bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum
Authors: Bubser Michael , Deutch Ariel Y.
Published: March 2003

Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side‐effects (EPS). Treatment with atypical APDs has a lower incidence of motor side‐effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate‐early gene c‐fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos‐li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD‐treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.
Mechanisms controlling bursting activity induced by disinhibition in spinal cord networks
Authors: Darbon Pascal , Scicluna Luke , Tscherter Anne , Streit Jürg
Published: March 2003

Disinhibition reliably induces regular synchronous bursting in networks of spinal interneurons in culture as well as in the intact spinal cord. We have combined extracellular multisite recording using multielectrode arrays with whole cell recordings to investigate the mechanisms involved in bursting in organotypic and dissociated cultures from the spinal cords of embryonic rats. Network bursts induced depolarization and spikes in single neurons, which were mediated by recurrent excitation through glutamatergic synaptic transmission. When such transmission was blocked, bursting ceased. However, tonic spiking persisted in some of the neurons. In such neurons intrinsic spiking was suppressed following the bursts and reappeared in the intervals after several seconds. The suppression of intrinsic spiking could be reproduced when, in the absence of fast synaptic transmission, bursts were mimicked by the injection of current pulses. Intrinsic spiking was also suppressed by a slight hyperpolarization. An afterhyperpolarization following the bursts was found in roughly half of the neurons. These afterhyperpolarizations were combined with a decrease in excitability. No evidence for the involvement of synaptic depletion or receptor desensitization in bursting was found, because neither the rate nor the size of spontaneous excitatory postsynaptic currents were decreased following the bursts. Extracellular stimuli paced bursts at low frequencies, but failed to induce bursts when applied too soon after the last burst. Altogether these results suggest that bursting in spinal cultures is mainly based on intrinsic spiking in some neurons, recurrent excitation of the network and auto‐regulation of neuronal excitability.
Task‐dependent and cell‐type‐specific Fos enhancement in rat sensory cortices during audio‐visual discrimination
Authors: Sakata Shuzo , Kitsukawa Takashi , Kaneko Takeshi , Yamamori Tetsuo , Sakurai Yoshio
Published: March 2003

Attention modulates neural activities in sensory cortices. Because cortical neurons are composed of many types of neurons, the activities of these different types of cells can exhibit different modifications depending on whether an animal pays attention to a particular sensory stimulus or not. In the present study, we examined which types of cortical neurons change their activities in rats during one of two types of audio‐visual discrimination (AVD) tasks by using Fos immunohistochemistry. In the tasks, both auditory and visual stimuli were simultaneously presented but only one of the two modalities was task‐relevant. Once the rats had learned one of the AVD tasks, presenting only relevant sensory stimuli was sufficient for them to perform the task correctly. These results suggest that the rats indeed attended to the relevant stimuli during the performance of the tasks. We found that Fos expression in the primary auditory and visual cortices was enhanced in a task‐dependent manner during the performance of the AVD tasks. The enhancement of Fos expression depended on the behavioural significance of the stimulus in the tasks. Moreover, using double immunohistochemistry of Fos and a cell type‐specific marker protein (phosphate‐activated glutaminase, nonphosphorylated neurofilament protein, parvalbumin, calretinin or somatostatin), the task‐dependent Fos expression was observed preferentially in excitatory neurons but not in inhibitory interneurons. These results suggest that modulation in cortical excitatory neurons might have critical roles in selecting and processing behaviourally relevant sensory stimuli.
c‐Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery
Authors: Maloney Karen J. , Mainville Lynda , Jones Barbara E.
Published: March 2003

Evidence suggests that dopaminergic neurons of the ventral mesencephalic tegmentum (VMT) could be important for paradoxical sleep (PS). Here, we examined whether dopamine (DA) and adjacent γ‐aminobutyric acid (GABA)‐synthesizing neurons are active in association with PS recovery as compared to PS deprivation or control conditions in different groups of rats by using c‐Fos expression as a reflection of neural activity, combined with dual immunostaining for tyrosine hydroxylase (TH) or glutamic acid decarboxylase (GAD). Numbers of TH+/c‐Fos+ neurons in the substantia nigra (SN) were not significantly different across groups, whereas those in the ventral tegmental area (VTA) were significantly different and greatest in PS recovery. Numbers of GAD+/c‐Fos+ neurons in both VTA and SN were greatest in PS recovery. Thus, DA neuronal activity does not appear to be suppressed by local GABAergic neuronal activity during PS but might be altered in pattern by this inhibitory as well as other excitatory, particularly cholinergic, inputs such as to allow DA VTA neurons to become maximally active during PS and thereby contribute to the unique physiological and cognitive aspects of that state.
Transient forebrain ischemia induces persistent hyperactivity of large conductance Ca2+‐activated potassium channels via oxidation modulation in rat hippocampal CA1 pyramidal neurons
Authors: Gong Liang‐Wei , Gao Tian M. , Huang Hao , Zhuang Zhi‐Ye , Tong Zhenqing
Published: March 2003

The present study examined temporal changes in activity of large conductance, Ca2+‐activated potassium (BKCa) channels in postischemic CA1 pyramidal neurons at 2, 6, 24 and 48 h after reperfusion. These changes in activity and possible cellular mechanisms were examined using the inside–out configuration of patch clamp. The unitary conductance of postischemic BKCa channels increased transiently to 119% of the control at 2 h after reperfusion, and recovered to the control level thereafter. A persistent increase in [Ca2+]i sensitivity of BKCa channels was observed in postischemic CA1 neurons with the maximal sensitivity to [Ca2+]i at 6 h after reperfusion while channel voltage‐ dependence showed no obvious changes. Kinetic analyses showed that the postischemic enhancement of BKCa channel activity was due to longer open times and shorter closed times as there was no significant changes in opening frequency after ischemia. Glutathione disulphide markedly increased BKCa channel activity in normal CA1 neurons, while reducing glutathione caused a decrease in BKCa channel activity by reducing the sensitivity of this channel to [Ca2+]i in postischemic CA1 neurons. Similar modulatory effects on postischemic BKCa channels were also observed with another redox couple, DTNB and DTT, suggesting an oxidation modulation of BKCa channel function after ischemia. The present results indicate that a persistent enhancement in activity of BKCa channels, probably via oxidation of channels, in postischemic CA1 pyramidal neurons may account for the decrease in neuronal excitability and increase in fAHP after ischemia. The ischemia‐induced augmentation in BKCa channel activity may be also associated with the postischemic neuronal injury.
Different respiratory control systems are affected in homozygous and heterozygous kreisler mutant mice
Authors: Chatonnet Fabrice , Del Toro Eduardo Domínguez , Voiculescu Octavian , Charnay Patrick , Champagnat Jean
Published: March 2003

During embryonic development, restricted expression of the regulatory genes Krox20 and kreisler are involved in segmentation and antero‐posterior patterning of the hindbrain neural tube. The analysis of transgenic mice in which specific rhombomeres (r) are eliminated points to an important role of segmentation in the generation of neuronal networks controlling vital rhythmic behaviours such as respiration. Thus, elimination of r3 and r5 in Krox20–/– mice suppresses a pontine antiapneic system (Jacquin et al., 1996). We now compare Krox20–/– to kreisler heterozygous (+/kr) and homozygous (kr/kr) mutant neonates. In +/kr mutant mice, we describe hyperactivity of the antiapneic system: analysis of rhythm generation in vitro revealed a pontine modification in keeping with abnormal cell specifications previously reported in r3 (Manzanares et al., 1999b). In kr/kr mice, elimination of r5 abolished all +/kr respiratory traits, suggesting that +/kr hyperactivity of the antiapneic system is mediated through r5‐derived territories. Furthermore, collateral chemosensory pathways that normally mediate delayed responses to hypoxia and hyperoxia were not functional in kr/kr mice. We conclude that the pontine antiapneic system originates from r3r4, but not r5. A different rhythm‐promoting system originates in r5 and kreisler controls the development of antiapneic and chemosensory signal transmission at this level.
The speeding of EPSC kinetics during maturation of a central synapse
Authors: Wall Mark J. , Robert Antoine , Howe James R. , Usowicz Maria M.
Published: March 2003

Several factors contribute to the shape of excitatory postsynaptic currents (EPSCs) in CNS neurons, among them the kinetics of presynaptic release, transmitter clearance, and the properties and distribution of postsynaptic receptors. The decays of AMPA receptor‐mediated EPSCs at rat cerebellar mossy fibre–granule cell (MF–gc) synapses follow a bi‐exponential time‐course. The fast component dominates the decay, accounting for 84–94% of the peak amplitude. Here we show that both components of decay, and also the risetimes, became faster during postnatal maturation. At adult, but not immature, synapses, the risetimes and decays of evoked multiquantal EPSCs were similar to those of monoquantal miniature (m)EPSCs. The faster risetimes at mature synapses reflected increased synchrony of multivesicular release, whereas the faster decays appeared to reflect changes in the properties of postsynaptic receptors. Inhibition of glutamate uptake was without effect on evoked EPSCs at both ages. Furthermore, after slowing receptor desensitization with cyclothiazide, the EPSCs at mature synapses decayed as slowly as EPSCs at immature synapses, suggesting that faster glutamate clearance does not account for the developmental speeding of EPSC decay. Our results support previous conclusions that glutamate clearance and receptor deactivation are important determinants of the fast decay component at immature synapses. Desensitization becomes increasingly important during development and plays a major role in shaping EPSC decay at mature synapses.
Genetic labelling of specific axonal pathways in the mouse central nervous system
Authors: Zubair Mohamad , Watanabe Eiji , Fukada Masahide , Noda Masaharu
Published: March 2003

We report on transgenic mouse lines in which several sensory systems in the brain are specifically visualized genetically. We employed GAP‐lacZ as an axon‐targeted reporter protein that was constructed by fusing the membrane‐anchoring domain of the GAP‐43 protein to lacZ. The reporter gene was introduced into the genome under the control of a promoter element of Brn3b transcription factor to establish transgenic mouse lines. The individual lines thus generated afforded clear images of specific axonal pathways of the visual, vomeronasal, pontocerebellar, and auditory systems. The reporter protein labelled the entire axonal process as well as the cell body of developing and mature neurons on staining with X‐gal. We show that these lines facilitate the developmental and anatomical study of these neural systems. This strategy should be applicable to a variety of neural systems by using various specific promoter elements.
Orientation specificity of contrast adaptation in visual cortical pinwheel centres and iso‐orientation domains
Authors: Sengpiel Frank , Bonhoeffer Tobias
Published: March 2003

Exposure to a high‐contrast visual stimulus causes adaptation, a psychophysical phenomenon that is quite selective for stimulus orientation. Its mechanism is largely cortical but the underlying circuitry is still not unambiguously resolved. It has been suggested that adaptation could be the result of integration of inputs from cells within a large local pool, effectively scaling their outputs with respect to local contrast. In this case, orientation selectivity of neuronal adaptation should depend on the location of neurons within the cortical map of orientation preference. We tested this hypothesis by quantifying adaptation to optimally oriented and to orthogonal‐to‐optimum gratings among neurons recorded either from iso‐orientation domains or orientation pinwheel centres, as identified by optical imaging of cat visual cortex. We did not find a significant difference in adaptation characteristics for these two populations of cells, implying that these characteristics do not depend on the local functional architecture. Surprisingly, however, we additionally observed that under isoflurane (but not halothane) anaesthesia, most neurons exhibited adaptation by cross‐oriented gratings, regardless of their location within the orientation map. It seems likely that, under isoflurane, inputs became visible that were masked by the commonly used, deeper halothane anaesthesia. For individual cells, the presence of these inputs was independent of their location within the cortical orientation map.
Selective targeting of zebrafish olfactory receptor neurons by the endogenous OMP promoter
Authors: Çelik Arzu , Fuss Stefan H. , Korsching S. I.
Published: March 2003

The olfactory nervous system of fish, in particular zebrafish, has become a valid model for that of higher vertebrates. However, no genetic markers for olfactory specific cell types, e.g. the olfactory receptor neurons, have been established in this species. Olfactory marker protein (OMP) is a reliable marker for olfactory receptor neurons in several other vertebrates. We have cloned zOMP, the zebrafish homologue of olfactory marker protein. During development, zOMP is expressed exclusively in the olfactory placode, presumably in olfactory receptor neurons, as shown by in situ hybridization. In the adult nasal epithelium zOMP is found restricted to the sensory region. zOMP appears to be a single gene, without close family members. The 5′‐flanking region lacks most of the expected regulatory sequence motifs, both general and cell type‐specific ones. Nevertheless, it drives reporter gene expression strongly and specifically in olfactory receptor neurons during the whole developmental period examined. Thus the zOMP promoter constitutes a powerful tool which should be useful to selectively introduce a wide variety of genetic modifications into olfactory receptor neurons.
Periwound dopaminergic sprouting is dependent on numbers of wound macrophages
Authors: Batchelor P. E. , Porritt M. J. , Nilsson S. K. , Bertoncello I. , Donnan G. A. , Howells D. W.
Published: March 2003

Injury to many regions of the central nervous system, including the striatum, results in a periwound or ‘abortive’ sprouting response. In order to directly evaluate whether macrophages play an important role in stimulating periwound sprouting, osteopetrotic (op/op) mice, which when young are deficient in a variety of macrophage subtypes, were given striatal wounds and the degree of dopaminergic sprouting subsequently assessed. Two weeks postinjury, significantly fewer wound macrophages were present in the striata of op/op mice compared with controls (144 ± 30.1 in op/op mice vs. 416.6 ± 82.3 in controls, P < 0.005, analysis performed on a section transecting the middle of the wound). Dopamine transporter immunohistochemistry revealed a marked decrease in the intensity of periwound sprouting in the op/op group of animals. Quantification of this effect using [H3]‐mazindol autoradiography confirmed that periwound sprouting was reduced significantly in the op/op mice compared with controls (71.4 ± 21.7 fmol/mg protein in op/op mice vs. 210.7 ± 27.1 fmol/mg protein in controls, P < 0.0005). In the two groups of animals the magnitude of the sprouting response in individuals was closely correlated with the number of wound macrophages (R = 0.83, R2 = 0.69). Our findings provide strong support for the crucial involvement of macrophages in inducing dopaminergic sprouting after striatal injury.
µ/δ Cooperativity and opposing κ‐opioid effects in nucleus accumbens‐mediated antinociception in the rat
Authors: Schmidt Brian L. , Tambeli Claudia H. , Levine Jon D. , Gear Robert W.
Published: March 2003

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw‐opening nociceptive reflex responses in the rat to assess the role of intra‐accumbens µ‐, δ‐ and κ‐opioid receptors in the antinociceptive effect of noxious stimulation and intra‐accumbens opioid agonism. Whilst intra‐accumbens injection of either the µ‐receptor‐selective antagonist Cys2,Tyr3,Orn5,Pen7amide (CTOP) or the δ‐receptor‐selective antagonist naltrindole blocked capsaicin‐induced antinociception, neither the selective µ‐agonist [D‐Ala2,N‐Me‐Phe4,Gly5‐ol]‐enkephalin (DAMGO; 150 or 300 ng) nor the selective δ‐agonist D‐Pen2,5‐enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin‐induced antinociception was not blocked by the selective κ‐receptor antagonist nor‐binaltorphimine, but was blocked by the κ‐agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, µ‐ and δ‐ but not κ‐opioid receptors contributed to capsaicin‐induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of µ‐ and δ‐opioid receptors induced antinociception, and κ‐receptors appeared to play an antianalgesic role in nucleus accumbens.
Spinal cord injury induces expression of RGS7 in microglia/macrophages in rats
Authors: Hausmann Oliver N. , Hu Wen‐Hui , Keren‐Raifman Tal , Witherow D. Scott , Wang Qiang , Levay Konstantin , Frydel Beata , Z. Slepak Vladlen , R. Bethea John
Published: March 2003

RGS proteins regulate G protein‐mediated signalling pathways through direct interaction with the Gα subunits and facilitation of GTP hydrolysis. An RGS subfamily consisting of RGS 6, 7, 9, and 11 also interacts with the G protein β subunit Gβ5 via a characteristic Gγ‐like domain. Thus far, these complexes were found only in neurons, with RGS7 being the most widely distributed in the brain. Here we confirm the expression of RGS7 in spinal neurons and show as a novel finding that following an experimental spinal cord injury in rats, expression of RGS7 is induced in a subpopulation of other cells. Immunofluorescent confocal microscopy using a series of cell specific antibodies identified these RGS7 positive cells as activated microglia and/or invading peripheral macrophages. To rule out interference from the adjacent neurons and confirm the presence of RGS7‐Gβ5 complex in inflammatory cells, we performed immunocytochemistry, RT‐PCR, Western blot, and immunoprecipitation using microglial (BV2) and peripheral macrophage (RAW) cell lines. Expression of RGS7 mRNA and protein are nearly undetectable in non‐stimulated BV2 and RAW cells, but remarkably increased after stimulation with LPS or TNF‐α In addition, RGS7‐positive cells were also found in the perinodular rim in the rat spleen. Our findings show that RGS7‐Gβ5 complex is expressed in immunocompetent cells such as resident microglia and peripheral macrophages following spinal cord injury. This expression might contribute to the post‐traumatic inflammatory responses in the central nervous system.
Altered regulation of the 5‐HT system in the brain of MAO‐A knock‐out mice
Authors: Evrard A. , Malagié I. , Laporte A.‐M. , Boni C. , Hanoun N. , Trillat A.‐C. , Seif I. , De Maeyer E. , Gardier A. , Hamon M. , Adrien J.
Published: March 2003

Genetic deficiency of monoamine oxidase‐A (MAO‐A) induces major alterations of mood and behaviour in human. Because serotonin (5‐HT) is involved in mood regulation, and MAO‐A is responsible for the catabolism of 5‐HT, we investigated 5‐HT mechanisms in knock‐out mice (2‐month‐old) lacking MAO‐A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild‐type mice, basal extracellular 5‐HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO‐A mutant mice. Conversely, spontaneous firing rate of 5‐HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was ∼40% lower in mutants. Acute 5‐HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5‐HT levels (by ∼4 fold) and decrease in DRN neuronal firing (with a ∼4.5 fold decrease in the drug's ED50) in MAO‐A knock‐out mice, which expressed lower levels of the 5‐HT transporter throughout the brain (−13 to −34% compared to wild‐type levels). The potency of the 5‐HT1Aagonist 8‐OH‐DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5‐HT1Aautoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (−27%) in the DRN. Altogether, these data indicate that, in MAO‐A knock‐out mice, the enhancement of extracellular 5‐HT levels induces a down‐regulation of the 5‐HT transporter, and a desensitization of 5‐HT1Aautoreceptors which allows the maintenance of tonic activity of 5‐HT neurons in the DRN.
D2‐mediated modulation of N‐type calcium currents in rat globus pallidus neurons following dopamine denervation
Authors: Stefani Alessandro , Spadoni Francesca , Martorana Alessandro , Lavaroni Franco , Martella Giuseppina , Sancesario Giuseppe , Bernardi Giorgio
Published: March 2003

We have studied the effects of dopamine and the D2‐like agonist quinpirole on calcium currents of neurons isolated from the striatum and the globus pallidus (GP). Experiments were performed in young adult rats, either in control conditions or following lesion of the nigrostriatal pathway by the unilateral injection of 6‐hydroxydopamine (6‐OHDA) in the substantia nigra. Apomorphine‐driven contralateral turning, 15 days after lesioning, assessed the severity of the dopamine denervation. In addition, the loss of tyrosine hydroxylase immunohistochemistry confirmed the extent of the toxin‐induced damage. In both striatal medium spiny (MS) and GP neurons of control animals dopamine and quinpirole promoted a very modest inhibition of calcium conductance. Following 6‐OHDA, the inhibition was unaltered in MS (from 10 to 12%), but significantly augmented in GP neurons (21% vs. 9%). Interestingly, analogous inhibition was observed in GP neurons dissociated 20 h after reserpine treatment. Further features of the D2 response were thus studied only in neurons isolated from 6‐OHDA‐lesioned GP. The D2 modulation was G‐protein‐mediated but not strictly voltage‐dependent. ω‐Conotoxin‐GVIA occluded the response implying the involvement of N‐type calcium channels. The effect of quinpirole developed fast and was insensitive to alterations of cytosolic cAMP. The incubation in phorbol esters or OAG blocked the D2 effect, supporting the involvement of PKC. These findings suggest that postsynaptic D2‐like receptors are functionally expressed on GP cell bodies and may supersensitize following dopamine‐denervation. A direct D2 modulation of calcium conductance in GP may alter GP firing properties and GABA release onto pallidofugal targets.
Group III metabotropic glutamate receptors and D1‐like and D2‐like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity
Authors: David Hélène N. , Abraini Jacques H.
Published: March 2003

Evidence for functional interactions between metabotropic glutamate (mGlu) receptors and dopamine (DA) neurotransmission is now clearly established. In the present study, we investigated interactions between group III mGlu receptors and D1‐ and D2‐like receptors in the nucleus accumbens (NAcc). Administration, into the NAcc, of the selective group III mGlu receptor agonist, AP4, resulted in an increase in locomotor activity, which was blocked by pretreatment with the group III mGlu receptor antagonist, MPPG. In addition, pretreatment with AP4 further blocked the increase in motor activity induced by the D1‐like receptor agonist, SKF 38393, but potentiated the locomotor responses induced by either the D2‐like receptor agonist, quinpirole, or coinfusion of SKF 38393 and quinpirole. MPPG reversed the effects of AP4 on the motor responses induced by D1‐like and/or D2‐like receptor activation. These results confirm that glutamate transmission may control DA‐dependent locomotor function through mGlu receptors and further indicate that group III mGlu receptors oppose the behavioural response produced by D1‐like receptor activation and favour those produced by D2‐like receptor activation.
Comparison of neuronal activity in the rostral supplementary and cingulate motor areas during a task with cognitive and motor demands
Authors: Akkal D. , Bioulac B. , Audin J. , Burbaud P.
Published: March 2003

A number of cortical motor areas have been identified on the medial wall of the hemisphere in monkeys. However, their specific role in motor control remains unclear. In this study, we sought to describe and compare the functional properties of the presupplementary (pre‐SMA) and rostral cingulate (CMAr) motor areas in two monkeys performing a visually instructed, delayed, sequential movement. We recorded 134 task‐related neurons in the pre‐SMA and 149 in the CMAr. The main difference between the two areas was the abundance of responses to targets (46%) in the pre‐SMA, while CMAr activity was more related to reward (28%). Neuronal responses to targets were more phasic and higher in frequency in the pre‐SMA than in the CMAr. During the delay, the percentage of neuronal responses was similar in the two areas. The discharge pattern was different depending upon whether the delay duration was fixed or variable but in most neurons was the same regardless of the sequence performed. Movement‐related changes were common in the pre‐SMA (75%) and in the CMAr (81%) but they occurred earlier in the former. Neurons activated exclusively during movement were more numerous in the CMAr. Finally, neuronal activity in the pre‐SMA was more related to the sequential aspect of the task compared to the CMAr. Our results suggest that although the two areas share functional properties, they also participate in different aspects of motor behaviour. Their functional properties reflect their anatomical positions, which give them the potential to integrate external stimuli (pre‐SMA) and internal states (CMAr) during motor planning.
EEG theta synchronization conjoined with alpha desynchronization indicate intentional encoding
Authors: Mölle Matthias , Marshall Lisa , Fehm Horst L. , Born Jan
Published: March 2003

The involvement of different oscillating neuronal systems activated during intentional learning was investigated by measuring ongoing EEG activity. In 17 subjects, the EEG was recorded while learning pairs of words and faces. Subjective task difficulty was rated and a control condition of mental relaxation was also run. Spontaneous EEG activity during epochs which subsequently resulted in efficient encoding was associated with upper alpha desynchronization (10–12 Hz) and theta synchronization (4–8 Hz) when compared with spontaneous EEG activity during epochs of poor recall performance. The combined measure of theta synchronization plus upper alpha desynchronization was enhanced selectively over left frontotemporal cortical regions during efficient learning of words and over right parietal cortical regions during efficient learning of faces (P < 0.001). This striking topographical dissociation between learning materials for the combined measure of theta and upper alpha EEG activity suggests that the mode of intentional learning relies essentially on an interdependent regulation of two neuronal circuits: the thalamo‐cortical circuit and the hippocampo‐cortical circuit.
Reduction of drug‐induced yawning and penile erection and of noncontact erections in male rats by the activation of GABAAreceptors in the paraventricular nucleus: involvement of nitric oxide
Authors: Melis Maria Rosaria , Argiolas Antonio
Published: March 2003

The effect of muscimol, a GABAAreceptor agonist, injected into the paraventricular nucleus (PVN) of the hypothalamus on drug‐induced (apomorphine, oxytocin and NMDA) yawning and penile erection, and on the increase in the concentration of NO2–and NO3–occurring in the paraventricular dialysate in these experimental conditions, was studied in male rats. Muscimol (50, 100 and 200 ng) reduced, in a dose‐dependent manner, penile erection and yawning induced by apomorphine (50 ng), oxytocin (30 ng) and NMDA (50 ng) delivered into the PVN. The reduction of penile erection and yawning was parallel to a reduction of the concomitant NO2–and NO3–increase that occurs in the paraventricular dialysate in this experimental condition. In contrast, baclofen (200 ng), a GABABreceptor agonist, was ineffective. The muscimol effects on drug‐induced penile erection, yawning and NO2–increase were prevented by the prior administration of bicuculline (250 ng into the paraventricular nucleus). Muscimol (200 ng) but not baclofen (200 ng), injected into the PVN, reduced both noncontact erections in male rats placed in the presence of an inaccessible receptive female, and also the NO2–increase that occurs in the paraventricular dialysate in this experimental condition. As found with drug‐induced penile erection, the muscimol reduction of noncontact erections and of NO2–increase was prevented by bicuculline. The present results show that the activation of GABAAreceptors in the PVN reduces yawning and penile erection induced by drugs or physiological stimuli by reducing the increase in NO activity that occurs in this hypothalamic nucleus in these experimental conditions.
Oestrogen‐dependent tracing in the rat CNS after pseudorabies virus infection
Authors: Horváth Szatmár , Kis Zsolt , Boldogköi Zsolt , Nógrádi Antal , Toldi József
Published: March 2003

This study examines the hypothesis that neuronal infectivity and the spreading of the pseudorabies virus (PRV) through the synapses in the central nervous system (CNS) are influenced by the oestrogen levels. The arcuate nucleus (ARC) and the subfornical organ (SFO) were chosen as models for analysis; the neurons in both structures possess oestrogen receptors and are mutually connected. A genetically engineered pseudorabies virus (Ba‐DupLac) was used as a transneuronal tract tracer. This virus is taken up preferably by axon terminals, and transported very specifically through the synapses in a retrograde manner. Ba‐DupLac was injected into the ARC of rats, followed by monitoring of the PRV‐immunoreactivity (PRV‐IR) in the SFO 72 h following inoculation. We found no PRV immunolabelling in the SFO of ovariectomized (OVX) rats, or in those OVX animals that received oestrogen shortly (4 h) before PRV infection (OVX + E 4 h). In contrast, in those OVX animals that received oestrogen 12 h before PRV infection (OVX + E 12 h), and also in intact control animals, PRV‐IR was demonstrated in the SFO in all cases. Surprisingly, a reverse labelling was observed in the OVX rats; PRV‐IR appeared in the pyriform cortex, whereas PRV‐IR could not be detected in the control and OVX + E 12 h animals. As far as we are aware, this is the first study to demonstrate that transneuronal PRV labelling depends on the effects of oestrogen on certain CNS structures and connections.
Basolateral amygdala lesions block the memory‐enhancing effect of 8‐Br‐cAMP infused into the entorhinal cortex of rats after training
Authors: Roesler Rafael , Roozendaal Benno , McGaugh James L.
Published: March 2003

There is extensive evidence suggesting that the basolateral nucleus of the amygdala plays a critical role in modulating memory consolidation processes in other brain regions. The present experiments examined interactions between the basolateral amygdala and the entorhinal cortex in modulating memory consolidation for inhibitory avoidance training. Several studies have reported that activation of the second messenger system adenosine 3′,5′‐cyclic monophosphate (cAMP) in several brain regions enhances memory and induces long‐term plasticity. In the present experiments, a unilateral infusion of the cAMP analogue, 8‐Br‐cAMP (0.25 or 1.25 µg in 0.5 µL), administered into the entorhinal cortex of male Sprague–Dawley rats immediately after training, enhanced 48‐h retention. An N‐methyl‐d‐aspartate‐induced lesion of the ipsilateral basolateral amygdala did not impair retention, but blocked the memory‐enhancing effect of 8‐Br‐cAMP (infused into the entorhinal cortex) post‐training. A lesion of the contralateral basolateral amygdala did not block the 8‐Br‐cAMP‐induced retention enhancement. These findings indicate that an intact basolateral amygdala is essential for modulation of memory consolidation involving the entorhinal cortex, and are consistent with evidence that the basolateral amygdala regulates memory consolidation mediated by other brain regions.
Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain
Authors: Ingi Tatsuya , Aoki Yaeko
Published: March 2003

The abundant expression of RGS (regulator of G‐protein signalling) proteins in neurons, together with their modulatory function on G‐protein‐dependent neurotransmission, provides the basis for cellular adaptation to sensory inputs. To identify the molecular mechanism involved in the sensory experience‐induced neural development, we performed a systematic survey of the localization of mRNAs encoding three subtypes of the RGSs (RGS2, RGS4 and RGS7) in developing rat brains by in situ hybridization through postnatal day 2 (P2), P10 and P18 to adult. The most dramatic changes of expression patterns were observed in the discrete neuronal cell layers of the cerebral neocortex (for RGS2 and 4), the hippocampus (for RGS2, 4 and 7), the thalamus (for RGS4) and the cerebellum (for RGS2 and 7). In the neocortex, RGS2 mRNA was enriched in the superficial cortical plate at P2, in contrast to RGS4, which was enriched in more mature neurons of the deeper layer V and VI. In the hippocampus, the neuronal cell layer‐specific expression pattern of RGS2 developed from P2 to P18. RGS4 expression was temporarily confined to the CA pyramidal cell layer and not detectable in the dentate gyrus at P10 and P18. Similarly, a high level of expression of RGS7 was observed in the CA area, but not in the dentate gyrus at P2 and P10. In the cerebellum, the maturation of laminar expression patterns for the three RGSs correlated with neuronal maturation and synaptogenesis at P18. The most characteristic temporal pattern among the three RGSs was observed for RGS4 mRNA, which was highly enriched in the thalamocortical regions. The peaks of RGS4 expression were seen in the following regions with distinct onset and duration: the neocortex (from P2 onward), the hippocampus (P10 and P18) and the thalamus (from P18 onward). The divergent temporal and spatial expression of RGS subtypes and their dynamic control in the cortex, the hippocampus and the thalamus suggest that the RGS family could play multiple distinct roles in experience‐dependent brain development.
A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory
Authors: Higgins G. A. , Kew J. N. C. , Richards J. G. , Takeshima H. , Jenck F. , Adam G. , Wichmann J. , Kemp J. A. , Grottick A. J.
Published: March 2003

Using a combination of the selective opioid receptor‐like1 (ORL1) receptor agonist, Ro 64‐6198, and orphanin FQ/nociceptin (OFQ/N) peptide knockout (KO) mice, the influence of OFQ/N on cognition has been studied in the rodent. In wild type, C57BL/6J mice, Ro 64‐6198 (0.3–1 mg/kg i.p.) impaired the acquisition of spatial learning in the Morris water maze, although a mild neurological impairment was evident which complicated precise interpretation. In Lister hooded rats, Ro 64‐6198 (6 mg/kg i.p.) produced delay dependent impairments in rats performing either a delayed matching or a delayed nonmatching to position task with only a modest (< 20%) effect on omissions – an effect consistent with a short‐term memory impairment. Electrophysiological studies demonstrated an inhibitory effect of OFQ/N on LTP recorded from the CA1 region of wild type mice, but not in ORL1 receptor knockout mice. In contrast to the ORL1 agonist, mice deficient in the OFQ/N peptide showed some evidence of improved spatial learning, fear conditioning and passive avoidance retention. However, CA1 LTP was similar between OFQ/N peptide KO mice and wild type controls. Subsequent receptor radioautography studies demonstrated the presence of ORL1 receptors within various regions of the medial temporal lobe system: i.e. CA1, dentate gyrus molecular layer, subiculum, perirhinal cortex. Taken together, these results suggest a bi‐directional effect of OFQ/N containing systems on aspects of cognitive behaviour, particularly those elements associated with hippocampal function. This is consistent with a likely modulatory role of OFQ/N on hippocampal and associated cortical circuitry.
Inhibition of spinal or hypoglossal motoneurons of the newborn rat by glycine or GABA
Authors: Marchetti Cristina , Pagnotta Sara , Donato Roberta , Nistri Andrea
Published: March 2003

The function of GABA or glycine during early postnatal development remains controversial as their action is reported as either excitatory or inhibitory. The present study addressed the question of the functional role of GABA or glycine on rat motoneurons shortly after birth. For this purpose, using in vitro preparations from immature rats (postnatal age, P0‐P4 days), we recorded from lumbar spinal motoneurons and hypoglossal motoneurons. All data were obtained under current clamp conditions (recording with potassium methylsulphate containing electrodes) from cells at about −70 mV resting potential. On spinal motoneurons we used the glycinergic and GABAergic recurrent postsysnaptic potential (PSP) mediated by Renshaw cells to assess its impact on excitatory synaptic inputs from dorsal afferent fibres. Despite its depolarizing nature, the recurrent PSP consistently inhibited synaptic excitation of lumbar motoneurons. On hypoglossal motoneurons, exogenously applied GABA or glycine produced depolarization with decreased input resistance. This response was always associated with inhibition of cell firing induced by intracellular current pulses. Even when the membrane potential was repolarized to resting level in the presence of GABA or glycine, hypoglossal motoneurons failed to generate spikes. Conversely, similar depolarization produced by glutamate consistently facilitated spike firing. GABAergic and glycinergic synaptic potentials evoked by focal stimulation of the reticular formation inhibited firing and/or increased firing latency in the majority of hypoglossal motoneurons. These results indicate that, immediately after birth, rat motoneurons were inhibited by synaptically released or exogenously applied GABA or glycine.
Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat
Authors: Barassin Stéphane , Raison Sylvie , Saboureau Michel , Bienvenu Christèle , Maître Michel , Malan André , Pévet Paul
Published: March 2003

Serotonin (5‐HT) plays an important role in the regulation of the time‐keeping system in rodents. In the present study, we have investigated the interplay between the rhythms of 5‐HT synthesis and release in the suprachiasmatic nuclei (SCN) of the rat. The quantitative distribution of tryptophan hydroxylase (TpH) protein was used as an index of 5‐HT synthesis, in perikarya and terminals areas. In the raphe medianus, the maximal levels of TpH was reached in the early daytime period, followed by a decrease before the onset of darkness. Conversely, in the axon terminals of the SCN the highest levels of TpH were found before the onset of the dark‐period. Furthermore, TpH amount in SCN displays variations depending on the anatomical area of the SCN. Extracellular 5‐HT peaked at the beginning of the night, as evidenced byin vivomicrodialysis in the SCN. The 5‐HT metabolite, 5‐HIAA, presented a similar pattern, but the acrophase occurred in the middle of the dark period. These results suggest that TpH is transported from the soma to the nerve terminals in which 5‐HT is synthesized during daytime. This would fill the intracellular stores of 5‐HT to provide for its nocturnal release.
Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation
Authors: Ohno‐Shosaku Takako , Shosaku Jumpei , Tsubokawa Hiroshi , Kano Masanobu
Published: March 2003

Endocannabinoids are retrograde messengers that are released from central neurons by depolarization‐induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole‐cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)‐3,5‐dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212–2, suppressed IPSCs in all DHPG‐sensitive pairs but not in most of DHPG‐insensitive pairs. The effects of both DHPG and WIN55,212–2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization‐induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization‐induced and group I mGluR‐induced endocannabinoid release. DHPG caused no change in depolarization‐induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.
Dynamics of nitric oxide during simulated ischaemia‐reperfusion in rat striatal slices measured using an intrinsic biosensor, soluble guanylyl cyclase
Authors: Griffiths Charmaine , Garthwaite Giti , Goodwin David A. , Garthwaite John
Published: March 2003

Nitric oxide (NO) may act as a toxin in several neuropathologies, including the brain damage resulting from cerebral ischaemia. Rat striatal slices were used to determine the mechanism of enhanced NO release following simulated ischaemia and, for estimating the NO concentrations, the activity of guanylyl cyclase served as a biosensor. Exposure of the slices for 10 min to an oxygen‐ and glucose‐free medium caused a 70% fall in cGMP levels. On recovery, cGMP increased 2‐fold above basal, where it remained for 40 min before declining. The pattern of changes matched those of cGMP or NO oxidation products measured during and after brain ischaemia in vivo. The increase observed during the recovery period was blocked by inhibition of NO synthase or NMDA receptors and was curtailed by tetrodotoxin, implying that it was caused by glutamate release leading to activation of the NMDA receptor‐NO synthase pathway. Calibration of the cGMP levels against NO‐stimulated guanylyl cyclase yielded a basal NO concentration of 0.6 nm. The peak NO concentration achieved on recovery from simulated ischaemia was estimated as 0.8 nm. These values are compatible with the low micromolar concentrations of NO oxidation products (chiefly nitrate) found by microdialysis in vivo, providing the NO inactivation rate (forming nitrate) is accounted for. NO at a concentration around 1 nm is unlikely to be toxic to cells. However, if the NO inactivation mechanism were to fail (as it can) the NO production rate normally providing only subnanomolar NO could readily generate toxic (µM) NO concentrations.