longer step in place on a firm floor. Instead, they invariably rotated themselves relative to space without perceiving their rotation, a phenomenon termed podokinetic after‐rotation (PKAR). We speculated that prolonged optokinetic stimulation (OK) alone may generate similar PKAR. The purpose of this study was to evaluate the effects of prolonged OK on podokinetic (PK) responses. Ten healthy subjects participated in the study. After a control stepping test, they were seated in a circular closed cage and randomly (right or left) exposed to an OK (45°/s) covering the whole visual field for 30 min. After this procedure, blindfolded subjects attempted to step in place on the stationary floor for 30 min. When trying to do so, all subjects turned relative to space without any perception of rotation. The direction of this optokinetically after‐rotation (oPKAR) was opposite of that of the direction of OK. Mean peak velocity of oPKAR was 7.8 ± 4.1°/s, and it was reached after approximately 6 min of stepping. After that, there was a progressive velocity decay, which exhibited a discharging time constant on the order of 42 min toward a final positive asymptote of 3.1°/s. We conclude that OK alone causes oPKAR. Long‐term OK probably charges a storage element for podomotor activity with a relatively prolonged time constant. This novel form of neural interaction and adaptive plasticity may have significant implications for the treatment of vestibular and parietal lobe disorders.
A Modeling Approach to the Human Spatial Orientation System
Authors: MERGNER T. , BECKER W.
Published: January 2004

The human spatial orientation system is highly complex and nonlinear. It is difficult, therefore, to arrive at an unequivocal model of the underlying processing by merely combining the known elementary mechanisms (“bottom‐up” approach); additional “top‐down” concepts are required to narrow the choice between several formally equivalent solutions. We here suggest a concept in which sensorimotor control is based on a meta‐level that provides an internal representation of the physical stimuli acting upon a subject (e.g., tilt of the support surface), whereas the classic reflex concept essentially proceeds from a direct coupling between physiological stimuli, sensors and actuators. At the hypothesized meta‐level, the axial body segments are represented as a stack of superimposed platforms with the lowermost platform (generally the feet) riding on a support surface that acts as the buttress for the subject's active movements. From the sensory point of view, this stack constitutes a system of nested references. This concept explains data from various experiments dealing with self‐ and object motion perception and body stabilization in a more exhaustive way than does the classic concept. In our view, it provides a robust, flexible, and modular framework for perception and action in space.
Evaluating Small Eye Movements in Patients with Saccadic Palsies
Authors: GARBUTT SIOBHAN , HARWOOD MARK R. , KUMAR ARUN N. , HAN YANNING H. , LEIGH R. JOHN
Published: January 2004

Slow saccades are an important diagnostic feature of a range of degenerative, metabolic, and genetic diseases of the nervous system. Many affected patients have difficulty initiating saccades, and the movements themselves may be small, making it difficult to make comparisons with control subjects. A large‐field optokinetic stimulus may elicit quick phases of nystagmus in patients who cannot initiate voluntary saccades, but these movements may also be small. We show that it is still possible to compare amplitude‐duration and amplitude‐peak velocity relations with controls if data are fit with a power function (rather than an exponential equation). When analyzed this way, the dynamic properties of small saccades and quick phases from patients with progressive supranuclear palsy (PSP) could be differentiated from fast movements made by patients with idiopathic Parkinson's disease or controls. Normal saccades show a fairly constant ratio: peak velocity/mean velocity (Q ∼1.6 for vertical saccades). This ratio was abnormally high (Q >3) for some larger saccades made by patients with PSP, suggesting that either these movements were not entirely saccadic or that they were composed of a series of small saccades.
Adaptations and Deficits in the Vestibulo‐Ocular Reflex after Peripheral Ocular Motor Palsies
Authors: SHARPE JAMES A. , TWEED DOUGLAS , WONG AGNES M.F.
Published: January 2004

Palsy of a nerve might be expected to lower vestibulo‐ocular reflex (VOR) responses in its fields of motion, but effects of peripheral neuromuscular disease were unknown. We recorded the VOR during sinusoidal head rotations in yaw, pitch, and roll at 0.5‐2 Hz and static torsional gain in 43 patients with unilateral nerve palsies. Sixth nerve palsy (n= 21) reduced both abduction and adduction VOR gains in darkness. In light, horizontal visually enhanced VOR (VVOR) gains were normal in moderate and mild palsy. In severe palsy, horizontal VVOR gains remained low in the paretic eye when it was fixating, whereas gains in the nonparetic eye became higher than normal. Third nerve palsy (n= 10) decreased VOR and VVOR gains during abduction, adduction, elevation, depression, extorsion, and intorsion. Fourth nerve palsy (n= 13) reduced VOR gains of the paretic eye during intorsion, extorsion, elevation, depression, abduction, and adduction, but in light vertical and horizontal VVOR gains were normal. In the nonparetic eye, all gains were normal. Reduced VOR gains in the direction of paretic muscles and also in the direction of their antagonists, together with normal gains in the nonparetic eye, indicate a selective adjustment to the antagonists of paretic muscles. Increase of VVOR gains to normal in the paretic eye, when used for fixation, without conjugate increase in gains in the occluded nonparetic eye, provides further evidence of selective adaptation for the paretic eye. Motions of the eyes after nerve palsies indicate monocular VOR adaptation in three dimensions.
Mortality After Cure of Testicular Seminoma
Authors: Zagars Gunar K. , Ballo Matthew T. , Lee Andrew K. , Strom Sara S.
Published: January 2004

Purpose

To determine the incidence of potentially treatment-related mortality in long-term survivors of testicular seminoma treated by orchiectomy and radiation therapy (XRT).

Patients and Methods

From all 477 men with stage I or II testicular seminoma treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX) with postorchiectomy megavoltage XRT between 1951 and 1999, 453 never sustained relapse of their disease. Long-term survival for these 453 men was evaluated with the person-years method to determine the standardized mortality ratio (SMR). SMRs were calculated for all causes of death, cardiac deaths, and cancer deaths using standard US data for males.

Results

After a median follow-up of 13.3 years, the 10-, 20-, 30-, and 40-year actuarial survival rates were 93%, 79%, 59%, and 26%, respectively. The all-cause SMR over the entire observation interval was 1.59 (99% CI, 1.21 to 2.04). The SMR was not excessive for the first 15 years of follow-up: SMR, 1.30 (95% CI, 0.93 to 1.77); but beyond 15 years the SMR was 1.85 (99% CI, 1.30 to 2.55). The overall cardiac-specific SMR was 1.61 (95% CI, 1.21 to 2.24). The cardiac SMR was significantly elevated only beyond 15 years (P < .01). The overall cancer-specific SMR was 1.91 (99% CI, 1.14 to 2.98). The cancer SMR was also significant only after 15 years of follow-up (P < .01). An increased mortality was evident in patients treated with and without mediastinal XRT.

Conclusion

Long-term survivors of seminoma treated with postorchiectomy XRT are at significant excess risk of death as a result of cardiac disease or second cancer. Management strategies that minimize these risks but maintain the excellent hitherto observed cure rates need to be actively pursued.
CEBPA Mutations in Younger Adults With Acute Myeloid Leukemia and Normal Cytogenetics: Prognostic Relevance and Analysis of Cooperating Mutations
Authors: Fröhling Stefan , Schlenk Richard F. , Stolze Ina , Bihlmayr Jörg , Benner Axel , Kreitmeier Sylvia , Tobis Karen , Döhner Hartmut , Döhner Konstanze
Published: January 2004

Purpose

To assess the prognostic relevance of mutations in the CEBPA gene encoding CCAAT/enhancer binding protein alpha (C/EBPα) in a large prospective series of younger adults with acute myeloid leukemia (AML) and normal cytogenetics.

Patients and Methods

The entire CEBPA coding region was sequenced in diagnostic samples from 236 AML patients 16 to 60 years of age with normal cytogenetics who were uniformly treated on two consecutive protocols of the AML Study Group Ulm, and CEBPA mutation status was correlated with clinical outcome.

Results

CEBPA mutations were detected in 36 (15%) of 236 patients. Twenty-one (9%) of 236 patients had mutations predicted to result in loss of C/EBPα function. Remission duration and overall survival (OS) were significantly longer for the 36 patients with CEBPA mutations (P = .01 and P = .05, respectively). On multivariate analysis, wild-type CEBPA was an independent prognostic marker affecting remission duration (hazard ratio, 2.85; P = .01) and OS (hazard ratio, 1.87; P = .04). Analysis of cooperating mutations (both types of activating FLT3 mutations and MLL partial tandem duplications) showed that FLT3 mutations had no significant prognostic influence in patients with CEBPA mutations. Furthermore, there was no significant overlap between the subgroup of patients with CEBPA mutation with predicted loss of C/EBPα function and patients with FLT3 or MLL mutations, suggesting that CEBPA loss-of-function mutations define a distinct biologic subclass of AML with normal cytogenetics.

Conclusion

Mutant CEBPA predicts favorable prognosis and may improve risk stratification in AML patients with normal cytogenetics.
Trans-Activation of Mutant Follicle-Stimulating Hormone Receptors Selectively Generates Only One of Two Hormone Signals
Authors: Ji Inhae , Lee ChangWoo , Jeoung MyoungKun , Koo YongBum , Sievert Gail A. , Ji Tae H.
Published: January 2004

Previously, we reported that a liganded LH receptor (LHR) is capable of activating itself (cis-activation) and other nonliganded LHRs to induce cAMP (trans-activation). Trans-activation of the LHR raises two crucial questions. Is trans-activation unique to LHR or common to other G protein-coupled receptors? Does trans-activation stimulate phospholipase Cβ as it does adenylyl cyclase? To address these questions, two types of novel FSH receptors (FSHRs) were constructed, one defective in hormone binding and the other defective in signal generation. The FSHR, a G protein-coupled receptor, comprises two major domains, the N-terminal extracellular exodomain that binds the hormone and the membrane-associated endodomain that generates the hormone signals. For signal defective receptors, the exodomain was attached to glycosyl phosphatidylinositol (ExoGPI) or the transmembrane domain of CD8 immune receptor (ExoCD). ExoGPI and ExoCD can trans-activate another nonliganded FSH. Surprisingly, the trans-activation generates a signal to activate either adenylyl cyclase or phospholipase Cβ, but not both. These results indicate that trans-activation in these mutant receptors is selective and limited in signal generation, thus providing new approaches to investigating the generation of different hormone signals and a novel means to selectively generate a particular hormone signal. Our data also suggest that the FSHR’s exodomain could not trans-activate LHR.
DrosophiladMyc is required for ovary cell growth and endoreplication
Authors: Maines Jean Z. , Stevens Leslie M. , Tong Xianglan , Stein David
Published: January 2004

Although the Myc oncogene has long been known to play a role in many human cancers, the mechanisms that mediate its effects in both normal cells and cancer cells are not fully understood. We have initiated a genetic analysis of the Drosophila homolog of the Myc oncoprotein (dMyc),which is encoded by the dm locus. We carried out mosaic analysis to elucidate the functions of dMyc in the germline and somatic cells of the ovary during oogenesis, a process that involves cell proliferation, differentiation and growth. Germline and somatic follicle cells mutant for dm exhibit a profound decrease in their ability to grow and to carry out endoreplication,a modified cell cycle in which DNA replication occurs in the absence of cell division. In contrast to its dramatic effects on growth and endoreplication,dMyc is dispensable for the mitotic division cycles of both germline and somatic components of the ovary. Surprisingly, despite their impaired ability to endoreplicate, dm mutant follicle cells appeared to carry out chorion gene amplification normally. Furthermore, in germline cysts in which the dm mutant cells comprised only a subset of the 16-cell cluster,we observed strictly cell-autonomous growth defects. However, in cases in which the entire germline cyst or the whole follicular epithelium was mutant for dm, the growth of the entire follicle, including the wild-type cells, was delayed. This observation indicates the existence of a signaling mechanism that acts to coordinate the growth rates of the germline and somatic components of the follicle. In summary, dMyc plays an essential role in promoting the rapid growth that must occur in both the germline and the surrounding follicle cells for oogenesis to proceed.
TheSp8zinc-finger transcription factor is involved in allometric growth of the limbs in the beetle Tribolium castaneum
Authors: Beermann Anke , Aranda Manuel , Schröder Reinhard
Published: January 2004

Members of the Sp gene family are involved in a variety of developmental processes in both vertebrates and invertebrates. We identified the ortholog of the Drosophila Sp-1 gene in the red flour beetle Tribolium castaneum, termed T-Sp8 because of its close phylogenetic relationship to the vertebrate Sp8 genes. During early embryogenesis, T-Sp8 is seen in segmental stripes. During later stages, TSp8 is dynamically expressed in the limb buds of the Tribolium embryo. At the beginning of bud formation, TSp8 is uniformly expressed in all body appendages. As the limbs elongate, a ring pattern develops sequentially and the expression profile at the end of embryogenesis correlates with the final length of the appendage. In limbs that do not grow out like the labrum and the labium, T-Sp8 expression remains uniform, whereas a two-ring pattern develops in the longer antennae and the maxillae. In the legs that elongate even further, four rings of T-Sp8 expression can be seen at the end of leg development. The role of T-Sp8 for appendage development was tested using RNAi. Upon injection of double stranded T-Sp8 RNA, larvae develop with dwarfed appendages. Affected T-Sp8RNAi legs were tested for the presence of medial and distal positional values using the expression marker genes dachshund and Distal-less, respectively. The results show that a dwarfed TSp8RNAi leg consists of proximal,medial and distal parts and argues against T-Sp8 being a leg gap gene. Based on the differential expression pattern of T-Sp8 in the appendages of the head and the thorax and the RNAi phenotype, we hypothesise that T-Sp8 is involved in the regulation of limb-length in relation to body size - a process called allometric growth.