bluuebunny/crossref_metadata_2025 huggingface dataset:
Migration of cells into and out of peripheral nerve isografts in the peripheral and central nervous systems of the adult mouse
Authors: Symons Natalie A. , Danielsen Nils , Harvey Alan R.
Published: March 2003

Peripheral nerve (PN) isografts provide a favourable environment for axon regeneration after peripheral and central nervous system (CNS) injury, but definitive information on the extent of cellular intermixing between donor and host tissues is lacking. We wished to compare migration patterns in fresh and predegenerate PN grafts, and also compare the extent of cell migration after transplantation to peripheral nervous system (PNS) versus CNS. To discern how host and donor cells interact after PN transplantation, sciatic nerve segments were transplanted from inbred adult mice into PN defects (PN–PN grafts) or into lesioned cerebral cortex of opposite gender siblings. Migrating male cells were identified using a Y‐chromosome‐specific probe and in situ hybridization methods, and characterized immunohistochemically. The extent of donor and host cellular intermixing was similar in fresh and predegenerate PN–PN isografts. There was substantial intermixing of donor and host cells by 8 days. Many host cells migrating into epineurial regions of grafts were immunopositive for F4/80 (macrophages). The endoneurium of grafted PN was also colonized by host cells; some were F4/80+ but many were immunostained with S‐100 (Schwann cell marker). Donor S‐100+ Schwann cells rapidly migrated out into proximal and distal host PN and by 12 weeks were found at least 2 mm from the grafts. Endoneurial microvessels in grafts were mostly donor‐derived. By comparison, in male PN grafts to female CNS, even after 6 weeks few donor cells had migrated out into surrounding host cortex, despite the observation that almost all grafts contained regenerating axons and were thus attached to host CNS tissue.
Mobilization of the cell adhesion glycoprotein F3/contactin to axonal surfaces is activity dependent
Authors: Pierre Karin , Dupouy Bernard , Allard Michèle , Poulain Dominique A. , Theodosis Dionysia T.
Published: March 2003

F3/contactin is a cell adhesion/recognition molecule of the immunoglobulin superfamily implicated in axonal growth. We examined its subcellular distribution and mobilization to the cell surface in oxytocin‐ (OT‐) secreting neurons, which express it throughout life and the axons of which undergo activity‐dependent remodelling. This was performed in hypothalamic organotypic slice cultures containing OT neurons with properties of adult neurosecretory cells. Immunocytochemistry and immunoblot analysis confirmed that OT neurons express high levels of F3/contactin in vitro. Light and confocal microscopy of cultures that underwent double immunofluorescence after fixation showed F3/contactin immunoreactivity throughout the cytoplasm of OT somata, dendrites and axons, and also in non‐OT axons and in putative synaptic boutons which contacted OT neurons. By contrast, after treatment of live cultures with anti‐F3/contactin antibodies followed by double immunofluorescence for the glycoprotein and OT, F3/contactin immunoreactivity was visible only on the surface of axons, whether or not OT‐immunoreactivity was present. Because of its glycosylphosphatidyl‐inositol (GPI) linkage, F3/contactin can occur in a membrane‐bound or soluble form. As seen from immunocytochemistry of live cells and immunoblot analysis, treatment of cultures with a GPI‐specific phospholipase C (GPI‐PLC) resulted in loss of F3/contactin immunoreactivity from all cell surfaces. F3/contactin immunoreactivity reappeared on axonal surfaces within 5 h after enzyme washout. Such re‐expression was accelerated by neuronal activity facilitation (by K+ depolarization or γ‐aminobutyric acid (GABA)‐A receptor blockade with bicuculline) and inhibited by neuronal activity repression [by blockade of Ca2+ channels with Mn2+, Na+ channels with tetrodotoxin (TTX) or excitatory inputs with glutamate antagonists]. Our observations establish therefore that F3/contactin surface expression in hypothalamic neurons is polarized to the axons where it occurs mainly in a GPI‐linked form. We also provide direct evidence that externalization of F3/contactin depends on Ca2+ entry and neuronal electrical activity. Taken together with our earlier finding that the glycoprotein is localized in neurosecretory granules, we demonstrate that F3/contactin is mobilized to the axonal surface via the activity‐dependent regulated pathway, thus arriving at the correct place and time to intervene in activity‐dependent remodelling of axons.
Doublecortin expression in the adult rat telencephalon
Authors: Nacher Juan , Crespo Carlos , McEwen Bruce S.
Published: March 2003

Doublecortin (DCX) is a protein required for normal neuronal migration in the developing cerebral cortex, where it is widely expressed in both radially and tangentially migrating neuroblasts. Moreover, it has been observed in the adult rostral migratory stream, which contains the neuronal precursors traveling to the olfactory bulb. We have performed DCX immunocytochemistry in the adult rat brain to identify precisely the neuronal populations expressing this protein. Our observations confirm the presence of DCX immunoreactive cells with the characteristic morphology of migrating neuroblasts in the subventricular zone, rostral migratory stream and the main and accessory olfactory bulbs. We have also found putative migratory cells expressing DCX in regions were no adult neuronal migration has been described, as the corpus callosum, the piriform cortex layer III/endopiriform nucleus and the striatum. Surprisingly, many cells with the phenotype of differentiated neurons were DCX immunoreactive; e.g. certain granule neurons in the hilar border of the granular layer of the dentate gyrus, some neuronal types in the piriform cortex layer II, granule and periglomerular neurons in the main and accessory olfactory bulbs, and isolated cells in the striatum. Almost all DCX immunoreactive cells also express the polysialylated form of neural cell adhesion molecule and have a similar distribution to rat collapsin receptor‐mediated protein‐4, two molecules involved in neuronal structural plasticity. Given these results, we hypothesize that DCX expression in differentiated neurons could be related to its capacity for microtubule reorganization and that this fact could be linked to axonal outgrowth or synaptogenesis.
Regional pacemakers composed of multiple oscillator neurons in the rat suprachiasmatic nucleus
Authors: Nakamura Wataru , Honma Sato , Shirakawa Tetsuo , Honma Ken‐ichi
Published: March 2003

Regional specificities of the dorsal and ventral regions of the suprachiasmatic nucleus (SCN) were examined to elucidate the structure of multioscillator circadian organization. The circadian rhythms of arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) release, and of electrical activity of individual neurons were measured in an organotypic, static slice culture of the SCN obtained from neonatal rats. Five days after the start of culture, robust circadian rhythms were detected in AVP release with a peak located consistently at the middle of the original light phase, while the 24 h profiles of VIP release were either arrhythmic or rhythmic. In the latter case, a phase delay of 5–7 h was observed in the circadian peak from the AVP rhythm. Multi‐channel, extracellular recording revealed that 51 (76.1%) out of 67 firing neurons, examined in the SCN, showed circadian rhythms in their firing rate. The percentage of rhythmic neurons was significantly larger in the dorsal (86.8%) than in the ventral (62.1%) region of the SCN, where the AVP and VIP containing neurons predominate, respectively. Twenty‐seven percent of the firing rhythms were almost antiphasic from the majority of rhythms. There was no regional specificity in the distribution of the antiphasic rhythm. These findings, that the dorsal and ventral regions of the SCN both contain circadian pacemakers with different properties that regulate the AVP and VIP release separately, is probably due to differences in the number and, hence, the coupling strength of oscillating neurons.
Identification of corticosteroid‐responsive genes in rat hippocampus using serial analysis of gene expression
Authors: Datson Nicole A. , Van Der Perk Jeannette , De Kloet E. Ronald , Vreugdenhil Erno
Published: March 2003

Adrenal corticosteroids (CORT) have a profound effect on the function of the hippocampus. This is mediated in a coordinated manner by mineralocorticoid (MR) and glucocorticoid receptors (GR) via activation or repression of target genes. The aim of this study was to identify, using serial analysis of gene expression (SAGE), CORT‐responsive hippocampal genes regulated via MR and/or GR. SAGE profiles were compared under different conditions of CORT exposure, resulting in the identification of 203 CORT‐responsive genes that are involved in many different cellular processes like, energy expenditure and cellular metabolism; protein synthesis and turnover; signal transduction and neuronal connectivity and neurotransmission. Besides some previously identified CORT‐responsive genes, the majority of the genes identified in this study were novel. In situ hybridization revealed that six randomly chosen CORT‐responsive genes had distinct expression patterns in neurons of the hippocampus. In addition, using in situ hybridization, we confirmed that these six genes were indeed regulated by CORT, underscoring the validity of the SAGE data. Comparison of MR‐ and GR‐dependent expression profiles revealed that the majority of the CORT‐responsive genes were regulated either by activated MR or by activated GR, while only a few genes were responsive to both activated MR and GR. This indicates that the molecular basis for the differential effects of activated MR and GR is activation or repression of distinct, yet partially overlapping sets of genes. The putative CORT‐responsive genes identified here will provide insight into the molecular mechanisms underlying the differential and sometimes opposing effects of MR and GR on neuronal excitability, memory formation and behaviour as well as their role in neuronal protection and damage.
Rat microglial cells secrete predominantly the precursor of interleukin‐1β in response to lipopolysaccharide
Authors: Chauvet Nathalie , Palin Karine , Verrier Danielle , Poole Steve , Dantzer Robert , Lestage Jacques
Published: March 2003

Little is known on the forms of interleukin‐1β (IL‐1β) that are produced by microglial cells in the nervous system. Mixed glial cell cultures of rats produced IL‐1β in response to lipopolysaccharide (LPS). Using Western blot, pro‐IL‐1β was found to be localized both intracellularly and in the supernatant, whereas mature IL‐1β was found only in the supernatant but in lower quantities than pro‐IL‐1β. Immunocytochemistry confirmed that microglial cells are the exclusive source of IL‐1β. Blockade of the IL‐1β‐converting enzyme (ICE) by Tyr‐Val‐Ala‐Asp‐aldehyde (YVAD‐CHO) decreased the levels of mature IL‐1β but had no effect on pro‐IL‐1β. Release of pro‐IL‐1β was not associated with cell death nor with the extracellular release of ICE. Using gelatin zymography, glial cells were found to express constitutive matrix metalloproteinases (MMP) in the form of MMP‐2. Exposure to LPS induced MMP‐9 expression in a time‐dependent manner similar to the pro‐IL‐1β expression profile. MMP activation and inhibition experiments indicated a possible role of MMPs in the cleavage of pro‐IL‐1β but not in the generation of mature IL‐1β. Microglial cells share with macrophages the ability to release large amounts of pro‐IL‐1β of which the extracellular role remains to be determined.
Differential activation of hippocampus and amygdala following spatial learning under stress
Authors: Akirav Irit , Sandi Carmen , Richter‐Levin Gal
Published: March 2003

We examined the activation of memory‐related processes in the hippocampus and the amygdala following spatial learning under stress, in the rat. Animals were trained in a water maze in a massed spatial task under two stress conditions (cold and warm water). In the dorsal CA1, training was accompanied by increased phosphorylation of ERK2 only in animals that have acquired the task (irrespective of whether they were trained in cold or warm water). In the amygdala, significant activation of ERK2 was found only in animals that learned the task well under high levels of stress. Hence, the results suggest that the amygdala and the hippocampus are differentially activated following spatial learning, depending on the level of stress involved.
Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat
Authors: Oliver K. R. , Kane S. A. , Salvatore C. A. , Mallee J. J. , Kinsey A. M. , Koblan K. S. , Keyvan‐Fouladi N. , Heavens R. P. , Wainwright A. , Jacobson M. , Dickerson I. M. , Hill R. G.
Published: March 2003

Calcitonin gene‐related peptide (CGRP), adrenomedullin (ADM), amylin and calcitonin (CT) are structurally and functionally related neuropeptides. It has recently been shown that the molecular pharmacology of CGRP and ADM is determined by coexpression of one of three receptor activity‐modifying proteins (RAMPs) with calcitonin receptor‐like receptor (CRLR). Furthermore, RAMP proteins have also been shown to govern the pharmacology of the calcitonin receptor, which in association with RAMP1 or RAMP3, binds amylin with high affinity. In this study, we have cloned the rat RAMP family and characterized the pharmacology of rat CGRP and ADM receptors. Rat RAMP1, RAMP2 and RAMP3 shared 72%, 69% and 85% homology with their respective human homologues. As expected CRLR‐RAMP1 coexpression conferred sensitivity to CGRP, whilst association of RAMP2 or RAMP3 with CRLR conferred high affinity ADM binding. Using specific oligonucleotides we have determined the expression of RAMP1, RAMP2 and RAMP3 mRNAs in the rat central nervous system by in situ hybridization. The localization of RAMP mRNAs was heterogeneous. RAMP1 mRNA was predominantly expressed in cortex, caudate putamen and olfactory tubercles; RAMP2 mRNA was most abundant in hypothalamus; and RAMP3 was restrictively expressed in thalamic nuclei. Interestingly, in specific brain areas only a single RAMP mRNA was often detected, suggesting mutual exclusivity in expression. These data allow predictions to be made of where each RAMP protein may heterodimerize with its partner G‐protein‐coupled receptor(s) at the cellular level and consequently advance current understanding of cellular sites of action of CGRP, ADM, amylin and CT. Furthermore, these localization data suggest that the RAMP family may associate and modify the behaviour of other, as yet unidentified neurotransmitter receptors.
Pattern and component motion selectivity in cortical area PMLS of the cat
Authors: Li Bing , Chen Yao , Li Bao‐Wang , Wang Lian‐Hong , Diao Yun‐Cheng
Published: March 2003

Visual motion perception is one of the most prominent functions performed by the mammalian cerebral cortex. The moving images are commonly considered to be processed in two stages. The first‐stage neurons are sensitive to the motion of one‐dimensional orientated components, and their outputs are combined at the second stage to perceive the global motion of the whole pattern. Alternatively, the pattern motion may be signalled by monitoring a distinctive feature of the image, such as a line‐end or a corner. In the present study, a series of ‘random‐line’ patterns were used to measure the direction‐tuning responses of 138 neurons in the posteromedial lateral suprasylvian area of the cat. The novel stimuli comprised identical thin line segments, with a length : width ratio no less than 10 : 1, which were moved perpendicularly or obliquely to their common orientation during the recordings. When the component lines were much shorter than the size of receptive field, the majority of cells were selective to the direction of pattern motion while only a small subset was sensitive to the direction of component motion. However, the response profiles of most cells became more component‐motion selective with the increment of orientation element in stimulus by elongating the component lines in the patterns. These findings imply that the two‐stage theory might be incomplete for modelling the visual motion analysis. Even at relatively low levels of the visual system, some kind of nonorientation‐based processing may coexist with the orientation‐sensitive processing in a dynamic competition, where one rises as the other falls depending upon the strength of the orientation element in the stimulus, so that under some circumstances it becomes possible to signal the veridical direction of pattern motion.
Development of brain‐derived neurotrophic factor and neurotrophin‐3 immunoreactivity in the lower auditory brainstem of the postnatal gerbil
Authors: Tierney Travis S. , P. Doubell Timothy , Xia Gao , Moore David R.
Published: March 2003

The localization of brain‐derived neurotrophic factor (BDNF) and neurotrophin‐3 (NT‐3) in the gerbil auditory brainstem was studied during normal postnatal development. The principal objective of this paper was to compare the developmental distribution of BDNF and NT‐3 proteins to the known developmental distribution of their cognate, high‐affinity tyrosine kinase receptors. BDNF and NT‐3 proteins were localized using standard immunohistochemistry. No specific immunoreactivity for BDNF or NT‐3 was detected on the day of birth (P0) in any auditory structure, although fibers comprising the spinal tract of the Vth cranial nerve were well labelled with antibodies against BDNF. Diffuse immunoreactivity for both BDNF and NT‐3 was first detected at P3 in the cochlear nucleus and in several second order auditory nuclei in the superior olivary complex. This diffuse immunoreactivity became clustered and restricted to neuronal cell bodies by P10. Immunoreactivity for both BDNF and NT‐3 transiently disappeared in the lateral and medial superior olivary nuclei at P10. However, neurons in the medial nucleus of the trapezoid body remained immunopositive for both BDNF and NT‐3. Fibers in the trapezoid body were labelled with BDNF immunoreactivity by P12. Between P12 and P15, the distribution of BDNF and NT‐3 immunoreactivity in the cochlear nucleus and superior olivary complex became comparable to adult (P140) immunolabel. These results show that the normal developmental distribution of the neurotrophins BDNF and NT‐3 in the lower auditory brainstem occurs during the first two postnatal weeks in parallel with the developmental expression of their cognate receptors, trkB and trkC.
Postnatal maternal deprivation produces long‐lasting modifications of the stress response, feeding and stress‐related behaviour in the rat
Authors: Penke, Zsuzsa , Felszeghy, Klára , Fernette, Brigitte , Sage, Dominique , Nyakas Csaba , Burlet Arlette
Published: March 2003

The hypothalamo‐pituitary‐adrenal (HPA) axis plays a central role both in the regulation of the stress response, and in the control of feeding behaviour. Sensitivity of the HPA axis to respond to stress varies both during ontogeny and between individuals, and can be altered by neonatal events. The aim of our experiments was to determine whether early events that affect the HPA axis could also induce persistent modifications in food intake (quantitatively and qualitatively), as well as alterations of anxiety‐related behaviour. Twenty‐four‐hour maternal deprivation was introduced at two different periods of HPA maturation, on day 5 (DEP5) or day 14 (DEP14) after birth. Sequential measurements of plasma levels of adrenocorticotropin hormone (ACTH) and corticosterone showed that this deprivation altered the HPA axis of adults; the response to restraint stress was prolonged in DEP5 and a higher ACTH peak appeared in DEP14. The neonatal stress also produced long‐lasting modifications of rat behaviour, as DEP14 adults became more anxious. Standard food intake decreased in both groups of deprived rats. Diet preferences also changed, as carbohydrate intake decreased in DEP5 rats. Corticosteroid receptor binding did not vary in the hippocampus of the deprived rats. The modifications of the stress response and the behaviour parameters could be due to the alteration of corticosteroid receptors in the hypothalamic paraventricular nucleus and/or corticotropin‐releasing hormone or vasopressin function, but these parameters have yet to be determined. This early stress paradigm altering feeding behaviour could become an interesting model for research into human eating disorders.
Optical imaging of spreading depolarization waves triggered by spinal nerve stimulation in the chick embryo: possible mechanisms for large‐scale coactivation of the central nervous system
Authors: Mochida Hiraku , Sato Katsushige , Arai Yoshiyasu , Sasaki Shinichi , Kamino Kohtaro , Momose‐Sato Yoko
Published: March 2003

Using a multiple‐site optical recording technique with a voltage‐sensitive dye, we found that widely spreading depolarization waves were evoked by dorsal root stimulation in embryonic chick spinal cords. Spatiotemporal maps of the depolarization waves showed that the signals were mainly distributed in the ventral half of the slice, with the highest activity in the ventrolateral area. The propagation velocity of the waves was estimated to be in the order of mm/s. Depolarization waves were evoked in the ventral root‐cut preparation, but not in the dorsal root‐cut preparation, suggesting that the wave was triggered by synaptic inputs from the primary afferents, and that activation of the motoneurons was not essential for wave generation. In intact spinal cord–brain preparations, the depolarization wave propagated rostrally and caudally for a distance of several spinal segments in normal Ringer's solution. In a Mg2+‐free solution, the amplitude and extent of the signals were markedly enhanced, and the depolarization wave triggered in the cervical spinal cord propagated to the brainstem and the cerebellum. The depolarization wave demonstrated here had many similarities with the vagus nerve‐evoked depolarization wave reported previously. The results suggest that functional cell‐to‐cell communication systems mediated by the depolarization wave are widely generated in the embryonic central nervous system, and could play a role in large‐scale coactivation of the neurons in the spinal cord and brain.
Choroid plexus and ageing in rats: a morphometric and ultrastructural study
Authors: Serot Jean‐Marie , Foliguet Bernard , Béné Marie Christine , Faure Gilbert C.
Published: March 2003

Choroid plexuses (CP) are intraventricular structures involved in the production of cerebrospinal fluid (CSF) and in the synthesis and transport of numerous CSF components. Age‐related modifications of the CP structure are still ill defined. We performed an ultrastructural and morphometric study of ageing CP in nine Sprague–Dawley rats 6, 18 and 30 months of age. Epithelial cells of CP villi were cubic in shape at 6 months, more dome‐like at 18 months, and significantly flattened at 30 months of age. Epithelial basement membranes were thin and regular at 6 months, significantly thicker at 18 months and thicker and irregular at 30 months. Intravillous stroma increased nonhomogeneously with age. The ageing of CP in rats is characterized morphologically by epithelial atrophy, irregular fibrosis of the stroma and a thickening of epithelial basement membranes. These modifications suggest an alteration of secretory and filtrating functions in ageing CP.
Brain correlates of fast and slow handwriting in humans: a PET–performance correlation analysis
Authors: Siebner Hartwig R. , Limmer Claus , Peinemann Alexander , Bartenstein Peter , Drzezga Alexander , Conrad Bastian
Published: March 2003

The present study examined the cerebral control of velocity during handwriting. We employed H215O positron emission tomography (PET) to measure the regional cerebral blood flow (rCBF) in 10 healthy subjects. Participants were required to write the German verb ‘bellen’ (‘to bark’) either at their normal speed (i.e. fast open‐loop handwriting) or to write at approximately half of their normal speed without visual feedback. The second task required a continuous modification of the motor output according to the kinaesthetic feedback from the hand (i.e. slow closed‐loop handwriting). Pencil movements were recorded during PET scanning and analysed off‐line using a stroke‐based analysing program. The mean number of inversions in velocity (NIV) per stroke was used to quantify the mode of motor control during each PET scan. A NIV of 1 indicates fast open‐loop processing, whereas an increase in NIV reflects a shift towards slow closed‐loop processing of handwriting. Foci in the left primary sensorimotor cortex, the right lateral premotor cortex, the left anterior parietal cortex, the left anterior putamen, the left rostral supplementary motor area and the right precuneus showed a graded increase in functional activation with the mean NIV per stroke, suggesting that this set of brain regions is particularly involved in the processing of slow closed‐loop writing movements. No area showed a negative relationship between rCBF and the mean NIV per stroke, suggesting that fast open‐loop handwriting is achieved by an optimized cooperation of the manual sensorimotor network rather than by a selective activation of a distinct network component.
Regeneration in avian hair cell epithelia: identification of intracellular signals required for S‐phase entry
Authors: Witte Mark C. , Montcouquiol Mireille , Corwin Jeffrey T.
Published: March 2003

Balance epithelia in birds closely resemble their mammalian counterparts, but their cells turnover rapidly and they quickly regenerate hair cells, leading to functional recovery from damage that would be permanent for a mammal. We isolated and cultured sheets of the chicken's utricular epithelium in bromo‐deoxyuridine and specific inhibitors of different intracellular signalling pathways to identify signals that influence turnover and regeneration. Synthesis (S‐phase) entry was effectively blocked by inhibition of PI3‐K, TOR or MAPK, and significantly decreased by inhibitors of PKC. Comparisons indicate that activated PI3‐K and TOR are required for S‐phase entry in both avian and mammalian balance epithelia, but activation of the MAPK pathway appears to have a more significant role in avian utricles than in mammals. The dissimilarities in the requirements for these signalling pathways do not appear sufficient to explain the marked difference in regenerative capacity between the ears of birds and mammals.
Disrupting basolateral amygdala function impairs unconditioned freezing and avoidance in rats
Authors: Vazdarjanova Almira , Cahill Larry , McGaugh James L.
Published: March 2003

Lesions of the lateral/basolateral amygdala nuclei (BLC) disrupt freezing behaviour in response to explicit or contextual cues (conditioned stimuli – CS) paired previously with footshock (unconditioned stimulus). This deficit in expression of defensive behaviour in response to conditioned stimuli is often interpreted as inability of lesioned rats to learn CS–US associations. However, findings of several studies indicate that BLC‐lesioned rats can rapidly learn CS–US associations. Such findings suggest that lesioned rats can learn CS–US associations but are impaired in the expression of freezing behaviour. In the present study we report that both temporary inactivation (lidocaine) and permanent excitotoxic (NMDA) lesions of the BLC impair the unconditioned freezing and avoidance behaviours of rats in response to a novel fear‐eliciting stimulus, a ball of cat hair. These findings suggest that the BLC influences the expression of freezing and avoidance behaviours, and/or that it potentiates rats' experience of fear. Along with prior evidence of spared memory for aversive learning after BLC lesions, these findings suggest that disrupted freezing to conditioned cues in BLC‐lesioned rats does not necessarily reflect inability to form CS–US associations.
The effects of digital anaesthesia on predictive grip force adjustments during vertical movements of a grasped object
Authors: Nowak Dennis A. , Hermsdörfer Joachim , Glasauer Stefan , Philipp Jens , Meyer Ludger , Mai Norbert
Published: March 2003

Grip force adjustments to fluctuations of inertial loads induced by vertical arm movements with a grasped object were analysed during normal and impaired finger sensibility. Normally grip force is modulated in a highly economical way in parallel with fluctuations of load force. Two subjects performed vertical up and down movements of a grasped object, both with normal finger sensibility and then cutaneously anaesthetized finger sensibility. Short breaks were taken in between single movements, during which the object was held stationary. After digital anaesthesia was applied to the grasping fingers, both subjects substantially increased the grip force. The grip force amplitude and timing still anticipated changes in load force, although the established grip force had already overcome movement‐induced load force peaks. This implies that the increase of grip force and consequently the elevated force ratio between maximum grip and maximum load force are not processed to alter the feedforward system of grip force control. Cutaneous afferent information from the grasping digits appears to be necessary for economic scaling of the grip force level, but it plays a subordinate role in the precise anticipatory temporal coupling of grip and load forces during voluntary object manipulation.
Chronic desipramine treatment selectively potentiates somatostatin‐induced dopamine release in the nucleus accumbens
Authors: Pallis Eleftherios , Thermos Kyriaki , Spyraki Christina
Published: March 2003

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin‐14 (10−4 m) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin‐induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.
β‐Bungarotoxin is a potent inducer of apoptosis in cultured rat neurons by receptor‐mediated internalization
Authors: Herkert Matthias , Shakhman Olena , Schweins Elisabeth , Becker Cord‐Michael
Published: March 2003

The neurotoxic phospholipase A2, β‐bungarotoxin (β‐BuTx), is a component of the snake venom from the Taiwanese banded krait Bungarus multicinctus. β‐BuTx affects presynaptic nerve terminal function of the neuromuscular junction and induces widespread neuronal cell death throughout the mammalian and avian CNS. To analyse the initial events of β‐BuTx‐mediated cell death, the toxin was applied to cultured rat hippocampal neurons where it induced neuronal cell death in a concentration‐dependent manner (EC50≈ 5 × 10−13 m) within 24 h. Fluorescence labelled β‐BuTx was completely incorporated by neurons within < 10 min. Binding and uptake of β‐BuTx, as well as induction of cell death, were efficiently antagonized by preincubation with dendrotoxin I, a blocker of voltage‐gated potassium channels devoid of phospholipase activity. Binding of β‐BuTx was selective for neurofilament‐positive cells. As evident from intense annexin‐V and TUNEL stainings, application of β‐BuTx induced apoptotic cell death exclusively in neurons, leaving astrocytes unaffected. No evidence was obtained for any contribution of either caspases or calpains to β‐BuTx‐induced apoptosis, consistent with the inability of the inhibitors Z‐Asp‐DCB and calpeptin, respectively, to protect neurons from β‐BuTx‐induced cell death. These observations indicate that induction of cell death by β‐BuTx comprises several successive phases: (i) binding to neuronal potassium channels is the initial event, followed by (ii) internalization and (iii) induction of apoptotic cell death via a caspase‐independent pathway.
Control elements between −9.5 and −3.0 kb in the human tissue‐type plasminogen activator gene promoter direct spatial and inducible expression to the murine brain
Authors: Yu Hong , Schleuning Wolf‐Dieter , Michl Marna , Liberatore Gabriel , Tan Seong‐Seng , Medcalf Robert L.
Published: March 2003

Tissue‐type plasminogen activator (t‐PA) participates in the control of synaptic plasticity and memory formation in the central nervous system (CNS). Transgenic mice harbouring either 9.5, 3.0 or 1.4 kb of the human t‐PA promoter fused to the LacZ reporter gene were used to assess t‐PA promoter‐directed expression in vivo. The 9.5 kb t‐PA promoter directed expression to the brain, most notably to the dentate gyrus, superior colliculus, hippocampus, thalamus and piriform cortex. Staining was also observed in the retrosplenial and somatosensory cortex. The 3.0 kb t‐PA promoter directed generalized and poorly defined expression to the cortex and hippocampus, while the 1.4 kb t‐PA promoter directed expression selectively to the medial habenula. Intravenous administration of lipopolysaccharide into mice habouring the 9.5 kb t‐PA promoter resulted in an increase in reporter gene activity in the lateral orbital cortex and thalamus. Results of in vitro transfection experiments of NT2 cells with a series of t‐PA promoter deletion constructs confirmed the presence of regulatory elements throughout the 9.5 kb promoter region. Finally, we describe a cis‐acting element related to the NFAT recognition site that provides a protein‐binding site and which may play a role in the selective expression of the 1.4 t‐PA promoter in the medial habenula. These results indicate that elements between −3.0 and −9.5 kb of the t‐PA promoter confer constitutive and inducible expression to specific regions of the CNS.
Pallidal activity is involved in visuomotor association learning in monkeys
Authors: Inase M. , Li B.‐M. , Takashima I. , Iijima T.
Published: March 2003

In order to examine whether the basal ganglia are involved in arbitrary visuomotor association, we recorded neuronal activity in the internal segment of the globus pallidus (GPi) of monkeys during a conditional visuomotor learning task. Two monkeys were presented a cueing visual stimulus, and following a delay period required to push, pull or turn a manipulator according to the cue. GPi neurons showed changes in activity during the delay period when the animals performed the task on the basis of a familiar stimulus–response association. Those changes in delay activity were enhanced as the monkeys were learning a new visuomotor association. The enhancement of the changes was selective to a following response. These results suggest that the basal ganglia are involved in arbitrary visuomotor association, especially during the learning of new associations.
Involvement of intrinsic cholinergic and GABAergic innervation in the effect of NMDA on striatal dopamine efflux and metabolism as assessed by microdialysis studies in freely moving rats
Authors: Whitehead K. J. , Rose S. , Jenner P.
Published: March 2003

Microdialysis perfusion was used to study the participation of striatal cholinergic and γ‐aminobutyric acid‐ergic (GABAergic) neurotransmission in basal and N‐methyl‐d‐aspartate (NMDA) receptor‐modulated dopamine release and metabolism in the striatum of the freely moving rat. Reverse dialysis of atropine (1–50 µm) induced a concentration‐related increase in dopamine efflux and decrease in 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) efflux. (+)‐Bicuculline (10–100 µm) similarly increased dopamine efflux, but was without consistent effect on metabolite efflux. Reverse dialysis of NMDA (1 mm) evoked an approximately twofold increase in dopamine efflux and decreased DOPAC and HVA efflux to 30–40% of basal levels. The effect of NMDA on dopamine efflux was completely abolished by coadministration of tetrodotoxin (TTX; 1 µm) or atropine (10 µm), and markedly potentiated (approximately fourfold) by coadministration of (+)‐bicuculline (50 µm). The NMDA‐induced decrease in dopamine metabolite efflux was inhibited by coadministration of TTX or (+)‐bicuculline, but was unaffected by atropine. Our data suggest that dopamine release in the striatum is subject to both cholinergic and GABAergic tonic inhibitory mechanisms mediated through muscarinic and GABAA receptors, respectively. Furthermore, NMDA‐stimulated dopamine release also involves obligatory cholinergic facilitation and an inhibitory GABAergic component mediated through these respective receptors.
Independent receptors for diadenosine pentaphosphate and ATP in rat midbrain single synaptic terminals
Authors: Díaz‐Hernández M. , Pintor J. , Castro E. , Miras‐Portugal M. T.
Published: March 2003

Diadenosine pentaphosphate (Ap5A) and adenosine 5′‐triphosphate (ATP) stimulate a intrasynaptosomal calcium concentration [Ca2+]i increase via specific purinergic receptors in rat midbrain synaptosomes, although nothing is known about their distribution in presynaptic terminals. A microfluorimetric technique to measure [Ca2+]i increase using the dye FURA‐2AM, has permitted study of the presence of dinucleotide and P2X receptors in independent isolated synaptic terminals. Our results demonstrate the existence of three populations of synaptosomes: one with dinucleotide receptors (12%), another with P2X receptors (20%) and a third with both (14%). It has been possible to demonstrate that the activation of these receptors occurs only in the presence of extracellular Ca2+ and that it is also coupled with voltage‐dependent Ca2+ channels. Finally 54% of the synaptosomes that responded to K+ did not present any calcium increase mediated by the nucleotides used. In summary, ATP and dinucleotides exhibit specific ionotropic receptors that can coexist or not on the same synaptic terminal.
Scaffolding proteins organize multimolecular protein complexes for sensory signal transduction
Authors: Huber Armin
Published: March 2003

Scaffolding proteins composed of protein–protein interaction domains have emerged as organizers of multiprotein complexes in diverse cellular compartments, including neuronal synapses, cell–cell junctions of epithelial cells, and the stimulus perceiving structures of sensory neurons. This review focuses on the INAD‐assembled signalling complex of Drosophila photoreceptors, which organizes key components of the phototransduction cascade into a multiprotein signal transduction unit. The structure, the physiological consequences, and the assembly and targeting of the members of the INAD signalling complex will be described. In addition, the existence of signalling complexes in vertebrate photoreceptors, olfactory neurons and mechanosensitive hair cells will be discussed.
Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels
Authors: Schwarz Martin K. , Pawlak Verena , Osten Pavel , Mack Volker , Seeburg Peter H. , Köhr Georg
Published: March 2003

Homomeric glutamate receptor (GluR) channels become spontaneously active when the last alanine residue within the invariant SYTANLAAF‐motif in the third membrane segment is substituted by threonine. The same mutation in the orphan GluRδ2 channel is responsible for neurodegeneration in ‘Lurcher’ (Lc) mice. Since most native GluRs are composed of different subunits, we investigated the effect of an Lc‐mutated subunit in heteromeric kainate and AMPA receptors expressed in HEK293 cells. Kainate receptor KA2 subunits, either wild type or carrying the Lc mutation (KA2Lc), are retained inside the cell but are surface‐expressed when assembled with GluR6 sununits. Importantly, KA2Lc dominates the gating of KA2Lc/GluR6WT channels, as revealed by spontaneous activation and by slowed desensitization and deactivation kinetics of ligand‐activated whole‐cell currents. Moreover, the AMPA receptor subunit GluR‐BLc(Q) which forms spontaneously active homomeric channels with rectifying current‐voltage relationships, dominates the gating of heteromeric GluR‐BLc(Q)/GluR‐A(R) channels. The spontaneous currents of these heteromeric AMPAR channels show linear current–voltage relationships, and the ligand‐activated whole‐cell currents display slower deactivation and desensitization kinetics than the respective wild‐type channels. For heteromeric Lc‐mutated kainate and AMPA receptors, the effects on kinetics were reduced relative to the homomeric Lc‐mutated forms. Thus, an Lc‐mutated subunit can potentially influence heteromeric channel function in vivo, and the severity of the phenotype will critically depend on the levels of homomeric GluRLc and heteromeric GluRLc/GluRWT channels.
Electrical responses reveal the temporal dynamics of brain events during involuntary attention switching
Authors: Escera Carles , Yago Elena , Alho Kimmo
Published: March 2003

Surviving in the natural environment requires the rapid switching of attention among potentially relevant stimuli. We studied electrophysiologically the involuntary switching time in humans performing a task designed to study brain mechanisms of involuntary attention and distraction (C. Escera et al., 1998, J. Cogn. Neurosci., 10, 590–604). Ten subjects were instructed to discriminate visual stimuli preceded by a task‐irrelevant sound, this being either a repetitive tone (P = 0.8) or a distracting sound, i.e. a slightly higher deviant tone (P = 0.1) or an environmental novel sound (P = 0.1). In different conditions, the sounds preceded the visual stimuli by 245 or 355 ms. Deviant tones and novel sounds prolonged reaction times significantly to subsequent visual stimuli by 7.4 (P < 0.02) and 15.2 ms (P < 0.003), respectively. In addition to a mismatch negativity (MMN) and a positive‐polarity, 320‐ms latency, P3a event‐related potential associated, respectively, with detection of the distracting sound and the subsequent orienting of attention to it, a late frontal negative deflection was observed in distracting trials. The peak latency of this brain response from sound onset was 580 ms in the 245‐ms condition and 115 ms longer in the 355‐ms condition (P < 0.001), peaking consequently at 340 ms from visual stimulus onset, irrespective of the onset of the distracting sound. We suggest that this late frontal negative response may signal over the scalp the process of reallocating attention back to the original task after momentary distraction, and therefore that recovering from distraction may take a similar shifting time as orienting attention involuntarily towards unexpected novelty.
High expression and anterograde axonal transport of aminoterminal sonic hedgehog in the adult hamster brain
Authors: Traiffort Elisabeth , Moya Kenneth L. , Faure Hélène , Hässig Raymonde , Ruat Martial
Published: March 2003

Sonic hedgehog (SHH) is considered to play an important role in tissue induction and patterning during development, particularly in determining neuronal cell fate in the ventral neural tube and in the embryonic forebrain. SHH precursor is autoproteolytically cleaved to an aminoterminal fragment (SHHN) which retains all known SHH biological activities. Here, we demonstrate the expression of a 22‐kDa SHHN immunoreactive peptide in developing and adult hamster brain regions using a rabbit antiserum directed against a mouse SHHN fragment. Interestingly, SHHN was developmentally regulated with the highest expression observed in the adult brain, was resistant to Triton X‐100 solubilization at 4 °C and partitioned with the raft component ganglioside GM1 during density gradient centrifugation. In rat brain, Shh transcripts were identified by double in situ hybridization in GABAergic neurons located in various basal forebrain nuclei including globus pallidus, ventral pallidum, medial septum‐diagonal band complex, magnocellular preoptic nucleus and in cerebellar Purkinje cells as well as in motoneurons of several cranial nerve nuclei and of the spinal cord. We show that radiolabelled SHHN peptides are synthesized in the adult hamster retina and are transported axonally along the optic nerve to the superior colliculus in vivo. Our data indicate that SHHN is associated with cholesterol rich raft‐like microdomains and anterogradely transported in the adult brain, and suggest that the roles of this extracellular protein are more diverse than originally thought.
The psychoactive ingredient of marijuana induces behavioural sensitization
Authors: Rubino Tiziana , Viganò Daniela , Massi Paola , Parolaro Daniela
Published: March 2003

Here we describe, for the first time, the occurrence of behavioural sensitization after chronic exposure to Δ9‐tetrahydrocannabinol. Rats were treated twice a day, for five days, with increasing doses (5, 10, 20, 40, 40 mg/kg i.p.) of Δ9‐tetrahydrocannabinol or its vehicle and after 20 days of withdrawal, animals were challenged with 5 mg/kg (i.p.) of the drug and their behaviour was assessed. Contrary to the motor inhibition induced in control rats, challenge with Δ9‐tetrahydrocannabinol in pre‐exposed animals elicited a complex behavioural syndrome mainly characterized by oral stereotyped items. Due to the relevance of behavioural sensitization in drug‐seeking behaviour that persists long after discontinuation of drug use, our findings suggest that cannabinoids could trigger neurobiological alteration not dissimilar from those observed with more harmful abused drugs.
Homeostatic plasticity induced by chronic block of AMPA/kainate receptors modulates the generation of rhythmic bursting in rat spinal cord organotypic cultures
Authors: Galante Micaela , Avossa Daniela , Rosato‐Siri Marcelo , Ballerini Laura
Published: March 2003

Generation of spontaneous rhythmic activity is a distinct feature of developing spinal networks. We report that rat embryo organotypic spinal cultures contain the basic circuits responsible for pattern generation. In this preparation rhythmic activity can be recorded from ventral interneurons and is developmentally regulated. When chronically grown in the presence of an AMPA/kainate receptor blocker, this circuit expresses long‐term plasticity consisting largely of increased frequency of fast synaptic activity and reduction in slow GABAergic events. We examined whether, once this form of homeostatic plasticity is established, the network could still exhibit rhythmicity with properties similar to controls. Control or chronically treated ventral interneurons spontaneously generated (with similar probability) irregular, network‐driven bursts over a background of ongoing synaptic activity. In control cultures increasing network excitability by strychnine plus bicuculline, or by raising [K+]o, induced rapid‐onset, regular rhythmic bursts. In treated cultures the same pharmacological block of Cl–‐mediated transmission or high‐K+ application also induced regular patterned activity, although significantly faster and, in the case of high K+, characterized by slow onset due to postsynaptic current summation. Enhancing GABAergic transmission by pentobarbital surprisingly accelerated the high‐K+ rhythm of control cells (though depressing background activity), whereas it slowed it down in chronically treated cells. This contrasting effect of pentobarbital suggests that, to preserve bursting ability, chronic slices developed a distinct GABAergic inhibitory control on over‐expressed bursting circuits. Conversely, in control slices GABAergic transmission depressed spontaneous activity but it facilitated bursting frequency. Thus, even after homeostatic rearrangement, developing mammalian spinal networks still generate rhythmic activity.