bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in the effect of chronic and acute caffeine on self‐administration of cocaine in mice
Authors: Kuzmin A. , Johansson B. , Semenova S. , Fredholm B. B.
Published: March 2003

We have compared the ability of an acute injection of caffeine (3 mg/kg, i.p.) and long‐term peroral caffeine consumption for 10 days (≈ 150 mg/kg/day in tap water) to affect cocaine self‐administration in mice. The peak plasma and brain levels of caffeine and its metabolites were similar in the two experimental set‐ups. Moreover, the levels reached are close to those obtained in humans upon coffee ingestion. Neither type of caffeine administration affected the reinforcing effect of cocaine, defined as a selective increase in nose‐poke responses in mice self‐administering cocaine compared to their yoked controls. However, caffeine injection increased the amount of cocaine self‐administered whereas caffeine drinking reduced it. A low dose of cocaine, by itself essentially ineffective, produced an increase in c‐fos and NGFI‐A mRNA in the cerebral cortex in mice that had been drinking caffeine. An acute caffeine injection also enhanced the immediate early gene response to cocaine, but to a lesser degree. Cocaine and caffeine also synergistically increased NGFI‐A expression in caudate‐putamen. Thus, regular caffeine drinking decreased the cocaine intake without significantly affecting its reinforcing properties, perhaps because it enhanced the activation of the predominantly inhibitory frontal cortical areas produced by low doses of cocaine.
Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse
Authors: Bezard Erwan , Jaber Mohamed , Gonon François , Boireau Alain , Bloch Bertrand , Gross Christian E.
Published: March 2003

Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.
Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6‐hydroxydopamine‐induced lesions in the substantia nigra
Authors: Andringa G. , Van Oosten R. V. , Unger W. , Hafmans T. G. M. , Veening J. , Stoof J. C. , Cools A. R.
Published: March 2003

The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6‐Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014–1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6‐OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6‐hydroxydopamine (6‐OHDA), though at different doses. It prevented: abnormal stepping (0.0014–0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014–0.14 mg/kg and 0.0014–0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014–0.014 mg/kg). CGP 3466B (0.0014–0.14 mg/kg) induced no deficits in sham‐treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6‐OHDA‐lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham‐lesioned animals. It is concluded that CGP 3466B prevents all 6‐OHDA‐induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.
Ipsilateral involvement of primary motor cortex during motor imagery
Authors: Porro Carlo A. , Cettolo Valentina , Francescato Maria Pia , Baraldi Patrizia
Published: March 2003

To investigate whether motor imagery involves ipsilateral cortical regions, we studied haemodynamic changes in portions of the motor cortex of 14 right‐handed volunteers during actual motor performance (MP) and kinesthetic motor imagery (MI) of simple sequences of unilateral left or right finger movements, using functional magnetic resonance imaging (fMRI). Increases in mean normalized fMRI signal intensities over values obtained during the control (visual imagery) task were found during both MP and MI in the posterior part of the precentral gyrus and supplementary motor area, both on the contralateral and ipsilateral hemispheres. In the left lateral premotor cortex, fMRI signals were increased during imagery of either left or right finger movements. Ipsilateral cortical clusters displaying fMRI signal changes during both MP and MI were identified by correlation analyses in 10 out of 14 subjects; their extent was larger in the left hemisphere. A larger cortical population involved during both contralateral MP and MI was found in all subjects. The overall spatial extent of both the contralateral and the ipsilateral MP + MI clusters was ∼ 90% of the whole cortical volume activated during MP. These results suggest that overlapping neural networks in motor and premotor cortex of the contralateral and ipsilateral hemispheres are involved during imagery and execution of simple motor tasks.
Increased acetylcholine release in the rat medial prefrontal cortex during performance of a visual attentional task
Authors: Passetti F. , Dalley J. W. , O'connell M. T. , Everitt B. J. , Robbins T. W.
Published: March 2003

Recent studies have suggested a functional link between cortical cholinergic output and attentional task demands, whereby acetylcholine (ACh) release is regulated according to the outcome of ongoing behaviour. To explore this hypothesis we measured ACh efflux in the rat medial prefrontal cortex (mPFC) during between‐session manipulations of the cognitive demands of an attentional task. Rats were trained to detect visual stimuli in a five‐choice serial reaction time task (5‐CSRTT) which involves sustained and divided attention. Following habituation to tethering and implantation with a microdialysis probe in the mPFC, rats were tested in the 5‐CSRTT for three consecutive days, with different lengths of stimulus duration. During performance of the 5‐CSRTT we measured robust, reproducible, task‐related increases in ACh release in the mPFC across all sessions. Variations of the stimulus duration from the standard 0.5 s resulted in the predicted behavioural effects (reductions and increases in choice accuracy with 0.25 s and 5 s, respectively), but there was no evidence of either greater changes in ACh release in the more demanding condition or smaller changes in the less demanding condition. By contrast, in the session with 5‐s stimulus duration there was a positive correlation between prefrontal cortical ACh efflux and the total number of trials completed. In summary, the present study shows that ACh efflux in the rat mPFC is increased during performance of a 5‐CSRTT, but has found no evidence to support a specific relationship between cholinergic cortical output and attentional performance.
Galanin‐R1 and ‐R2 receptor mRNA expression during the development of rat brain suggests differential subtype involvement in synaptic transmission and plasticity
Authors: Burazin Tanya C. D. , Larm Jari A. , Ryan Mary C. , Gundlach Andrew L.
Published: March 2003

The present study employed 35S‐labelled oligonucleotides and in situ hybridization to examine the distribution in the developing rat brain of mRNA encoding two galanin receptor subtypes, i.e. Gal‐R1 and Gal‐R2. Gal‐R1 and/or Gal‐R2 mRNA was detected at embryonic day (E) 20 and from postnatal day (P) 0–70. Gal‐R1 mRNA was highly expressed in olfactory regions, ventral hippocampal CA fields, dorsomedial thalamic areas and many hypothalamic nuclei at all ages studied. In adult brain, Gal‐R2 mRNA was most abundant in the dentate gyrus, anterior and posterior hypothalamus, raphe and spinal trigeminal nuclei, and in the dorsal motor nucleus of the vagus. At P0–P7, Gal‐R2 mRNA was more widely distributed and abundant than at other ages, with highest levels of expression detected throughout the neocortex and thalamus. Thus, Gal‐R2 transcripts had a more restricted distribution than Gal‐R1 and were differentially abundant at different ages, while the distribution and relative abundance of Gal‐R1 mRNA did not alter substantially during postnatal development. In general, Gal‐R1 and ‐R2 mRNAs were localized in regions previously shown to contain [125I]‐galanin binding sites and galanin‐positive terminals in adult brain. Galanin‐immunostaining was assessed in postnatal brain to determine whether peptide innervation correlated with observed transient receptor expression, but was not particularly enriched in Gal‐R2 mRNA‐positive areas of P4 or P7 brain. These results, together with earlier findings [e.g. Burazin, T. C. D. & Gundlach, A. L. (1998) J. Neurochem., 71, 879–882], suggest that Gal‐R1 receptors have a broad role in normal synaptic transmission, while Gal‐R2 receptors, in addition to a similar role in particular pathways, may be involved in processes prominent during the establishment and maturation of synaptic connections in developing brain and during neural damage and repair in the mature nervous system.
Gluco‐ and mineralocorticoid receptor‐mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat
Authors: Hansson Anita C. , Cintra Antonio , Belluardo Natale , Sommer Wolfgang , Bhatnagar Maheep , Bader Michael , Ganten Detlev , Fuxe Kjell
Published: March 2003

Gluco‐ and mineralocorticoid receptors (GR and MR) act via common promoter elements but may exert different effects on gene regulation in various regions of the forebrain. In order to separately analyse the role of GR and MR in the regulation of neurotrophic factor genes and their receptors, we used adrenalectomy and subsequent hormone injections in the rat as a model system. Twenty‐four hours after adrenalectomy rats were injected with a single dose of corticosterone (2 and 10 mg/kg), aldosterone (0.5 mg/kg) or the synthetic glucocorticoid agonist RU 28362 (4 mg/kg). Gene expression of basic fibroblast growth factor (bFGF) and its high‐affinity receptors [fibroblast growth factor receptor subtypes 1–3 (FGF‐R1, FGF‐R2, FGF‐R3)], as well as brain‐derived growth factor (BDNF) and neurotrophin‐3 (NT‐3) was analysed at 4 h after the hormone injection in CA1–CA4 (cornus of Ammon areas of the hippocampus) and dentate gyrus of the dorsal hippocampus and in neocortex by means of in situ hybridization. We found that bFGF is regulated in CA2, CA3 and dentate gyrus by GR and MR together, and in CA1, CA4 and neocortex by GR alone. FGF‐R2 expression in the hippocampus seems to be regulated only by MR, while BDNF expression appears to depend on both receptors. FGF‐R1, FGF‐R3 and NT‐3 were only moderately affected by the hormone activation of GR and MR acting in concert or alone in the various regions. Thus, the present findings suggest that the adrenal cortical system through GR and MR participate in the control of neurotrophic factor signalling in a highly subregion‐ and cellular‐dependent manner.
Implication of Bcl‐2 and Caspase‐3 in age‐related Purkinje cell death in murine organotypic culture: an in vitro model to study apoptosis
Authors: Ghoumari Abdel M. , Wehrlé Rosine , Bernard Ora , Sotelo Constantino , Dusart Isabelle
Published: March 2003

Neuronal cell death is an essential feature of nervous system development and neurodegenerative diseases. Most Purkinje cells in murine cerebellar organotypic culture die when taken from 1–5‐day‐old mice (P1–P5), whereas they survive when taken before or after these ages. Using DNA gel electrophoresis, terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL) and electron microscopic analyses, we were able to show that this massive Purkinje cell death is apoptotic in nature and reaches a peak at P3. From the several endogenous genes known to be involved in the apoptotic process, we have focused on two: the bcl‐2 and the caspase‐3 that encode for anti‐apoptotic and pro‐apoptotic proteins, respectively. Immunostaining for activated Caspase‐3 correlated with Purkinje cell death. A better survival of Purkinje cells was observed in P3 slices taken from hu‐bcl‐2 transgenic mice, and in slices treated with z‐DEVD.fmk (an inhibitor of numerous caspases). Thus, these two genes are implicated in the age‐related Purkinje cell apoptosis in organotypic culture. As Purkinje cell death in vitro takes place at the same age as Purkinje cells engaged in intense synaptogenesis and dendritic remodeling in vivo, we propose that this apoptosis reflects a naturally occurring Purkinje cell death during this critical period.
The basolateral amygdala complex is involved with, but is not necessary for, rapid acquisition of Pavlovian ‘fear conditioning’
Authors: Cahill Larry , Vazdarjanova Almira , Setlow Barry
Published: March 2003

A major hypothesis about lateral/basolateral amygdala complex (BLC) function in memory proposes that the BLC is the site where conditioned stimulus–unconditioned stimulus (CS–US) associations are formed and permanently stored during Pavlovian ‘fear conditioning.’ Thus, according to this hypothesis, the BLC is necessary for the acquisition and expression of both discrete‐cue and contextual Pavlovian fear conditioning. This hypothesis clearly requires that animals with complete lesions of the BLC be completely unable to acquire Pavlovian fear conditioning. In this experiment, distribution of training and testing trials over three sessions revealed that rats with complete BLC lesions rapidly acquired a contextual CS–US association (as assessed with freezing behaviour), although their performance, as expected, did not equal that of sham operated controls. Irrespective of the nature of the freezing deficit relative to controls, the learning in the BLC‐lesioned rats strongly indicates that Pavlovian fear conditioning CS–US associations can be rapidly acquired in the absence of the BLC, and that the BLC cannot therefore be necessary for their acquisition.
Plateau potential‐dependent windup of the response to primary afferent stimuli in rat dorsal horn neurons
Authors: Morisset Valérie , Nagy Frédéric
Published: March 2003

In the spinal cord, repetitive stimulation of nociceptive afferent fibres induces a progressive build‐up of dorsal horn neuron (DHN) responses. This ‘action potential windup’ is used as a cellular model of central sensitization to pain. It partly relies on synaptic plasticity, being reduced after blocking NMDA and neurokinin receptors. Using intracellular recordings in a slice preparation of the rat spinal cord, we have analysed the implication of an additional non‐synaptic component of windup. Primary afferent fibres were electrically stimulated in the dorsal root. Of 47 responding deep DHNs, 17 (36%) produced action potential windup and afterdischarge during consecutive periods of repeated stimuli (0.4–1 Hz) activating high‐ (n = 13 neurons) and low‐threshold (n = 6 neurons) afferent fibres. When the NMDA receptors were blocked, the rate of windup did not change. In all neurons, there was an absolute correlation between expression of windup and the production of calcium‐dependent plateau potentials. Sensitization of the DHN response, similar to the synaptically induced windup, was obtained by repetitive intracellular injection of depolarizing current pulses. This intracellularly induced windup had the same pharmacology as the plateau potential. Synaptically induced windup was also abolished by nifedipine, an L‐type calcium‐channel blocker. Expression of plateau properties in DHNs is therefore a critical component of windup, operating downstream of synaptic processes. Being associated with calcium influx, generation of plateau potentials could be a link between short‐term plasticity and the long‐term modification of DHN excitability associated with central sensitization.
Blockade of the NMDA receptor increases developmental apoptotic elimination of granule neurons and activates caspases in the rat cerebellum
Authors: Monti Barbara , Contestabile Antonio
Published: March 2003

Elimination of neurons produced in excess naturally occurs during brain development through programmed cell death. Among the many survival factors affecting this process, a role for neurotransmitters acting on specific receptors has been suggested. We have performed an in vivo pharmacological blockade of the N‐methyl‐ d‐aspartate (NMDA) subtype of glutamate receptors, using the competitive NMDA receptor antagonist CGP 39551 at developmental stages corresponding to those at which a survival dependence on the stimulation of this receptor has been demonstrated for cerebellar granule neurons explanted in culture (typically from postnatal day 7 to postnatal day 11 or 13). We were able to demonstrate an increased level of DNA fragmentation in the cerebellum of the treated rats. At the P11 stage, in particular, the fragmented DNA extracted from the cerebellum of CGP 39551‐treated pups showed a clear laddering of nucleosomal fragments after agarose‐gel electrophoresis. Accordingly, in situ TUNEL technique showed a remarkable increase of cells positive for nucleosomal DNA fragmentation, particularly in the inner granular layer of the cerebellum of treated rats at P11 stage. Therefore, the natural rate of apoptotic elimination of cerebellar granule neurons is considerably enhanced under conditions of pharmacological blockade of the NMDA receptor, thus demonstrating, for the first time in vivo, a clear survival dependence of these neurons upon the stimulation of the NMDA receptor. Concomitantly with the increased rate of apoptotic elimination of granule neurons, the activity of two death proteases of the caspase family, in particular of caspase 3 and caspase 1 at a lower extent, was remarkably increased in the cerebellum of the treated rats. On the contrary, a marker related to the normal differentiation process of granule neurons, the enzyme ornithine decarboxylase, was strongly decreased in its activity in the cerebellum of treated rat pups.
Role played by sodium in activity‐dependent secretion of neurotrophins − revisited
Authors: Hoener M. C.
Published: March 2003

In previous experiments, a causal relationship between sodium influx and secretion of nerve growth factor (NGF) was deduced from the observation that the sodium substitute N‐methyl‐ d‐glucamine (NMDG) abolished any activity‐mediated NGF secretion that depends on intact internal calcium stores. However, all available experimental evidence speaks against sodium‐mediated calcium mobilization from these stores under physiological conditions. We now report that rapid sodium influx initiated by monensin or ouabain did not induce brain‐derived neurotrophic factor (BDNF) secretion from either native hippocampal slices or BDNF‐transduced hippocampal neuronal cultures. Additionally, we found marked differences between the replacement of sodium by NMDG and sucrose on the one hand, and choline and lithium on the other. Replacement of 100% (and as little as 10%) sodium by NMDG or sucrose not only blocked the activity‐mediated neurotrophin secretion, but itself led to a rapid and substantial increase of neurotrophin secretion. In contrast, the replacement of sodium (10% and 100%) by lithium and choline did not result in a release of neurotrophins, and only 100% replacement blocked the activity‐mediated neurotrophin secretion. We conclude that the blocking effects of NMDG and sucrose on neurotrophin secretion do not reflect the sodium replacement, but instead represent an independent blocking effect. These differences were also reflected in part by electrophysiological investigations in individually patched hippocampal neurons. The importance of the present observations lies not only in the reevaluation of the involvement of sodium in activity‐dependent neurotrophin secretion, but also in the demonstration that sodium replacement may initiate ‘side effects’ that are unrelated to sodium replacement.
Regulation of hippocampal cell adhesion molecules NCAM and L1 by contextual fear conditioning is dependent upon time and stressor intensity
Authors: Merino J. Joaquín , Cordero M. Isabel , Sandi Carmen
Published: March 2003

Cell adhesion molecules (CAMs) of the immunoglobulin superfamily, NCAM and L1, as well as the post‐translational addition of α‐2,8‐linked polysialic acid (PSA) homopolymers to NCAM (PSA–NCAM), have been implicated in the neural mechanisms underlying memory formation. Given that the degree of stress elicited by the training situation is one of the key factors that influence consolidation processes, this study questioned whether training rats under different stressor intensities (0.2, 0.4, or 1 mA shock intensity) in a contextual fear conditioning task might regulate subsequent expression of NCAM, PSA–NCAM and L1 in the hippocampus, as evaluated immediately after testing rats for conditioning at 12 and 24 h after training. Behavioural inhibition (evaluated as a ‘freezing’ index) at testing and post‐testing plasma corticosterone levels were also assessed. The results showed that 12 h post‐training, conditioned animals displayed reduced NCAM, but increased L1, expression. At this time point, the group trained at the highest shock intensity (1 mA) also presented decreased PSA–NCAM expression. Analyses performed 24 h post‐training indicated that the 1 mA group exhibited increased NCAM and L1 expression, but decreased expression of PSA–NCAM levels. In addition, L1 values that presented a shock intensity‐dependent U‐shaped pattern were also increased in the group trained at the lowest shock condition (0.2 mA) and remained unchanged in the intermediate shock condition (0.4 mA). Freezing and corticosterone values at both testing times were positively related with shock intensity experienced at training. Therefore, our results show a complex regulation of CAMs of the immunoglobulin superfamily in the hippocampus that depends upon stressor intensity and time factors. In addition, the pattern of CAMs expression found in the 1 mA group (which is the one that shows higher post‐training corticosterone levels and develops the stronger and longer‐lasting levels of fear conditioning) supports the view that, after a first phase of synaptic de‐adherence during consolidation, NCAM and L1 might participate in the stabilization of selected synapses underlying the establishment of long‐term memory for contextual fear conditioning, and suggests that glucocorticoids might play a role in the observed regulation of CAMs.
Alleviation of overtraining reversal effect by transient inactivation of the dorsal striatum
Authors: Van Golf Racht‐Delatour B. , Massioui N. El
Published: March 2003

In this study, we investigated the role of the dorsal striatum in the acquisition and the use (retrieval) of a specific learning developed during overtraining. The paradigm was such that rats had to respond differentially to two signals in order to obtain food or to avoid an electrical footshock. Overtraining was aimed at eliciting a facilitative effect on discrimination reversal as compared to simply trained rats. In this way, transient inactivation of the dorsal striatum by lidocaine enabled us to investigate, separately, the role of this structure during overtraining and reversal. The data show that inactivating the dorsal striatum before each reversal session prevented the overtraining reversal effect observed in control rats. Moreover, inactivation of the dorsal striatum during overtraining had no effect on the level of discriminative performance just as it did not affect the subsequent facilitative effect on reversal. These results show that even though the striatum might normally be part of a routine automatic system, clearly its contribution is not essential. Indeed, despite inactivation of the striatum in overtrained rats, their ability to develop an efficient selection process that can be used during reversal was observed. However, the integrity of the striatum became essential in order to mediate the modification of behaviour when this behavioural routine formed during overtraining had to be modified during reversal.
Dysfunctional regulation of αCaMKII and syntaxin 1B transcription after induction of LTP in the aged rat
Authors: Davis S. , Salin H. , Helme‐Guizon A. , Dumas S. , Stéphan A. , Corbex M. , Mallet J. , Laroche S.
Published: March 2003

Syntaxin 1B and αCaMKII are two genes that are upregulated after the induction of LTP and appear to underlie different mechanisms of synaptic plasticity. αCaMKII is directly implicated in strengthening the synapses that have been modified, whereas syntaxin 1B has been implicated in a mechanism for the propagation of synaptic plasticity within neural circuits. In these experiments we have investigated whether the regulation of these genes is altered after the induction of LTP in aged rats. We found, three hours after the induction of LTP in the dentate gyrus, that aged rats could be subgrouped into those in which LTP was maintained and those in which LTP had decayed back to basal levels. Both genes were upregulated in young adult rats, whereas there was a differential pattern of LTP‐induced expression in the aged rats. Dendritic αCaMKII was upregulated in aged rats only when LTP was maintained. In contrast, regulation of syntaxin 1B and αCaMKII was absent in the granule cell bodies of the aged rats regardless of whether LTP was maintained or not. These results suggest that molecular mechanisms implicated in two aspects of hippocampal synaptic plasticity malfunction during normal ageing and therefore may have some contributory role in the decline in memory function routinely observed in ageing.
Can a motion‐blind patient reach for moving objects?
Authors: Schenk Thomas , Mai Norbert , Ditterich Jochen , Zihl Josef
Published: March 2003

It has been claimed that the visual brain is organized in two separate processing streams for spatial vision: one for perception and one for action. To determine whether motion vision is also divided into vision for action and for perception we examined the interceptive behaviour of the motion‐blind patient LM. The task for LM and three age‐matched control subjects was to reach‐and‐grasp for an object that moved away. Three experiments were conducted to examine the effects on perfomance of target speed (Expt 1), observation time (Expt 2) and visual feedback (Expt 3). As LM is only able to reach for objects which move at 0.5 m/s or less, her performance is inferior to that of controls who can reach for objects moving at 1.0 m/s, but it is better than would be expected from her performance in psychophysical experiments on her motion vision. Kinematic analysis of LM's reaching movements showed that she adapted the speed of her moving hand to the speed of the target but only when full vision was available. In contrast to normal subjects, LM required long observation times and vision of her moving hand to produce successful reaching responses. Thus, the impairment of both perception and action in LM suggests that the motion area MT/V5 is located at an early stage of the extrastriate hierarchy and provides input to both the perception and the action processing streams.
Different functions of fetal and adult AChR subtypes for the formation and maintenance of neuromuscular synapses revealed in ε‐subunit‐deficient mice
Authors: Schwarz Holger , Giese Günter , Müller Holger , Koenen Michael , Witzemann Veit
Published: March 2003

Mice deficient in ε‐subunits of the acetylcholine receptor (AChR) channel die prematurely due to severe AChR deficiency that leads to the progressive reduction in AChR density at the neuromuscular endplate [Witzemann, V., Schwarz, H., Koenen, M., Berberich, C., Villarroel, A., Wernig, A., Brenner, H.R. & Sakmann, B. (1996) Proc. Natl Acad. Sci. USA, 93, 13286–13291]. The mice may serve as a model for studying AChR‐related myasthenic diseases. The postnatal development of the subsynaptic apparatus takes place in the absence of the adult type, ε‐subunit‐containing receptors which normally replace the fetal γ‐subunit‐containing receptors. During later development the secondary folds of the postsynaptic membrane disappear concomitant with the decrease in AChR density, so that the flattened‐out membrane with its remaining nicotinic receptors is in close proximity to the subsynaptic cytoplasmatic compartment and the subsynaptic myonuclei. The decrease in AChR concentration is correlated with a decrease of postsynaptic rapsyn, but has less effect on agrin, a neuronally released aggregating factor for AChRs. Thus, despite the presence of agrin at the synapse, AChR expression is not maintained at the level required to stabilize normal synaptic structure comprising secondary postsynaptic membrane folds. Collectively the results suggest that the postnatal switch from the global, activity‐sensitive γ‐subunit gene transcription to the synapse‐specific, activity‐independent ε‐subunit gene transcription is not required for the formation and differentiation of synapses but is essential for the maintenance of the highly organized structure of the neuromuscular endplate.
Transcriptional and post‐transcriptional regulation of a brain growth protein: regional differentiation and regeneration induction of GAP‐43
Authors: Namgung Uk , Routtenberg Aryeh
Published: March 2003

During axonal regeneration synthesis of different growth‐associated proteins is increased. As yet there is no clear picture of the specific contribution made by the transcriptional and post‐transcriptional machinery that provides the gene products necessary for process outgrowth. Here we focus our study on the transcriptional processes in neurons by using intron‐directed in situ hybridization to the primary transcript of a brain growth protein GAP‐43. In most brain regions, levels of primary transcript expression of GAP‐43 were highly correlated with levels of its mRNA. However, there were notable dissociations: in hippocampal granule cells, high levels of primary transcript were evident yet no GAP‐43 mRNA was detected. In locus coeruleus the reverse was true; there were high levels of GAP‐43 mRNA but no detectable primary transcript. A primary transcript antitermination mechanism is proposed to explain the first dissociation, and a post‐transcriptional mRNA stabilization mechanism to explain the second. Transcriptional activation during nerve regeneration was monitored by assessing primary transcript induction of GAP‐43 in mouse facial motor neurons. This induction, as well as its mRNA, was restricted to the side of the facial nerve crush. Increases were first observed at 24 h with a rapid increase in both measures up to 3 days. To our knowledge, this is the first in vivo evidence demonstrating transcriptional activation of a brain growth protein in regenerating neurons. The present study points to the GAP‐43 transcriptional mechanism as a key determinant of GAP‐43 synthesis. Along with the recruitment of post‐transcriptional mechanisms, such synthesis occurs in response to both intrinsic developmental programs and extrinsic environmental signals.
Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180
Authors: Stork O. , Welzl H. , Wolfer D. , Schuster T. , Mantei N. , Stork S. , Hoyer D. , Lipp H. ‐P. , Obata K. , Schachner M.
Published: March 2003

In the present study we further investigate functions of the neural cell adhesion molecule (NCAM) in the mature central nervous system and its implications for animal behaviour. To this end we generated transgenic mice expressing the major NCAM isoform with the largest cytoplasmic domain, NCAM180, under control of a promoter for the small form neurofilament gene. Transgenic mice were also bred with mice deficient in endogenous NCAM (Ncam–/– mice) so that effects of NCAM180 could be analysed in the presence and absence of endogenous NCAM. While overexpression of transgenic NCAM180 was without apparent behavioural or morphological effect, its expression in Ncam–/– mice counteracted NCAM ablation‐induced aggressive, anxiety‐like and antidepressant‐like behaviour. It furthermore prevented a hypersensitivity of Ncam–/– mice to the anxiolytic serotonin1A (5‐HT1A) receptor agonist buspirone. Such recovery of emotional behaviour and behavioural 5‐HT1A response occurred in spite of misdevelopment of the olfactory bulb and hippocampus that is characteristic of Ncam–/– mice, and without an apparent change in the expression of 5‐HT1A binding sites in the brain. Hippocampus‐ and amygdala‐dependent learning, though disturbed in Ncam–/– mice, remained unaffected by the transgenic NCAM180. We suggest an involvement of NCAM180‐mediated cell recognition processes in the serotonergic modulation of emotional behaviour in adult mice.
Evidence for coassembly of mutant GABACρ1 with GABAAγ2S, glycine α1 and glycine α2 receptor subunits in vitro
Authors: Pan Zhuo‐Hua , Zhang Dongxian , Zhang Xishan , Lipton Stuart A.
Published: March 2003

Functional coassembly of γ‐aminobutyric acid (GABA)Cρ1 subunits with GABAA (α1, β2, and γ2S) or glycine (α1, α2, and β) subunits was examined using two‐electrode voltage‐clamp recordings in the Xenopus laevis oocyte expression system. To facilitate this study, we took advantage of the unique gating and pharmacological properties of two mutant ρ1 subunits, ρ1(T314A) and ρ1(T314A/L317A). When the ρ1(T314A) subunit was coexpressed with GABA γ2S, glycine α1 or glycine α2 subunits, GABA response properties were different from those of homomeric ρ1(T314A) receptors. Additionally, the sensitivity of heteromeric ρ1(T314A) and γ2S receptors to picrotoxinin (PTX) blockade of GABA‐evoked responses was altered compared to that of homomeric ρ1(T314A) receptors. Changes in GABA response properties and picrotoxinin sensitivity were also observed when ρ1(T314A) subunits were coexpressed with wild‐type ρ1 subunits. When ρ1(T314A/L317A) subunits were coexpressed with GABA γ2S, glycine α1 or glycine α2 subunits, suppression by GABA of spontaneously active current was reduced compared to that of homomeric ρ1(T314A/L317A) receptors. Recovery of the spontaneous current from inhibition by GABA for GABA ρ1(T314A/L317A)/γ2S heteromeric receptors displayed an additional component. Coinjection of wild‐type ρ1 with γ2S cRNAs at a ratio of 1 : 1 resulted in a > 10‐fold reduction in GABA‐evoked current. Furthermore, coexpression of wild‐type ρ1 and γ2S subunits was found to shift the GABA dose–response curve. Our results provide functional evidence that the GABACρ1 subunit can coassemble with the GABAAγ2S subunit, and, at least in its mutated form, ρ1 can also form heteromeric receptors with glycine α1 or α2 subunits in vitro.
Unrelated course of subthalamic nucleus and globus pallidus neuronal activities across vigilance states in the rat
Authors: Urbain Nadia , Gervasoni Damien , Soulière Fabienne , Lobo Letícia , Rentéro Nicolas , Windels François , Astier Bernadette , Savasta Marc , Fort Patrice , Renaud Bernard , Luppi Pierre‐Hervé , Chouvet Guy
Published: March 2003

The pallido‐subthalamic pathway powerfully controls the output of the basal ganglia circuitry and has been implicated in movement disorders observed in Parkinson's disease (PD). To investigate the normal functioning of this pathway across the sleep–wake cycle, single‐unit activities of subthalamic nucleus (STN) and globus pallidus (GP) neurons were examined, together with cortical electroencephalogram and nuchal muscular activity, in non‐anaesthetized head‐restrained rats. STN neurons shifted from a random discharge in wakefulness (W) to a bursting pattern in slow wave sleep (SWS), without any change in their mean firing rate. This burst discharge occurred in the 1–2 Hz range, but was not correlated with cortical slow wave activity. In contrast, GP neurons, with a mean firing rate higher in W than in SWS, exhibited a relatively regular discharge whatever the state of vigilance. During paradoxical sleep, both STN and GP neurons increased markedly their mean firing rate relative to W and SWS. Our results are not in agreement with the classical ‘direct/indirect’ model of the basal ganglia organization, as an inverse relationship between STN and GP activities is not observed under normal physiological conditions. Actually, because the STN discharge pattern appears dependent on coincident cortical activity, this nucleus can hardly be viewed as a relay along the indirect pathway, but might rather be considered as an input stage conveying corticothalamic information to the basal ganglia.
Ultrastructural localization of mint1 at synapses in mouse hippocampus
Authors: Okamoto Masaya , Matsuyama Tomohiro , Sugita Minoru
Published: March 2003

Mint1 and mint2 were isolated in the course of seeking the protein ligands to munc18–1, a neuronal protein essential for synaptic vesicle exocytosis. The mint family of proteins has been highly conserved in the course of evolution, being retained from C. elegans to mammals. Several lines of biochemical and genetic evidence have suggested that mint1 and LIN‐10, its homologue in C. elegans, function at synapses in the brain. Because the precise subcellular location of mint1 is incompletely known, we used immunostaining to examine the distribution of mint1 in the mouse brain including ultrastructural localization in synapses. Strong, finely punctate mint1 immunolabeling was detected throughout the brain, including cerebral cortex, striatum, hippocampus, thalamus, basal ganglia and cerebellum. At the most synapses in the molecular layer, mint1 was particularly abundant at the active zone and to a lesser extent in association with synaptic vesicles in the presynaptic terminals. In contrast, a very few synapses showed mint1 immunoreactivity in the postsynaptic density and there was no synapse double‐positive in presynaptic and postsynaptic terminals. Mint1 distribution within presynaptic terminals overlapped that of munc18–1. These localization results are consistent with previously demonstrated biochemical interactions and strongly support functions of mint1 in synaptic vesicle exocytosis and synaptic organization in the central nervous system.
Volume‐regulated anion channels do not contribute extracellular adenosine during the hypoxic depression of excitatory synaptic transmission in area CA1 of rat hippocampus
Authors: Pearson Tim , Frenguelli Bruno G.
Published: March 2003

We investigated whether volume‐regulated anion channels (VRACs) contributed to the accumulation of extracellular adenosine during hypoxia in area CA1. The rapid hypoxic depression of the fEPSP was greatly attenuated by the selective adenosine A1 receptor antagonist DPCPX (50 nm), but not affected by the VRAC blockers tamoxifen (10–30 μm) or DNDS (1 mm). Our data argue against the efflux of adenosine per se or its precursor ATP through VRACs as making a significant contribution to extracellular adenosine during the early stages of hypoxia.
Melatonin sees the light: blocking GABA‐ergic transmission in the paraventricular nucleus induces daytime secretion of melatonin
Authors: Kalsbeek Andries , Garidou Marie‐Laure , Palm Inge F. , Van Der Vliet Jan , Simonneaux Valérie , Pévet Paul , Buijs Ruud M.
Published: March 2003

Despite a pronounced inhibitory effect of light on pineal melatonin synthesis, usually the daily melatonin rhythm is not a passive response to the surrounding world. In mammals, and almost every other vertebrate species studied so far, the melatonin rhythm is coupled to an endogenous pacemaker, i.e. a circadian clock. In mammals the principal circadian pacemaker is located in the suprachiasmatic nuclei (SCN), a bilateral cluster of neurons in the anterior hypothalamus. In the present paper we show in the rat that bilateral abolition of γ‐aminobutyric acid (GABA), but not vasopressin, neurotransmission in an SCN target area, i.e. the paraventricular nucleus of the hypothalamus, during (subjective) daytime results in increased pineal melatonin levels. The fact that complete removal of the SCN results in a pronounced increase of daytime pineal mRNA levels for arylalkylamine N‐acetyltransferase (AA‐NAT), i.e. the rate‐limiting enzyme of melatonin synthesis, further substantiates the existence of a major inhibitory SCN output controlling the circadian melatonin rhythm.
Close linkage between calcium/calmodulin kinase II α/β and NMDA‐2A receptors in the lateral amygdala and significance for retrieval of auditory fear conditioning
Authors: Moriya Takahiro , Kouzu Yasuko , Shibata Shigenobu , Kadotani Hiroshi , Fukunaga Kohji , Miyamoto Eishichi , Yoshioka Tohru
Published: March 2003

The general mechanism underlying memory and learning is an area under intense investigation and debate, yet this mechanism still remains elusive. Auditory fear conditioning (when a tone is paired with a foot shock) is a simple associative form of learning for which many mechanistic details are known. Lesions of the lateral/basolateral nuclei of the amygdala result in the selective impairment of fear conditioning, indicating that this is a key region for this type of learning. Fear conditioning induces a lasting synaptic potentiation in the lateral nuclei of the amygdala. In addition, recent results from several laboratories suggest that N‐methyl‐ d‐aspartate (NMDA) receptor activation in the amygdala is required for the acquisition and expression of cue‐conditioned fear responses using several kinds of antagonists. Little is known, however, about the signal transduction pathway and molecular substrate underlying fear conditioning. Here we use NMDA receptor‐deficient mice to demonstrate that calmodulin‐dependent kinase II, CaMKIIβ, and CaMKIIα activation involves the NR2A subunit in the lateral/basolateral amygdala during memory retrieval following auditory fear conditioning. These results suggest that auditory fear conditioning involves a close linkage between NMDA2A receptors and the CaMKII cascade.
Age‐ and species‐dependent maturation of synaptic transmission in the superficial superior colliculus
Authors: White Anne‐Marie , Platt Bettina
Published: March 2003

Both neonatal maturity and postnatal maturation are known to be species dependent. For instance, guinea pigs are born with their eyes open, while eye opening takes place 2 weeks after birth in rats. Moreover, several abnormalities have been observed in albino compared to pigmented species. The pigment melanin is proposed to play a protective role and its absence is thought to contribute to neuronal deficits. In the present study, we aimed to investigate functional differences in synaptic transmission in the visual, superficial layers of the superior colliculus (SC) of albino and pigmented rats and pigmented guinea pigs, at eye opening and 1 month after birth. This was achieved by analysing evoked field excitatory postsynaptic potentials (fEPSPs) in vitro, and by investigating the ability of these responses to express γ‐aminobutyric acid (GABA)‐induced long‐term potentiation (LTPG), an enduring increase in synaptic efficacy resulting from bath application of GABA.

Guinea pigs did not show any obvious differences with respect to overall fEPSP characteristics and synaptic plasticity at both ages studied, indicating that maturation must have occurred prenatally. Rats, however, underwent synaptic maturation and refinement to produce stronger fEPSPs and a more robust level of synaptic plasticity 1 month after birth compared to the conditions at eye opening. The state of pigmentation was found to have a crucial influence, with albino rats showing less enhancement of the strength of synaptic transmission in the SC.

It can therefore be concluded that profound developmental differences in pre‐ and postnatal maturation of the superficial SC exist between guinea pigs and rats, and that the state of pigmentation is a crucial factor in this process.
Assessment of behavioural recovery following spinal cord injury in rats
Authors: Muir Gillian D. , Webb Aubrey A.
Published: March 2003

Behavioural recovery is one of the primary goals of therapeutic intervention in animal models of disease. It is necessary, therefore, to have the means with which to quantify pertinent behavioural changes in experimental animals. Nevertheless, the number and diversity of behavioural measures which have been used to assess recovery after experimental interventions often makes it difficult to compare results between studies. The present review attempts to integrate and categorize the wide variety of behavioural assessments used to measure recovery in spinal‐injured rats. These categories include endpoint measures, kinematic measures, kinetic measurements, and electrophysiological measurements. Within this categorization, we discuss the advantages and disadvantages of each type of measurement. Finally, we make some recommendations regarding the principles for a comprehensive behavioural analysis after experimental spinal cord injury in rats.