bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective activation of the ventrolateral prefrontal cortex in the human brain during active retrieval processing
Authors: Cadoret Geneviève , Pike G. Bruce , Petrides Michael
Published: March 2003

The present study examined the role of the prefrontal cortex in retrieval processing using functional magnetic resonance imaging in human subjects. Ten healthy subjects were scanned while they performed a task that required retrieval of specific aspects of visual information. In order to examine brain activity specifically associated with retrieval, we designed a task that had retrieval and control conditions that were perfectly matched in terms of depth of encoding, decision making and postretrieval monitoring and differed only in terms of whether retrieval was required. In the retrieval condition, based on an instructional cue, the subjects had to retrieve either the particular stimulus that was previously presented or its location. In the control condition, the cue did not instruct retrieval but shared with the instructional cues the function of alerting the subjects of the impending test phase. The comparison of activity between the retrieval and control conditions demonstrated a significant and selective increase in activity related to retrieval processes within the ventrolateral prefrontal cortical region, more specifically within area 47/12. These activity increases were bilateral but stronger in the right hemisphere. The present study by strictly controlling the level of encoding, postretrieval monitoring, and decision making has demonstrated a specific increase in the ventrolateral prefrontal region that could be clearly related to active retrieval processing, i.e. the active selection of particular stored visual representations.
Characterization of serial order encoding in the monkey anterior cingulate sulcus
Authors: Procyk E. , Joseph J. P.
Published: March 2003

In a previous report we showed that neurons in the anterior cingulate cortex might encode the serial order of the three components (first, second and third) of motor sequences, irrespective of which component is performed, and irrespective of the component that precedes or follows. Here we further explore these data by comparing the magnitude of cell activity at the different ranks. We also compare the activity recorded in the motor sequences and in tasks with only one motor component. We finally discuss functional hypotheses, which may account for the serial order encoding.
Gaze shifts evoked by electrical stimulation of the superior colliculus in the head‐unrestrained cat. II. Effect of muscimol inactivation of the caudal fastigial nucleus
Authors: Guillaume Alain , Pélisson Denis
Published: March 2003

The medioposterior cerebellum [vermian lobules VI and VII and caudal fastigial nucleus (cFN)] is known to play a major role in the control of saccadic gaze shifts toward a visual target. To determine the relative contribution of the cFN efferent pathways to the brainstem reticular formation and to the superior colliculus (SC), we recorded in the head‐unrestrained cat the effects of cFN unilateral inactivation on gaze shifts evoked by electrical microstimulation of the deeper SC layers. Gaze shifts evoked after muscimol injection still exhibited the typical qualitative features of normal saccadic gaze shifts. Nevertheless, consistent modifications in amplitude and latency were observed. For ipsiversive movements (evoked by the SC contralateral to the inactivated cFN), these changes depended on the locus of stimulation on the motor map: for the anterior 2/3 of the SC, amplitude increased and latency tended to decrease; for the posterior 1/3 of the SC, amplitude decreased and latency increased. For the contraversive direction, amplitude moderately decreased and latency tended to increase for all but the caudal‐most stimulated SC site. These modifications of SC‐evoked gaze shifts during cFN inactivation differed from the ipsiversive hypermetria/contraversive hypometria pattern observed for visually triggered gaze shifts recorded during the same recording sessions. We conclude that (i) the topographical organization of gaze shift amplitude in the deeper SC layers is influenced by the cerebellum and is either severely distorted or demonstrates an amplitude reduction during inactivation of the contralateral or ipsilateral cFN, respectively; (ii) gaze shifts evoked by SC microstimulation and visually triggered gaze shifts either rely on distinct cerebellar‐dependent control processes or differ by the location of the caudal‐most active SC population. We present a functional scheme providing several predictions regarding the modulatory influence of the cerebellum on SC neuronal activities and on the topographical organization of fastigial–SC projections.
Insulin promotes functional induction of silent synapses in differentiating rat neocortical neurons
Authors: Plitzko Daniela , Rumpel Simon , Gottmann Kurt
Published: March 2003

Long‐term synaptic plasticity is thought to underlie synaptic reorganization phenomena that occur during neocortical development. Recently, it has been proposed, that the functional induction of AMPA receptors at silent glutamatergic synapses is of major importance in activity‐dependent, developmental plasticity. To investigate the mechanisms involved in the developmental regulation of silent synapses, we analysed the functional maturation of the thalamocortical projection in culture. A large proportion of the thalamocortical synapses were functionally silent at an early stage in vitro. During further differentiation, the incidence of silent synapses decreased drastically, indicating a conversion of silent into functional synapses. Chronic blockade of spontaneous network activity by addition of tetrodotoxin to the culture medium strongly impaired this developmental maturation. Moreover, the developmental decline in the proportion of silent synapses was dramatically accelerated by chronic addition of the neurotrophic factor, insulin. This effect of insulin was partly dependent on spontaneous activity. Thus, insulin appears to be involved in the modulation of long‐term developmental plasticity at immature glutamatergic synapses.
Noxious heat‐induced CGRP release from rat sciatic nerve axons in vitro
Authors: Sauer S. K. , Reeh P. W. , Bove G. M.
Published: March 2003

Noxious heat may act as an endogenous activator of the ionotropic capsaicin receptor (VR1) and of its recently found homologue VRL1, expressed in rat dorsal root ganglion cells and present along their nerve fibres. We have previously reported that capsaicin induces receptor‐mediated and Ca++‐dependent calcitonin gene‐related peptide (CGRP) release from axons of the isolated rat sciatic nerve. Here we extended the investigation to noxious heat stimulation and the transduction mechanisms involved. Heat stimulation augmented the CGRP release from desheathed sciatic nerves in a log–linear manner with a Q10 of ≈ 15 and a threshold between 40 and 42 °C. The increases were 1.75‐fold at 42 °C, 3.8‐fold at 45 °C and 29.1‐fold at 52 °C; in Ca++‐free solution these heat responses were abolished or reduced by 71 and 92%, respectively. Capsazepine (10 µm) and Ruthenium Red (1 µm) used as capsaicin receptor/channel antagonists did not significantly inhibit the heat‐induced release. Pretreatment of the nerves with capsaicin (100 µm for 30 min) caused complete desensitization to 1 µm capsaicin, but a significant heat response remained, indicating that heat sensitivity is not restricted to capsaicin‐sensitive fibres. The sciatic nerve axons responded to heat, potassium and capsaicin stimulation with a Ca++‐dependent CGRP release. Blockade of the capsaicin receptor/channels had little effect on the heat‐induced neuropeptide release. We conclude therefore that other heat‐activated ion channels than VR1 and VRL1 in capsaicin‐sensitive and ‐insensitive nerve fibres may cause excitation, axonal Ca++ influx and subsequent CGRP release.
Stimulation of α1‐adrenoceptors inhibits memory consolidation in the chick
Authors: Gibbs Marie E. , Summers Roger J.
Published: March 2003

Investigation of the effects of the different adrenoceptor (AR) subtypes in memory formation may reveal discrete actions of noradrenaline in memory modulation and storage mediated through particular AR subtypes. Noradrenaline injected intracerebrally in the chick produced biphasic effects on memory consolidation with enhancement at low doses and inhibition at high doses. We have previously shown that the enhancement by the lower doses of noradrenaline is attributable to actions at β2‐ and β3‐adrenoceptors, whereas the inhibitory effect of higher doses is attributable to α1‐adrenoceptors. The present studies show that the inhibition of memory by high doses of noradrenaline is mimicked by the α1‐AR agonist methoxamine, and the dose–response curve is shifted to the right by pretreatment with the α1‐AR antagonist prazosin. α1‐ARs may play a critical role in memory formation in highly stressful situations, when noradrenaline levels are high in particular brain regions. It is not known where the α1‐ARs responsible for the effect on memory are localized. α1‐ARs are found on neurons and astrocytes and in the cerebral vasculature and therefore the action of high doses of noradrenaline via α1‐AR agonists could be via an action at any of these sites. Activation of α1‐adrenoceptors in the intermediate hyperstriatum ventrale in the chick forebrain by the α1 adrenoceptor agonist methoxamine inhibits the consolidation of memory. Because the same effect is produced by high levels of noradrenaline, it is likely that stimulation of α1‐ARs is the mechanism underlying this effect.
Persistent changes in striatal gene expression induced by long‐term l‐DOPA treatment in a rat model of Parkinson's disease
Authors: Westin J. E. , Andersson M. , Lundblad M. , Cenci M. A.
Published: March 2003

Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with l‐DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained l‐DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and l‐dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/ΔFosB‐related proteins. Unilaterally 6‐hydroxydopamine‐lesioned rats were treated with therapeutical doses of l‐DOPA for one year (long‐term group) or a few weeks (short‐term group). Age‐matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion‐induced up‐regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. l‐DOPA, but not bromocriptine, induced high striatal levels of FosB/ΔFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short‐term and long‐term l‐DOPA‐treated rats. The present data provide the first demonstration that l‐DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short‐treatment paradigms studied thus far.
Gaze shifts evoked by electrical stimulation of the superior colliculus in the head‐unrestrained cat. I. Effect of the locus and of the parameters of stimulation
Authors: Guillaume Alain , Pélisson Denis
Published: March 2003

Several studies have suggested that the pattern of neuronal activity in the superior colliculus (SC) interacts with the well‐known topographical coding of saccades (motor map). To further describe this interaction, we recorded gaze saccades evoked by electrical microstimulation of SC deeper layers in the head‐unrestrained cat and systematically varied the collicular locus (25 sites) and parameters (intensity, frequency) of the stimulation. Long stimulation trains were used to avoid saccade truncation. We found that the direction and amplitude of evoked gaze shifts were related to the stimulation locus, describing a gaze shift map. For 18 out of 20 sites the amplitude, but not the direction, also strongly depended on stimulation strength. Indeed, gaze amplitude continuously increased when raising current intensity up to several times the threshold value T (the largest intensity tested was 6 × T), whereas varying pulse frequency from 150 to 750 pulses per second (p.p.s.) revealed an optimal frequency range (300 and 500 p.p.s.) eliciting the largest gaze shifts. Moreover, the intensity effect on amplitude increased in an orderly fashion with the rostro‐caudal stimulation locus. Gaze shift amplitude was not related to the number of delivered stimulation pulses. Concerning movement initiation, increasing either intensity or frequency led to an exponential decrease in gaze latency until minimal values near 30 ms were reached, but the number of pulses delivered during the corresponding latency period remained constant within a 300–500 p.p.s. frequency range. These findings indicate that the pattern of collicular discharge evoked by electrical stimulation strongly interacts with the gaze shift map and provide evidence for a summation of collicular activities by downstream premotor neurons.
Thyroid hormone regulates TAG‐1 expression in the developing rat brain
Authors: Alvarez‐Dolado Manuel , Figueroa Angélica , Kozlov Serguei , Sonderegger Peter , Furley Andrew J. , Muñoz Alberto
Published: March 2003

TAG‐1 is a member of the immunoglobulin superfamily of cell adhesion molecules thought to play important roles in neuronal differentiation and the establishment of connectivity during brain development. Because these are processes also affected by hypothyroidism, we studied the effects of thyroid hormone deprivation and administration on TAG‐1 expression in the developing rat brain. By in situ hybridization, immunohistochemistry and Western blotting we found that TAG‐1 RNA and protein levels are upregulated in the hypothyroid brain. From embryonic day 20 to postnatal day (P) 15, elevated TAG‐1 RNA was found in several areas including the cerebral cortex, hippocampus and olfactory bulb. In agreement with this, TAG‐1 protein was overexpressed in the major fibre tracts arising from these structures, including the corpus callosum, anterior and hippocampal commissures and lateral olfactory tract. A similar overexpression of TAG‐1 by hypothyroidism was detected in the cerebellum, but starting only at P15. In all cases, elevation of TAG‐1 RNA and protein expression could be reversed by thyroid hormone treatment. These results show that the deregulation of TAG‐1 might contribute to the alterations caused by the lack of thyroid hormone during brain development.
Postnatal maturation of GABAA and GABAC receptor function in the mammalian superior colliculus
Authors: Boller Mathias , Schmidt Matthias
Published: March 2003

In the stratum griseum superficiale (SGS) of the mammalian superior colliculus, GABAC receptors seem to control the excitability of projection neurons by selective inactivation of local GABAergic interneurons. As the onset of visual responses to SC begins well after birth in the rat, it is possible to study developmental changes in GABAergic mechanisms that are linked to the onset of visual information processing. In order to analyse postnatal changes in inhibitory mechanisms that involve GABA receptor function, we used extracellular field potential (FP) recordings and single cell patch‐clamp techniques in slices from postnatal day 4 (P4) to P32 and examined the effects of GABA and muscimol on electrically evoked SGS cell activity. While GABAA receptor activation affected FP amplitudes throughout postnatal development, GABAC receptor activation did not significantly change FP amplitudes until the third postnatal week. Results from patch‐clamping single cells, however, clearly demonstrate that GABAC receptors are already functional at P4 – similar to GABAA receptors. Throughout postnatal development, activation of GABAC receptors leads to a strong inhibition of inhibitory postsynaptic activity, indicating that GABAC receptors are expressed by inhibitory interneurons. Furthermore, the proportion of neurons that show decreased excitatory postsynaptic activity during GABAC receptor activation correlates with the proportion of GABAergic interneurons in SGS. Our patch‐clamp results indicate that the functional expression of GABAC receptors by GABAergic interneurons does not change significantly during postnatal development. However, our measurements of FP amplitudes indicate that the maturation of the efferent connections of these GABAergic neurons within SGS during the third postnatal week strongly changes GABAC receptor function.
Visual stimulation‐induced phosphorylation of neurofilament‐L in the visual cortex of dark‐reared rats
Authors: Hashimoto Ryota , Nakamura Yu , Imamura Kazuyuki , Nakadate Kazuhiko , Kashiwagi Yujiro , Matsumoto Naohiko , Takeda Masatoshi
Published: March 2003

In dark‐reared animals, visual exposure is expected to induce drastic changes in both the physiology and anatomy of the cortical neurons, including the rearrangement of their cytoskeletal structures. Phosphorylation of neurofilament‐L (NF‐L) is probably associated with relatively short‐term structural plasticity in vivo, because the assembly and disassembly of the filaments are regulated by phosphorylation of the head domain of NF‐L. Thus, by using a series of site‐ and phosphorylation state‐specific antibodies against NF‐L, we examined how visual activation induces the phosphorylation of NF‐L in the rat brain. We found no specific immunoreactivity for phosphorylated NF‐L in the brain of naive rats, whereas one‐hour ambient light exposure after dark rearing for ten weeks from birth induced marked phosphorylation of NF‐L selectively. Also, the NF‐L phosphorylation was found to be localized in the primary and secondary visual cortical areas. These findings suggest that the selective phosphorylation of NF‐L plays an important role in the structural plasticity related to the visual experience.
Dual effects of NMDA receptor activation on polysialylated neural cell adhesion molecule expression during brainstem postnatal development
Authors: Bouzioukh Farima , Tell Fabien , Rougon Geneviève , Jean André
Published: March 2003

Here we show a dual role of N‐methyl‐d‐aspartate receptor (NMDAR) activation in controlling polysialylated neural cell adhesion molecule (PSA‐NCAM) dynamic expression in the dorsal vagal complex (DVC), a gateway for many primary afferent fibres. In this structure the overall expression of PSA‐NCAM decreases during the first 2 weeks after birth to persist only at synapses in the adult. Electrical stimulation of the vagal afferents causes a rapid increase of PSA‐NCAM expression both in vivo and in acute slices before postnatal day (P) 14 whereas a similar stimulation induces a decrease after P15. Inhibition of NMDAR activity in vitro completely prevented these changes. These regulations depend on calmodulin activation and cGMP production at all stages. By contrast, blockade of neuronal nitric oxide synthase (nNOS) prevented these changes only after P10 in agreement with its late expression in the DVC. The pivotal role of NMDAR is also supported by the observation that chronic blockade induces a dramatic decrease in PSA‐NCAM expression.
Circadian activity rhythm in methamphetamine‐treated Clock mutant mice
Authors: Masubuchi Satoru , Honma Sato , Abe Hiroshi , Nakamura Wataru , Honma Ken‐ichi
Published: March 2003

It is well established that the Clock gene is essential for expressing circadian activity rhythms in mammals under constant darkness. The Clock gene product is a positive component of a molecular feedback loop which is assumed to generate the circadian rhythm. On the other hand, chronic treatment of methamphetamine (MAP) induces locomotor activity rhythm in a circadian domain, which is independent of the suprachiasmatic nucleus (SCN) and is driven by a pacemaker outside the SCN. However, it is not known whether the pacemaker outside the SCN possesses a similar molecular mechanism to that in the SCN. Here we show that MAP restores locomotor activity rhythm in arrhythmic homozygous Clock mutant (Clock/Clock) mice under constant darkness. This result indicates that the Clock mutation does not affect the MAP‐induced locomotor rhythm.
Presynaptic group I and II metabotropic glutamate receptors oppositely modulate striatal acetylcholine release
Authors: Marti M. , Paganini F. , Stocchi S. , Bianchi C. , Beani L. , Morari M.
Published: March 2003

The effect of metabotropic glutamate receptor agonists and antagonists on KCl (20 mm)‐induced endogenous acetylcholine release from rat striatal synaptosomes was investigated. The group I agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG), 1–1000 nm, potentiated in a concentration‐dependent way the KCl‐induced acetylcholine release, reaching maximal efficacy at 100 nm (+93 ± 14%). The effect of DHPG (10 nm) was counteracted by coapplication of (7‐hydroximino)cyclopropan‐b‐chromen‐1a‐carboxylate (CPCCOEt), 10 µm, a metabotropic glutamate receptor type one selective antagonist, and 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP), 10 µm, a metabotropic glutamate receptor type five selective antagonist, but not by application of either antagonist alone. The group II agonist (2S, 1′R, 2′R, 3′R)‐2‐(2,3‐dicarboxycyclopropyl)glycine (DCG‐IV), 1–1000 nm, inhibited in a concentration‐dependent way the KCl‐induced acetylcholine release displaying maximal efficacy at 300 nm (−32 ± 2%). The effect of DCG‐IV 300 nm was counteracted by the group II selective antagonist (2S)‐α‐ethylglutamic acid (EGLU), 300 µm. The group III agonist l‐amino‐4‐phosphonobutyric acid (L‐AP4) failed to alter the KCl‐induced acetycholine release up to 300 µm. We conclude that metabotropic glutamate receptors belonging to group I and II are located on the axon terminals of striatal cholinergic interneurons, their activation resulting in facilitation and inhibition, respectively, of acetylcholine release.
Brain‐derived neurotrophic factor induces long‐lasting potentiation of synaptic transmission in visual cortex in vivo in young rats, but not in the adult
Authors: Jiang Bin , Akaneya Yukio , Ohshima Minoru , Ichisaka Satoshi , Hata Yoshio , Tsumoto Tadaharu
Published: March 2003

Brain‐derived neurotrophic factor (BDNF) rapidly enhances excitatory synaptic transmission in cortical slices. To date, however, a question of how long such an action persists remains unanswered as it is hard to record synaptic responses longer than several hours in slice preparations. To address this question and to investigate possible age‐dependency of the action, we analysed effects of a brief application of BDNF and nerve growth factor (NGF) on field potentials of visual cortex in rats of postnatal days 13–17 and 19–24 and in the adulthood for 10–24 h. Evoked potentials to stimulation of the lateral geniculate nucleus were recorded simultaneously from two cortical sites into which the neurotrophin and control solution were injected. An application of BDNF induced a slowly developing increase in the field potential amplitude in young rats. The amplitude attained a plateau level 3–4 h after the infusion; 139 ± 26% (mean ± SD) and 132 ± 21% of the baseline in the rats at P13‐17 and P19‐24, respectively. This potentiation remained stable from 4 to 8 h, then gradually decreased to the baseline 15–16 h after the infusion. NGF applied in the same way did not induce potentiation. An inhibitor of BDNF receptors blocked the potentiation when it was applied immediately after the BDNF application, but was not effective about 2 h later. In the adults, BDNF did not potentiate field potentials. These results indicate that BDNF induces synaptic potentiation lasting for several hours only in the developing cortex through processes downstream of receptor activation.
Bax and caspases are inhibited by endogenous nitric oxide in dorsal root ganglion neurons in vitro
Authors: Thippeswamy T. , McKay J. S. , Morris R.
Published: March 2003

Axotomised dorsal root ganglia (DRG) neurons show an increased expression of neuronal nitric oxide synthase (nNOS) compared with neurons from the intact ganglia. Increased nNOS expression resulted in synthesis of nitric oxide (NO) and the subsequent activation of cGMP in satellite glia cells surrounding the DRG neuron soma. In dissociated DRG we have demonstrated that the increase in nNOS expression is regulated by nerve growth factor and that the subsequent inhibition of NO production or cGMP synthesis precipitates apoptosis of neurons expressing nNOS and some non‐nNOS neurons. Hence, NO or the NO–cGMP cascade appears to have a neuroprotective action in trophic factor‐deprived DRG neurons. In the present study, using immunocytochemistry, we have investigated some of the factors associated with apoptosis that are activated when nNOS activity is blocked with NOS inhibitor in DRG neurons in vitro. Marked elevation of bax was observed within a few hours of NOS inhibition in nNOS containing neurons, whereas pretreatment of cultures with l‐arginine completely abolished this effect in almost all nNOS neurons and 8‐bromo‐cGMP in some neurons. The apoptosis precipitated by NOS inhibition was also partially prevented by a number of caspase inhibitors; of those a caspase‐9 blocker was the most effective. These observations further support the neuroprotective role of NO/NO‐cGMP in stressed DRG neurons in an autocrine fashion that involves the suppression of bax, caspase‐3 and ‐9 activation.
Changes in reward‐induced brain activation in opiate addicts
Authors: Martin‐Soelch C. , Chevalley A.‐F. , Künig G. , Missimer J. , Magyar S. , Mino A. , Schultz W. , Leenders K. L.
Published: March 2003

Many studies indicate a role of the cerebral dopaminergic reward system in addiction. Motivated by these findings, we examined in opiate addicts whether brain regions involved in the reward circuitry also react to human prototypical rewards. We measured regional cerebral blood flow (rCBF) with H215O positron emission tomography (PET) during a visuo‐spatial recognition task with delayed response in control subjects and in opiate addicts participating in a methadone program. Three conditions were defined by the types of feedback: nonsense feedback; nonmonetary reinforcement; or monetary reward, received by the subjects for a correct response. We found in the control subjects rCBF increases in regions associated with the meso‐striatal and meso‐corticolimbic circuits in response to both monetary reward and nonmonetary reinforcement. In opiate addicts, these regions were activated only in response to monetary reward. Furthermore, nonmonetary reinforcement elicited rCBF increases in limbic regions of the opiate addicts that were not activated in the control subjects. Because psychoactive drugs serve as rewards and directly affect regions of the dopaminergic system like the striatum, we conclude that the differences in rCBF increases between controls and addicts can be attributed to an adaptive consequence of the addiction process.
Ethanol reduces excitability in a subgroup of primary sensory neurons by activation of BKCa channels
Authors: Gruß Marco , Henrich Michael , König Peter , Hempelmann Gunter , Vogel Werner , Scholz Andreas
Published: March 2003

Ethanol effects on the central nervous system have been well investigated and described in recent years; modulations, by ethanol, of several ligand‐gated and voltage‐gated ion channels have been found. In this paper, we describe a shortening of action potential duration (APD) by ethanol in ≈ 40% of small diameter neurons in rat dorsal root ganglia (DRG). In these neurons, designated as group A neurons, we observed an ethanol‐induced increase in whole‐cell outward‐current. As iberiotoxin, a specific blocker of large‐conductance calcium‐activated K+ channels (BKCa channels), blocks the effects of ethanol, we investigated the interaction between these channels and ethanol in outside‐out patches. Open probability of BKCa channels was increased 2–6 × depending on the concentration (40–80 mm≈ 2–4‰ v/v) of ethanol. Functional consequences were a prolongation of the refractory period, which was reversible after addition of iberiotoxin, and reduced firing frequency during ethanol application. In contrast, another type of neuron (group B) showed a prolonged APD during application of ethanol which was irreversible in most cases. In 90% of cases, neurons of group A showed a positive staining for isolectin B4 (I‐B4), a marker for nociceptive neurons. We suggest that the activation of BKCa channels induced by clinically relevant concentrations of ethanol, the resulting modulations of APD and refractory period of DRG neurons, might contribute to clinically well‐known ethanol‐induced analgesia and paresthesia.
Unilateral striatal dopamine depletion: time‐dependent effects on cortical function and behavioural correlates
Authors: Steiner Heinz , Kitai Stephen T.
Published: March 2003

Previously, we showed that unilateral blockade of D1 dopamine receptors in the striatum inhibits immediate‐early gene expression bilaterally throughout large parts of the cortex, including sensory‐evoked expression in the barrel cortex. To further investigate this dopamine regulation of cortical function, we examined the effects of dopamine depletion on cortical gene regulation and behavioural correlates. Two days after unilateral infusion of 6‐hydroxydopamine into the midbrain, rats displayed a (to some degree) bilateral reduction in cortical zif 268 expression that was more pronounced on the lesioned side. This decrease was found across motor, somatosensory, insular and piriform, but not cingulate, cortex, similar to the effects of blockade of striatal D1 receptors. Furthermore, whisker stimulation‐evoked c‐fos and zif 268 expression in the barrel cortex ipsilateral to the lesion was also attenuated by acute dopamine depletion. These cortical deficits were accompanied by a breakdown of spontaneous behaviours in an open‐field test. In contrast, 21 days after dopamine depletion, both basal and sensory‐evoked gene expression in the cortex were near‐normal. This cortical recovery was paralleled by recovery in locomotion and in sensory‐guided behaviour (scanning) related to the hemisphere contralateral to the lesion, but not in scanning by the dopamine‐depleted hemisphere. Our results suggest that striatal dopamine exerts a widespread facilitatory influence on cortical function that is necessary, but not sufficient, for normal behaviour. Moreover, the mechanisms mediating this cortical facilitation appear to be subject to substantial neuroplasticity after dopamine perturbation.
Cortico‐cortical connectivity of the human mid‐dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation
Authors: Paus Tomáš , Castro‐Alamancos Manuel A. , Petrides Michael
Published: March 2003

Modulation of cortico‐cortical connectivity in specific neural circuits might underlie some of the behavioural effects observed following repetitive transcranial magnetic stimulation (rTMS) of the human frontal cortex. This possibility was tested by applying rTMS to the left mid‐dorsolateral frontal cortex (MDL‐FC) and subsequently measuring functional connectivity of this region with positron emission tomography (PET) and TMS. The results showed a strong rTMS‐related modulation of brain activity in the fronto‐cingulate circuit. These results were confirmed in a parallel experiment in the rat using electrical stimulation and field‐potential recordings. Future studies are needed to provide a direct link between the rTMS‐induced modulation of cortical connectivity and its effects on specific behaviours.
Differences in auditory and physiological properties of HVc neurons between reproductively active male and female canaries (Serinus canaria)
Authors: Del Negro Catherine , Edeline Jean‐Marc
Published: March 2003

Based on neuronal recordings in the HVc, this study investigated differences between reproductively active male and sexually receptive female canaries. It is the first study to describe auditory responses and cell characteristics of HVc neurons in female songbirds and to compare them with the responses and characteristics obtained in males. Extracellular single unit recordings showed that in males HVc cells exhibited two types of auditory responses to conspecific and heterospecific song playbacks: tonic and phasic responses. The major finding of the present study is the absence of tonic responses in females. Neurons in the HVc of females only responded phasically to song playbacks. In both sexes, neurons exhibiting auditory responses had thinner action potentials than the others. As all the tonic cells recorded in males were thin spike cells (action potential = 0.6 ms) and had high firing rates (6 Hz in average), they are potentially interneurons. In both sexes, two categories of nonresponsive cells were found: neurons that did not fire at song onset and had the lowest spontaneous firing rate; and neurons that did not exhibit changes in activity in response to song playbacks. Analyses of physiological characteristics of HVc neurons revealed that the rate of spontaneous activity was higher in males than in females. This study is a first step towards in dentifying the cellular bases of the sexual dimorphism in HVc function and highlights the pivotal role of interneurons in HVc auditory processing.
Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A2A receptors in the caudate‐putamen of rats
Authors: Hauber Wolfgang , Neuscheler Patric , Nagel Jens , Müller Christa E.
Published: March 2003

The present study sought to determine, in more detail, the effects of an unselective and a selective adenosine A2A receptor blockade on catalepsy induced by a blockade of dopamine D1 or D2 receptors in rats. The results demonstrated that systemic administration of the unselective A1/A2 receptor antagonist, theophylline and the selective A2A receptor antagonist, CSC potently reversed catalepsy induced by a systemic D2 receptor blockade with raclopride or by a bilateral blockade of D2 receptors in the caudate‐putamen (CPu) with S(–)sulpiride. Likewise, systemic administration of theophylline and CSC reversed catalepsy induced by a systemic D1 receptor blockade with SCH23390; theophylline also counteracted catalepsy after an intra‐CPu D1 receptor blockade with SCH23390. Intracerebral co‐microinfusions of the selective A2A receptor antagonist, MSX‐3 together with a D1 (SCH23390) or D2 receptor [S(–) sulpiride] antagonist revealed that catalepsy due to intra‐CPu D1 or D2 receptor blockade can be potently reversed by an intra‐CPu A2A receptor blockade. In conclusion, our results with systemic and intra‐CPu drug administration demonstrate that D1 and D2 receptor‐mediated catalepsy can both be reversed by a concomitant blockade of A2A receptors. Our results implicate that the CPu is a critical neural substrate for antagonistic interactions of a D1/D2 receptor blockade and an A2A receptor blockade in control of motor activity. The present results provide further support for the view that A2A receptor antagonists may be potential therapeutics for the treatment of Parkinson's disease.
The projections of the midbrain periaqueductal grey to the pons and medulla oblongata in rats
Authors: Odeh Francis , Antal Miklós
Published: March 2003

It is now established that stimulation of the ventrolateral midbrain periaqueductal grey (PAG) evokes inhibition of nociceptive spinal neurons, which results in analgesia and a powerful attenuation of pain behaviour. It is postulated that the PAG exerts this inhibitory effect on spinal nociceptive functions through the activation of descending serotonergic and noradrenergic pathways that arise from the rostral ventromedial medulla (RVM) and pontine noradrenergic nuclei. To investigate the neuroanatomical substrate of this functional link between the PAG and RVM, as well as the pontine noradrenergic nuclei in the rat, we labelled axons that project from the ventrolateral PAG to various regions of the pons and medulla oblongata using the anterograde tracing substance, Phaseolus vulgaris leucoagglutinin. We demonstrated that some of PAG efferents really do terminate in the RVM and pontine noradrenergic nuclei, but a substantial proportion of them project to the intermediate subdivision of the pontobulbar reticular formation. Combining the axonal tracing with serotonin‐ and tyrosine‐hydroxylase‐immunohistochemistry, we also found that, in contrast to previous results, PAG efferents make relatively few appositions with serotonin‐ and tyrosine‐hydroxylase‐immunoreactive neurons in the RVM and pontine noradrenergic nuclei; most of them terminate in nonimmunoreactive territories. The results suggest that the ventrolateral PAG may activate a complex pontobulbar neuronal assembly including neurons in the intermediate subdivision of the pontobulbar reticular formation, serotonin‐ and tyrosine‐hydroxylase‐immunoreactive and nonimmunoreactive neurons in the RVM and pontine noradrenergic nuclei. This pontobulbar neural circuitry, then, may mediate the PAG‐evoked activities towards the spinal dorsal horn resulting in the inhibition of spinal nociceptive functions.
Detection and discrimination of chromatic targets in hemianopic macaque monkeys and humans
Authors: Cowey Alan , Stoerig Petra
Published: March 2003

We measured the ability of three macaque monkeys with unilateral removal of primary visual cortex to detect 9°, 200‐ms targets presented at random in the upper or lower quadrants of the normal and hemianopic visual fields. The white or variously coloured target could differ from the background in both colour and luminance, or in either of them. Blue and red targets were detectable at any luminance contrast, but green and white targets were barely or not at all detectable at and near isoluminance in the hemianopic field. Blue and red targets were better detected than white targets at the same luminance difference. However, when both the target and the background were dynamically luminance‐masked, detection in the hemianopic field failed at isoluminance whatever the colour. In addition, the monkeys were unable to discriminate between simultaneously presented red and green or blue and green targets in the hemianopic field when both targets had similar luminance contrast with the background. Two hemianopic patients tested on a subset of the tasks performed similarly to the monkeys. Together, the results indicate that the residual colour‐opponent system that survives damage to V1 is involved in the detection of chromatic changes but cannot sustain simultaneous discrimination between pairs of colours.
Biological activity of RE‐1 silencing transcription factor (REST) towards distinct transcriptional activators
Authors: Lietz Michael , Bach Karl , Thiel Gerald
Published: March 2003

The zinc finger protein RE‐1 silencing transcription factor (REST) is a transcriptional repressor that represses neuronal genes in non‐neuronal tissues. We have analyzed the ability of REST and the REST mutants, RESTΔN and RESTΔC lacking either the N‐terminal or C‐terminal repression domains of REST, to inhibit transcription mediated by distinct transcriptional activator proteins. For this purpose we have designed an activator specific assay where transcription is activated as a result of only one distinct activation domain. In addition, binding sites for REST were inserted in the 5′‐untranslated region or at a distant position downstream of the polyadenylation signal. The results show that REST or the REST mutants containing only one repression domain were able to block transcriptional activation mediated by the transcriptional activation domains derived from p53, AP2, Egr‐1, and GAL4. Moreover, REST, as well as the REST mutants, blocked the activity of the phosphorylation‐dependent activation domain of Elk1. However, the activity of the activation domain derived from cAMP response element binding protein 2 (CREB2), was not inhibited by REST, RESTΔN or RESTΔC, suggesting that REST is able to distinguish between distinct transcriptional activation domains. Additionally, the activator specific assay, together with a positive‐dominant mutant of REST that activated instead of repressed transcription, was used in titration experiments to show that REST has transcriptional repression and no transcriptional activation properties when bound to the 5′‐untranslated region of a gene.
Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus
Authors: Banasr Mounira , Hery Micheline , Brezun Jean Michel , Daszuta Annie
Published: March 2003

Characterizing the mechanisms by which endogenous factors stimulate neurogenesis is of special interest in view of the possible implication of newly generated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5‐HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long‐lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5‐HT synthesis using p‐chlorophenylalanine (PCPA) treatment produced approximately the same decreases in the number of bromodeoxyuridine (BrdU) and PSA‐NCAM immunolabelled cells in the subgranular layer as ovariectomy alone. Administration of 5‐hydroxytryptophan (5‐HTP) restored cell proliferation primarily decreased by ovariectomy, whereas oestradiol was unable to reverse this change in ovariectomized rats treated with PCPA. These findings demonstrate that 5‐HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomitant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5‐HT and oestradiol. Finally, oestrogen may regulate structural plasticity by stimulating PSA‐NCAM expression independently of neurogenesis, as shown for instance by the increases in the number of PSA‐NCAM labelled cells in pregnants. As 5‐HT and oestrogen are involved in mood disorders, our data suggest that the positive regulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.
GABAA‐receptor expression in glioma cells is triggered by contact with neuronal cells
Authors: Synowitz Michael , Ahmann Petra , Matyash Marina , Kuhn Susanne A. , Hofmann Birte , Zimmer Claus , Kirchhoff Frank , Kiwit Jürgen C. W. , Kettenmann Helmut
Published: March 2003

The expression of functional GABAA‐receptors in glioma cells correlates with low malignancy of tumours and cell lines from glioma lack these receptors. Here we show that contact with neurons induces the expression of functional GABAA‐receptors. C6 and F98 glioma cell lines were labelled by recombinant expression of enhanced green fluorescent protein injected into rat brain and studied in acute slices after two to three weeks of tumour growth. The cells responded to GABA or the specific agonist, muscimol with a current typical for GABAA‐receptors, as studied with the patch‐clamp technique. To get insight into the mechanism of GABAA receptor induction, the C6 or F98 cells were co‐cultured with neurons, astrocytes, oligodendrocytes and microglia. Glioma cells expressed functional GABAA receptors within 24 h only in cultures where physical contact to neurons occurred. Activation of GABAA‐receptors in the co‐cultures attenuated glioma cell metabolism while blockade of the receptors increased metabolism. We conclude that with this form of interaction, neurons can influence tumour behaviour in the brain.
Mice transgenic for exon 1 of the Huntington's disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6‐hydroxydopamine
Authors: Petersén Åsa , Hansson Oskar , Puschban Zoe , Sapp Ellen , Romero Norma , Castilho Roger F. , Sulzer David , Rice Margaret , DiFiglia Marian , Przedborski Serge , Brundin Patrik
Published: March 2003

Huntington's disease is an autosomal dominant hereditary neurodegenerative disorder characterized by severe striatal cell loss. Dopamine (DA) has been suggested to play a role in the pathogenesis of the disease. We have previously reported that transgenic mice expressing exon 1 of the human Huntington gene (R6 lines) are resistant to quinolinic acid‐induced striatal toxicity. In this study we show that with increasing age, R6/1 and R6/2 mice develop partial resistance to DA‐ and 6‐hydroxydopamine‐mediated toxicity in the striatum. Using electron microscopy, we found that the resistance is localized to the cell bodies and not to the neuropil. The reduction of dopamine and cAMP regulated phosphoprotein of a molecular weight of 32 kDa (DARPP‐32) in R6/2 mice does not provide the resistance, as DA‐induced striatal lesions are not reduced in size in DARPP‐32 knockout mice. Neither DA receptor antagonists nor a N‐methyl‐d‐aspartate (NMDA) receptor blocker reduce the size of DA‐induced striatal lesions, suggesting that DA toxicity is not dependent upon DA‐ or NMDA receptor‐mediated pathways. Moreover, superoxide dismutase‐1 overexpression, monoamine oxidase inhibition and the treatment with the free radical scavenging spin‐trap agent phenyl‐butyl‐tert‐nitrone (PBN) also did not block DA toxicity. Levels of the antioxidant molecules, glutathione and ascorbate were not increased in R6/1 mice. Because damage to striatal neurons following intrastriatal injection of 6‐hydroxydopamine was also reduced in R6 mice, a yet‐to‐be identified antioxidant mechanism may provide neuroprotection in these animals. We conclude that striatal neurons of R6 mice develop resistance to DA‐induced toxicity with age.
Stress alleviates reduced expression of cell adhesion molecules (NCAM, L1), and deficits in learning and corticosterone regulation of apolipoprotein E knockout mice
Authors: Grootendorst J. , Oitzl M. S. , Dalm S. , Enthoven L. , Schachner M. , De Kloet E. R. , Sandi C.
Published: March 2003

Cell adhesion molecules (CAMs) involved in synaptic changes underlying learning and memory processes, are implicated in the effect of stress on behavioural performance. The present study was designed to test the hypothesis that (i) expression of CAMs is apolipoprotein E‐ (apoE) genotype dependent and (ii) repeated exposure to stress modulates the synthesis of CAMs in an apoE‐genotype dependent manner. Using ELISA we tested this hypothesis and measured expression of NCAM and L1 in different brain regions of naïve and stressed apolipoprotein E‐knockout (apoE0/0) and C57Bl6 (wild‐type) mice. Naïve apoE0/0 mice had elevated basal morning corticosterone and ACTH concentrations and decreased expression of NCAM and L1 compared to wild‐type mice. Repeated exposure of mice to rats, as the common stressor, alleviated the reduction in expression of CAMs in apoE0/0 mice; seven days after the last rat exposure, expression of NCAM was increased in frontal brain and hippocampus whereas expression of L1 was increased in hippocampus and cerebellum. Rat stress attenuated the elevation of basal morning corticosterone concentration in apoE0/0 mice towards concentrations detected in wild‐type mice. Moreover, rat stress improved learning and memory of apoE0/0 mice in the water maze. In conclusion, repeated exposure to stress eliminated apoE‐genotype‐related differences in expression of CAMs. Under these same conditions the differences in cognitive performance and corticosterone concentrations were abolished between wild type and apoE0/0 mice.