bluuebunny/crossref_metadata_2025 huggingface dataset:
Cloning and functional characterization of two glycine receptor α‐subunits from the perch retina
Authors: Gisselmann G. , Galler A. , Friedrich F. , Hatt H. , Bormann J.
Published: March 2003

Glycine receptors are ligand‐gated ion channel proteins mediating synaptic inhibition in the spinal cord, retina and brain of vertebrates. We have cloned and functionally characterized two glycine receptor α‐subunits from the perch (Roccus americana) retina. Based on sequence homology with the mammalian counterparts, we termed these subunits α1 and α3. RT‐PCR revealed the presence of both subunits in retina and brain, whereas α1 was predominant in spinal cord. A short splice variant of α1 was detected in the brain but not in the retina. Functional expression of the perch subunits in HEK‐293 cells yielded robust glycine‐gated currents sensitive to strychnine. The perch receptors displayed a high efficacy for taurine and GABA and thus differ from the mammalian counterparts. Because the retina is a rich source for taurine, this finding could be of physiological importance. The structural features of the ligand binding domain strongly support the notion of increased glycine/GABA discrimination in higher vertebrates.
Ciguatoxin‐induced oscillations in membrane potential and action potential firing in rat parasympathetic neurons
Authors: Hogg R. C. , Lewis R. J. , Adams D. J.
Published: March 2003

The actions of ciguatoxins from the Pacific (P‐CTX‐1) and Caribbean (C‐CTX‐1) regions were investigated in isolated parasympathetic neurons from rat intracardiac ganglia using patch‐clamp recording techniques. Under current‐clamp conditions, bath application of P‐CTX‐1 (1–10 nm) or C‐CTX‐1 (10–30 nm) caused a gradual depolarization that was accompanied by oscillation of the membrane potential leading to tonic action potential firing. Membrane potential oscillations were observed between −45 and −60 mV and had an amplitude of 10–20 mV and a mean frequency of 10 Hz. Oscillation frequency was temperature‐dependent with a Q10 of 2.0. Membrane oscillations were temporarily inhibited by hyperpolarizing current pulses and potentiated by weak depolarizing current pulses. The amplitude of oscillations was reduced upon lowering the external Na+ concentration and inhibited by tetrodotoxin (TTX), tetracaine or Zn2+. Tetraethylammonium, 4‐aminopyridine, Cs+, Cd2+, Ba2+, 1,4,4′‐diothiocyanato‐2,2′‐stilbenedisulphonic acid (DIDS) and ouabain had no effect on the CTX‐1‐induced membrane depolarization and oscillations. Brevetoxin (PbTx‐3, 100 nm), in contrast to CTX‐1, caused a membrane depolarization that was not associated with oscillation of the membrane potential. Under voltage‐clamp conditions, P‐CTX‐1 inhibited the peak amplitude of the voltage‐dependent Na+ current and shifted the activation curve to more negative potentials, but membrane oscillations were not seen in this configuration. These results suggest that ciguatoxins cause oscillation of the membrane potential in mammalian autonomic neurons by modifying the activation and inactivation properties of a population of TTX‐sensitive Na+ channels.
Differential modulation of Ih by 5‐HT receptors in mouse CA1 hippocampal neurons
Authors: Bickmeyer Ulf , Heine Martin , Manzke Till , Richter Diethelm W.
Published: March 2003

CA1 pyramidal neurons of the hippocampus express various types of serotonin (5‐HT) receptors, such as 5‐HT1A, 5‐HT4 and 5‐HT7 receptors, which couple to Gαi or Gαs proteins and operate on different intracellular signalling pathways. In the present paper we verify such differential serotonergic modulation for the hyperpolarization‐activated current Ih. Activation of 5‐HT1A receptors induced an augmentation of current‐induced hyperpolarization responses, while the responses declined after 5‐HT4 receptors were activated. The resting potential of neurons hyperpolarized (−2.3 ± 0.7 mV) after 5‐HT1A receptor activation, activation of 5‐HT4 receptors depolarized neurons (+3.3 ± 1.4 mV). Direct activation of adenylyl cyclase (AC) by forskolin also produced a depolarization. In voltage clamp, the Ih current was identified by its characteristic voltage‐ and time‐dependency and by blockade with CsCl or ZD7288. Activation of 5‐HT1A receptors reduced Ih and shifted the activation curve to a more negative voltage by −5 mV at half‐maximal activation. Activation of 5‐HT4 and 5‐HT7 receptors increased Ih and shifted the activation curve to the right by +5 mV. Specific activation of 5‐HT4 receptors by BIMU8 increased membrane conductance and showed an increase in Ih in a subset of cells, but did not induce a significant alteration in the activation curve. In order to verify spatial differences, we applied BIMU8 selectively to the soma and to the dendrites. Only somatic application induced receptor activation. These data are confirmed by immunofluorescence stainings with an antibody against the 5‐HT4A receptor, revealing receptor expression at the somata of the CA1 region. A similar expression pattern was found with a new antibody against 5‐HT7 receptors which reveals immunofluorescence staining on the cell bodies of pyramidal neurons.
Early sequential formation of functional GABAA and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus
Authors: Hennou Sonia , Khalilov Ilgam , Diabira Diabé , Ben‐Ari Yehezkel , Gozlan Henri
Published: March 2003

During postnatal development of CA1 pyramidal neurons, GABAergic synapses are excitatory and established prior to glutamatergic synapses. As interneurons are generated before pyramidal cells, we have tested the hypothesis that the GABAergic interneuronal network is operative before glutamate pyramidal neurons and provides the initial patterns of activity. We patch‐clamp recorded interneurons in foetal (69 neurons) and neonatal P0 (162 neurons) hippocampal slices and performed a morphofunctional analysis of biocytin‐filled neurons. At P0, three types of interneurons were found: (i) non‐innervated ‘silent’ interneurons (5%) with no spontaneous or evoked synaptic currents; (ii) G interneurons (17%) with GABAA synapses only; and (iii) GG interneurons with GABA and glutamatergic synapses (78%). Relying on the neuronal capacitance, cell body size and arborization of dendrites and axons, the three types of interneurons correspond to three stages of development with non‐innervated neurons and interneurons with GABAA and glutamatergic synapses being, respectively, the least and the most developed. Recordings from both pyramidal neurons and interneurons in foetuses (E18–20) revealed that the majority of interneurons (65%) had functional synapses whereas nearly 90% of pyramidal neurons were quiescent. Therefore, interneurons follow the same GABA–glutamate sequence of synapse formation but earlier than the principal cells. Interneurons are the source and the target of the first synapses formed in the hippocampus and are thus in a position to modulate the development of the hippocampus in the foetal stage.
Modelling of the III–IV loop, a domain involved in calcium channel Cav2.1 inactivation, highlights a structural homology with the γ subunit of G proteins
Authors: Fathallah Mohamed , Sandoz Guillaume , Mabrouk Kamel , Geib Sandrine , Urbani Julie , Villaz Michel , Ronjat Michel , Sabatier Jean‐Marc , De Waard Michel
Published: March 2003

We have modelled the conformation of the III–IV loop of the Cav2.1 subunit of P/Q calcium channels, a loop that is implicated in fast voltage‐dependent inactivation. Change in channel inactivation requires its direct interaction with the I–II loop. This interaction occurs with an affinity in the order of 70 nm. Intracellular injection of a 40‐mer III–IV loop‐derived peptide produces an increase in the rate of fast inactivation. This alteration in channel kinetic is also accompanied by a hyperpolarizing shift in the steady‐state voltage‐dependence of inactivation. None of these effects are observed in the presence of a β subunit, suggesting the existence of a competitive mechanism of action between the β subunit and the III–IV loop. Amino acid sequence comparison using BLAST reveals that the III–IV loop shares 53% identity with the γ subunit of G proteins. Because of the pivotal contribution of the III–IV loop to inactivation, an atomic model of the III–IV loop was generated by both homology modelling and molecular mechanics calculations. Using the X‐ray structures of the βγ dimer of the heterotrimeric G‐proteins as templates, the III–IV loop is predicted to contain a well‐structured α‐helix at the amino‐terminus with both the N‐ and C‐termini having the same orientation in the plane of the inner lipid bilayer. We provide a hypothetical working model in which we propose that the III–IV loop interacts with the I–II loop via its Gβγ binding domain.
Nuclear localization of N‐terminal mutant huntingtin is cell cycle dependent
Authors: Martín‐Aparicio Ester , Avila Jesús , Lucas José J.
Published: March 2003

Unlike normal huntingtin (htt) which is located predominantly in the cytoplasm, mutant htt is also found in the nucleus of affected neurons. Nuclear localization of toxic polyglutamine‐containing proteins has been postulated to be necessary for the pathogenesis of triplet repeat disorders. However, little is known about the mechanism by which mutant htt enters the nucleus. We have recently reported exclusive nuclear localization of exon 1 mutant htt in striatal primary neuronal cultures from the HD94 conditional mouse model of HD. This seemed to contradict the predominant cytoplasmic localization of N‐terminal htt reported from transfection experiments and prompted us to hypothesize that subcellular localization of the toxic htt fragment might be favoured in nondividing cells. To test this, we analyzed subcellular localization of mutant htt in HD94 mixed neuron‐glia cultures. Subconfluent glial cells showed cytoplasmic localization. However, nuclear localization was prompted by confluence, by serum withdrawal, and by treatment with cell cycle progression inhibitors such as Ara C or lactacystin. BrdU labelling experiments further confirmed that nuclear localization does not occur in dividing cells. Our findings offer an explanation for the neuronal specific toxicity of mutant htt despite its ubiquitous expression. Unraveling the mechanism of this cell cycle arrest‐dependent entrance into the nucleus may offer new opportunities for therapeutic intervention.
Electromyographic activity associated with spontaneous functional recovery after spinal cord injury in rats
Authors: Kaegi Sibille , Schwab Martin E. , Dietz Volker , Fouad Karim
Published: March 2003

This investigation was designed to study the spontaneous functional recovery of adult rats with incomplete spinal cord injury (SCI) at thoracic level during a time course of 2 weeks. Daily testing sessions included open field locomotor examination and electromyographic (EMG) recordings from a knee extensor (vastus lateralis, VL) and an ankle flexor muscle (tibialis anterior, TA) in the hindlimbs of treadmill walking rats. The BBB score (a locomotor score named after Bassoet al., 1995,J. Neurotrauma,12, 1–21) and various measures from EMG recordings were analysed (i.e. step cycle duration, rhythmicity of limb movements, flexor and extensor burst duration, EMG amplitude, root‐mean‐square, activity overlap between flexor and extensor muscles and hindlimb coupling). Directly after SCI, a marked drop in locomotor ability occurred in all rats with subsequent partial recovery over 14 days. The recovery was most pronounced during the first week. Significant changes were noted in the recovery of almost all analysed EMG measures. Within the 14 days of recovery, many of these measures approached control levels. Persistent abnormalities included a prolonged flexor burst and increased activity overlap between flexor and extensor muscles. Activity overlap between flexor and extensor muscles might be directly caused by altered descending input or by maladaptation of central pattern generating networks and/or sensory feedback.
Regenerative and survival capabilities of Purkinje cells overexpressing c‐Jun
Authors: Carulli Daniela , Buffo Annalisa , Botta Cristina , Altruda Fiorella , Strata Piergiorgio
Published: March 2003

Following axotomy, cerebellar Purkinje cells (PCs) do not elongate their axons, even in a favourable environment, and are resistant to death. They have no constitutive presence of common growth‐associated proteins, such as GAP‐43 and c‐Jun Previous experiments show that injured transgenic PCs overexpressing GAP‐43 exhibit a profuse sprouting along the axon and at its severed end. Nevertheless, the lesioned axons are unable to regenerate either spontaneously or into growth‐permissive environments. In addition, a considerable number of GAP‐43 transgenic PCs degenerate after injury. c‐Jun is an inducible transcription factor expressed in axotomized central neurons and regenerating peripheral neurons. It also contributes to programmed cell death during development. To test whether c‐Jun could modify the response of PCs to axotomy or enhance the growth/death phenomena of GAP‐43 Purkinje neurons, we generated transgenic mice overexpressing c‐Jun in PCs. However, c‐Jun upregulation did not affect the adult intact phenotype of these neurons and their regenerative and survival capabilities after axotomy. Also in the cross‐bred GAP‐43/c‐Jun mice, c‐Jun did not modify the response of GAP‐43 PCs to axotomy. By contrast, in organotypic cultures of cerebellum taken from 9‐day‐old‐pups, the survival capabilities of PCs overexpressing c‐Jun decreased, in association with a consistent c‐Jun phosphorylation. On the whole our data show that c‐Jun alone is unable to trigger regenerative or degenerative phenomena in PCs and suggest that the cellular action of this early gene in developing and mature neurons strongly depends on interplaying intracellular signals.
SHORT COMMUNICATION Sodium channel β1‐subunit expression is increased in reactive astrocytes in a rat model for mesial temporal lobe epilepsy
Authors: Gorter Jan A. , Van Vliet Erwin A. , Da Silva Fernando H. Lopes , Isom Lori L. , Aronica Eleonora
Published: March 2003

As several epilepsy syndromes are associated with changes in sodium channel subunits we investigated the expression of β1 sodium channel protein in a rat epilepsy model. In this model a chronic epileptic syndrome develops after electrically induced status epilepticus (SE). Many neuropathological characteristics of mesial temporal lobe epilepsy can be reproduced (cell loss, gliosis and synaptic reorganization). In control hippocampus β1 subunit protein was moderately expressed in neurons and weakly expressed in resting astrocytes. β1 sodium channel immunoreactivity increased markedly within 1 week after SE mainly in astrocytes that were colocalized with vimentin (marker for reactive astrocytes). This up‐regulation was still present in reactive astrocytes of chronic epileptic rats (> 3 months after SE). Considering the fact that the β1 subunits may function as cell adhesion molecules interacting with extracellular matrix, the observed increase in reactive astrocytes might subserve a function in cellular and synaptic reorganization during epileptogenesis.
The functional properties of the human ether‐à‐go‐go‐like (HELK2) K+ channel
Authors: Becchetti Andrea , De Fusco Maurizio , Crociani Olivia , Cherubini Alessia , Restano‐Cassulini Rita , Lecchi Marzia , Masi Alessio , Arcangeli Annarosa , Casari Giorgio , Wanke Enzo
Published: March 2003

The voltage‐dependent K+ channels belonging to the ether‐à‐go‐go family (eag, erg, elk) are widely expressed in the mammalian CNS. Their neuronal function, however, is poorly understood. Among the elk clones, elk2 is the most abundantly expressed in the brain. We have characterized the human ELK2 channel (HELK2) expressed in mammalian cell lines. Moreover, we have detected helk2 mRNA and ELK2‐like currents in freshly dissociated human astrocytoma cells. HELK2 was inhibited by Cs+ in a voltage‐dependent way (Kd was 0.7 mm, at −120 mV). It was not affected by Way 123398 (5 µm), dofetilide (10 µm), quinidine (10 µm), verapamil (20 µm), haloperidol (2 µm), astemizole (1 µm), terfenadine (1 µm) and hydroxyzine (30 µm), compounds known to inhibit the biophysically related HERG channel. The crossover of the activation and inactivation curves produced a steady state ‘window’ current with a peak around −20 mV and considerably broader than it usually is in voltage‐dependent channels, including HERG. Similar features were observed in the ELK2 clone from rat, in the same experimental conditions. Thus, ELK2 channels are active within a wide range of membrane potentials, both sub‐ and suprathreshold. Moreover, the kinetics of channel deactivation and removal of inactivation was about one order of magnitude quicker in HELK2, compared to HERG. Overall, these properties suggest that ELK2 channels are very effective at dampening the neuronal excitability, but less so at producing adaptation of action potential firing frequency. In addition, we suggest experimental ways to recognize HELK2 currents in vivo and raise the issue of the possible function of these channels in astrocytoma.
Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord
Authors: Bao Lan , Wang Hui Fredrik , Cai Hai‐Jiang , Tong Yong‐Guang , Jin Shan‐Xue , Lu Ying‐Jin , Grant Gunnar , Hökfelt Tomas , Zhang Xu
Published: March 2003

Peripheral axotomy‐induced sprouting of thick myelinated afferents (A‐fibers) from laminae III–IV into laminae I–II of the spinal cord is a well‐established hypothesis for the structural basis of neuropathic pain. However, we show here that the cholera toxin B subunit (CTB), a neuronal tracer used to demonstrate the sprouting of A‐fibers in several earlier studies, also labels unmyelinated afferents (C‐fibers) in lamina II and thin myelinated afferents in lamina I, when applied after peripheral nerve transection. The lamina II afferents also contained vasoactive intestinal polypeptide and galanin, two neuropeptides mainly expressed in small dorsal root ganglion (DRG) neurons and C‐fibers. In an attempt to label large DRG neurons and A‐fibers selectively, CTB was applied four days before axotomy (pre‐injury‐labelling), and sprouting was monitored after axotomy. We found that only a small number of A‐fibers sprouted into inner lamina II, a region normally innervated by C‐fibers, but not into outer lamina II or lamina I. Such sprouts made synaptic contact with dendrites in inner lamina II. Neuropeptide Y (NPY) was found in these sprouts in inner lamina II, an area very rich in Y1 receptor‐positive processes. These results suggest that axotomy‐induced sprouting from deeper to superficial layers is much less pronounced than previously assumed, in fact it is only marginal. This limited reorganization involves large NPY immunoreactive DRG neurons sprouting into the Y1 receptor‐rich inner lamina II. Even if quantitatively small, it cannot be excluded that this represents a functional circuitry involved in neuropathic pain.
Lactate in the brain of the freely moving rat: voltammetric monitoring of the changes related to the sleep–wake states
Authors: Shram Nataliya , Netchiporouk Larissa , Cespuglio Raymond
Published: March 2003

Cortical lactate was monitored voltammetrically in freely moving rats equipped with polygraphic electrodes. Differential normal pulse voltammetric measurements were carried out using a lactate biosensor coated with lactate oxidase and cellulose acetate. Changes occurring in lactate level were in keeping with sleep–wake states. During slow wave sleep (SWS), the lactate level decreased significantly (−16.2%) vs. the spontaneous waking state (W) referenced to as 100%. During paradoxical sleep (PS), and still vs. W, it remained low (−9.0%) but this variation was not statistically significant. However, when this PS change was compared to the SWS variation, a significant increase in lactate level was then revealed (+8.5%). Finally, during the active waking (aW) triggered by a water puff stress, lactate level rose significantly in accordance with the animal activity (+53% compared to W). Long‐term monitoring also allowed the determination of a circadian component in lactate production, the lowest and highest values being monitored during light and dark periods, respectively. The acrophasis of the circadian change occurred during the dark period, about 3 h after the light‐off (+89%). It is suggested that during wakefulness astrocyte metabolism allows the transformation of the blood‐borne glucose into lactate. The increase in this substrate observed during PS may fulfil the oxidative phosphorylation in order to supply the important ATP need of PS.
New genomic avenues in behavioural neuroendocrinology *
Authors: Lightman S. L. , Insel T. R. , Ingram C. D.
Published: March 2003

Neuroendocrine systems play a key role not only in the maintenance of whole‐body homeostasis but also as the link between behavioural, endocrine and autonomic responses to environmental stimuli. It is becoming increasingly clear that neuroendocrine regulatory mechanisms are under the control of a combination of factors including genetic background, environment and early‐life programming. Patterns of gene expression are increasingly being used to provide information on the genotypes associated with particular behaviours, and modulation of specific parts of the genome allow investigation of the contribution of particular genes. The sequencing of the genome provides a unique opportunity to elucidate the genetic contribution to neuroendocrine and behavioural processes, and to investigate the interactions between genetic and environmental factors. Although drugs can be used to activate or inhibit neurotransmitters and receptors, they lack specificity. New technologies now permit the activation or inactivation of both neurotransmitters and receptors in specific areas of the brain for defined periods, including crucially important developmental windows when activation appears to have long‐term consequences. The future challenges are to define the critical mechanisms through which the genetic constitution of an individual human or experimental animal interacts with environmental cues to result in altered physiological or even pathological behaviour and endocrine function.
Variation in the vasopressin V1a receptor promoter and expression: implications for inter‐ and intraspecific variation in social behaviour*
Authors: Hammock Elizabeth A. D. , Young Larry J.
Published: March 2003

Instability in highly repetitive microsatellite DNA located in the regulatory regions of genes may be a major factor producing diversity in both region‐specific gene expression and the resulting phenotypes. Polymorphisms in promoter regions affecting expression of genes involved in regulating behaviour may play a role in generating individual variation in behaviour, including psychopathologies in humans, and probably are also important for the evolution of behaviour. Here we discuss the prairie vole vasopressin V1a receptor gene as a model that may be useful for understanding the evolution of promoter sequences and the relationship between gene sequence, expression and behavioural phenotype.
The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens
Authors: Rougé‐Pont Françoise , Mayo Willy , Marinelli Michela , Gingras Mireille , Le Moal Michel , Piazza Pier Vincenzo
Published: March 2003

Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently from peripheral sources. Clinical studies in humans have associated these hormones with depression and postpartum mood disorders. In rodents, allopregnanolone (AlloP) has been shown to have anxiolytic and rewarding properties. These observations suggest that neurosteroids could interact with mood and motivation. However, the possible neural substrates of these effects remain unknown. In this report, we have studied the action of AlloP on the activity of the mesencephalic dopaminergic (DA) projection to the nucleus accumbens, which is considered one of the biological substrates of motivation and reward. This study was conducted by measuring extracellular concentrations of dopamine (DA) in the nucleus accumbens by means of microdialysis in freely moving rats. We studied both the direct effect of AlloP and the influence of this hormone on the DA response to an injection of morphine. AlloP dose‐dependently increased the release of DA in the nucleus accumbens. Furthermore, this hormone doubled the DA response to morphine. These effects were observed for AlloP doses of 50 and 100 pmol injected intracerebroventricularly. These results suggest that the stimulatory effect of AlloP on DA could mediate some of the behavioural effects of neurosteroids and, in particular, the interaction of these hormones with mood and motivation.
Two mechanisms of protracted reaction times mediated by dissociable cortical networks
Authors: Herath Priyantha , Young Jeremy , Roland Per
Published: March 2003

When people divide attention between two sensory modalities and respond rapidly to stimuli in either modality, the reaction times (RTs) are longer than when they selectively attend and respond to one sensory modality. There is a further increase in RT when subjects use different fingers to respond to stimuli from different modalities as compared to when they use the same finger for both modalities. Here we use functional magnetic resonance imaging to show that division of attention bilaterally activates the caudal prefrontal areas near the precentral sulcus and areas in the intraparietal sulcus. All RT tasks, whether different fingers for different modalities or one finger for both modalities was used, activated identical motor areas 4a, 4p, supplementary and cingulate, the basal ganglia and the ventral anterior thalami. The increased blood oxygen level‐dependent signal from motor cortical areas was anatomically distinct from the prefrontal/parietal areas. These anatomically dissociable neural substrates of division of attention and motor control may be responsible for the different types of RT delays that we have found. In the brain, there were no differences in the BOLD signal irrespective of whether the effector was specified a priori or was specified only after the sensory signal was received.
Long‐lasting modification of intrinsic discharge properties in subicular neurons following status epilepticus
Authors: Wellmer Jörg , Su Hailing , Beck Heinz , Yaari Yoel
Published: March 2003

A single episode of status epilepticus (SE) induces neuropathological changes in the brain that may lead to the development of a permanent epileptic condition. Most studies of this plasticity have focused on the hippocampus, where both synaptic function and intrinsic neuronal excitability have been shown to be persistently modified by SE. However, many other brain structures are activated during SE and may also be involved in the subsequent epileptogenic process. Here we have investigated whether SE, induced in rats with pilocarpine and terminated after 40 min with diazepam, persistently modifies the intrinsic excitability of pyramidal neurons in the subiculum. Subicular slices were prepared from control and SE‐experienced rats (2–5 weeks after SE). In the control group, only 4% of the neurons fired bursts in response to intrasomatic, threshold‐straddling depolarizing current pulses (low‐threshold bursters). The remaining neurons either fired bursts in response to strong (3× threshold) depolarizations (35%; high‐threshold bursters) or fired in a completely regular mode (61%; nonbursters). In the SE‐experienced group, the fractions of low‐ and high‐threshold bursters markedly increased to 29% and 53%, respectively. This change in firing behaviour was associated with a marked increase in the size of the spike afterdepolarization, particularly in low‐threshold bursters. Experimental suppression of Ca2+currents selectively blocked low‐threshold bursting but did not affect high‐threshold bursting, suggesting that a dual Ca2+‐ dependent and Ca2+‐ independent mechanism controls bursting in these neurons. The persistent up‐regulation of intrinsic bursting in the subiculum, in concert with similar changes in the hippocampus, undoubtedly contributes to epileptogenesis following pilocarpine‐induced SE.
THIS ARTICLE HAS BEEN RETRACTED  Repeated massage‐like stimulation induces long‐term effects on nociception: contribution of oxytocinergic mechanisms
Authors: Lund Iréne , Yu Long‐Chuan , Uvnas‐Moberg Kerstin , Wang Jing , Yu Cheng , Kurosawa Mieko , Agren Greta , Rosén Annika , Lekman Magnus , Lundeberg Thomas
Published: March 2003

Massage‐like stroking induces acute antinociceptive effects that can be reversed by an oxytocin antagonist, indicating activation of oxytocin on endogenous pain controlling systems. We now demonstrate an increase in hindpaw withdrawal latencies (HWLs), in response to thermal and mechanical stimuli, which was present after six treatments of massage‐like stroking every other day and which continued to increase through the remaining seven treatments. Repeated massage‐like stroking also resulted in increased oxytocin‐like immunoreactivity (oxytocin‐LI) levels in plasma and periaquaductal grey matter (PAG). Furthermore, increases in HWLs were also present after injections of oxytocin into the PAG (0.1, 0.5 and 1.0 nmol). Intra‐PAG oxytocin injection of 1 nmol followed by 1 or 20 nmol of naloxone attenuated the increments in HWL. Also, there was a dose‐dependent attenuation of the oxytocin‐induced antinociceptive effects following intra‐PAG injection of the µ‐opioid antagonist β‐funaltrexamine (β‐FNA) and the κ‐opioid antagonist nor‐binaltorphimine (nor‐BNI) but not the δ‐antagonist naltrindole. The long‐term antinociceptive effects of massage‐like stroking may be attributed, at least partly, to the oxytocinergic system and its interaction with the opioid system, especially the µ‐ and the κ‐receptors in the PAG.
Locomotor recovery in the chronic spinal rat: effects of long‐term treatment with a 5‐HT2 agonist
Authors: Antri M. , Orsal D. , Barthe J.‐Y.
Published: March 2003

A complete transection of the spinal cord at a low thoracic level induces a paraplegic syndrome that is accompanied by a loss of spinal cord serotonin content. Former experimental data suggest that the central pattern generator for locomotion, located in the lumbar segments of the spinal cord, might be able to generate rhythmic motor outputs (similar to automatic walking under certain circumstances) involving exteroceptive stimulations and activation of serotonergic receptors. In the present study, we investigated the effects of a chronic treatment using a serotonergic agonist, delivered continuously to the sublesionned spinal cord, and its effect on motor function recovery. The data obtained from behavioural, kinematic and electromyographic measurements suggest that the chronic stimulation of 5‐HT2 type receptors allows motor function recovery. Behavioural measurements show a clear improvement in motor performances when compared to spinal animals (confirmed by kinematic observations): alternating steps and foot placement is recovered in these animals. However, electromyographic data demonstrate that the pattern of activation of the muscles is only restored partially.
Interaction between glucocorticoid hormones, stress and psychostimulant drugs*
Authors: Marinelli Michela , Piazza Pier Vincenzo
Published: March 2003

In this review we summarize data obtained from animal studies showing that glucocorticoid hormones have a facilitatory role on behavioural responses to psychostimulant drugs such as locomotor activity, self‐administration and relapse. These behavioural effects of glucocorticoids involve an action on the meso‐accumbens dopamine system, one of the major systems mediating the addictive properties of drugs of abuse. The effects of glucocorticoids in the nucleus accumbens are site‐specific; these hormones modify dopamine transmission in only the shell of this nucleus without modifying it in the core. Studies with corticosteroid receptor antagonists suggest that the dopaminergic effects of these hormones depend mostly on glucocorticoid, not on mineralocorticoid receptors. These data suggest that an increase in glucocorticoid hormones, through an action on mesolimbic dopamine neurons, could increase vulnerability to drug abuse. We also discuss the implications of this finding with respect to the physiological role of glucocorticoids. It is proposed that an increase in glucocorticoids, by activating the reward pathway, could counteract the aversive effects of stress. During chronic stress, repeated increases in glucocorticoids and dopamine would result in sensitization of the reward system. This sensitized state, which can persist after the end of the stress, would render the subject more responsive to drugs of abuse and consequently more vulnerable to the development of addiction.
Mesencephalic and diencephalic afferent connections to the thalamic nucleus rotundus in the lizard, Psammodromus algirus
Authors: Dávila José Carlos , Andreu Manuel José. , Real M. Ángeles , Puelles Luis. , Guirado Salvador
Published: March 2003

The present work is an analysis of the afferent projections to the thalamic nucleus rotundus in a lizard, both at the light‐ and electron‐microscopic level, using biotinylated dextran amine (BDA) as a neuroanatomical tracer. This study has confirmed previously reported afferent projections to nucleus rotundus in reptiles and has also identified a number of new cellular aggregates projecting to this dorsal thalamic nucleus. After BDA injections into nucleus rotundus, retrogradely labelled neurons were observed consistently within the following neuronal groups in the midbrain and the diencephalon: (i) the stratum griseum centrale of the optic tectum; (ii) the nucleus subpretectalis in the pretectum; (iii) the nucleus ansa lenticularis posterior, the posterior nucleus of the ventral supraoptic commissure, and the posteroventral nucleus, in the dorsal thalamus and (iv) the lateral suprachiasmatic nucleus and part of the reticular complex in the ventral thalamus. Tectal axons entering nucleus rotundus were fine and varicose and formed exclusively asymmetric synaptic contacts, mainly on small dendritic profiles. Rotundal neurons had symmetric synapses made by large boutons probably of nontectal origin. After comparing our results with those in other reptiles, birds and mammals, we propose that the sauropsidian nucleus rotundus forms part of a visual tectofugal pathway that conveys mesencephalic visual information to the striatum and dorsal ventricular ridge, and is similar to the mammalian colliculo‐posterior/intralaminar–striatoamygdaloid pathway, the function of which may be to participate in visually guided behaviour.
Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release
Authors: Cangioli Iacopo , Baldi Elisabetta , Mannaioni Pier Francesco , Bucherelli Corrado , Blandina Patrizio , Passani M. Beatrice
Published: March 2003

The basolateral amygdala (BLA) is involved in learning that certain environmental cues predict threatening events. Several studies have shown that manipulation of neurotransmission within the BLA affects the expression of memory after fear conditioning. We previously demonstrated that blockade of histaminergic H3 receptors decreased spontaneous release of acetylcholine (ACh) from the BLA of freely moving rats, and impaired retention of fear memory. In the present study, we examined the effect of activating H3 receptors within the BLA on both ACh release and expression of fear memory. Using the microdialysis technique in freely moving rats, we found that the histaminergic H3 agonists R‐α‐methylhistamine (RAMH) and immepip, directly administered into the BLA, augmented spontaneous release of ACh in a similar manner. Levels of ACh returned to baseline on perfusion with control medium. Rats receiving intra‐BLA, bilateral injections of the H3 agonists at doses similar to those enhancing ACh spontaneous release, immediately after contextual fear conditioning, showed stronger memory for the context–footshock association, as demonstrated by longer freezing assessed at retention testing performed 72 h later. Post‐training, bilateral injections of 15 ng oxotremorine also had a similar effect on memory retention, supporting the involvement of the cholinergic system. Thus, our results further support a physiological role for synaptically released histamine, that in addition to affecting cholinergic transmission in the amygdala, modulates consolidation of fear memories
Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment
Authors: Hellsten Johan , Wennström Malin , Mohapel Paul , Ekdahl Christine T. , Bengzon Johan , Tingström Anders
Published: March 2003

Major depression is often associated with elevated glucocorticoid levels. High levels of glucocorticoids reduce neurogenesis in the adult rat hippocampus. Electroconvulsive seizures (ECS) can enhance neurogenesis, and we investigated the effects of ECS in rats where glucocorticoid levels were elevated in order to mimic conditions seen in depression. Rats given injections of corticosterone or vehicle for 21 days were at the end of this period treated with either a single or five daily ECSs. Proliferating cells were labelled with bromodeoxyuridine (BrdU). After 3 weeks, BrdU‐positive cells in the dentate gyrus were quantified and analyzed for co‐labelling with the neuronal marker neuron‐specific nuclear protein (NeuN). In corticosterone‐treated rats, neurogenesis was decreased by 75%. This was counteracted by a single ECS. Multiple ECS further increased neurogenesis and no significant differences in BrdU/NeuN positive cells were detected between corticosterone‐ and vehicle‐treated rats given five ECS. Approximately 80% of the cells within the granule cell layer and 10% of the hilar cells were double‐labelled with BrdU and NeuN.

We therefore conclude that electroconvulsive seizures can increase hippocampal neurogenesis even in the presence of elevated levels of glucocorticoids. This further supports the hypothesis that induction of neurogenesis is an important event in the action of antidepressant treatment.
Cerebellar LTD facilitates but is not essential for long‐term adaptation of the vestibulo‐ocular reflex
Authors: Van Alphen A. M. , De Zeeuw C. I.
Published: March 2003

The induction of cerebellar long‐term depression (LTD) at the parallel fibre–Purkinje cell synapse is selectively blocked in L7‐PKCi transgenic mice, rendering these mice unable to adaptively modify their vestibulo‐ocular reflex (VOR) during visuo‐vestibular training for a few hours. Despite this deficit, their eye movement performance as well as their general motor behaviour appears unaffected. This combination suggests that, in the long term, residual forms of plasticity in the vestibulo‐cerebellar circuitry can compensate for the absence of cerebellar LTD. To investigate whether LTD‐deficient mice exhibit motor learning in the long run, we subjected L7‐PKCi transgenic mice to visuo‐vestibular training paradigms that were aimed at either increasing or decreasing the VOR response in the course of eight consecutive days. During the increasing paradigm, the VOR gain of transgenic mice increased significantly, while VOR gain decreased and VOR phase‐lead increased during the decreasing paradigm. The impact of these long training periods on the VOR was significantly smaller in LTD‐deficient mice than in wild type littermates. Thus, while LTD may be necessary for short‐term VOR adaptation, it facilitates but is not required for long‐term adaptation of the VOR.
The genetic basis for psychiatric illness in man*
Authors: Tandon Kopal , McGuffin Peter
Published: March 2003

Following the influential genetic studies of Heston and Kety, there has been growing acceptance of the role of genes in determining behaviour. It is now recognized that most types of behaviour, from normal variations in traits such as personality to complex psychiatric disorders, are influenced not only by environmental factors but also by multiple genes. While twin and adoption studies have been vital in demonstrating the heritability of behaviour, the focus is now on the identification of the genes involved using the molecular genetic strategies linkage analysis and allelic association. This article will discuss techniques that have been used in psychiatric genetics, and how they have advanced our understanding of complex behaviour.
Differences in GABAergic transmission between two inputs into the perirhinal cortex
Authors: Garden Derek L. F. , Kemp Nicola , Bashir Zafar I.
Published: March 2003

We have investigated properties of GABAergic synaptic transmission in perirhinal cortex evoked by stimulation of temporal and entorhinal cortex sides. GABAA IPSCs were isolated by blockade of glutamatergic transmission in slices of adult perirhinal cortex; IPSC decay was best fitted with two exponentials. Interestingly, temporal IPSCs had a larger slow component of decay (P < 0.05) compared to entorhinal IPSCs. Depression of IPSCs by the GABAB receptor agonist baclofen was greater (P < 0.05) in the temporal input (79 ± 4% depression) than the entorhinal input (65 ± 3% depression). Furthermore, baclofen abolished the slow component of IPSC decay in both inputs. Activity‐dependent depression of IPSCs at 5 Hz was greater (P < 0.05) in the temporal input [paired pulse ratio (PPR) 0.5 ± 0.04] compared to that in the entorhinal input (PPR 0.67 ± 0.02, n = 10). The differences in paired pulse depression between the inputs were removed by the GABAB receptor antagonist CGP55845A. This study demonstrates several differences in GABA transmission between temporal and entorhinal inputs including the differential activation of presynaptic GABAB receptors and differential regulation of inhibitory synaptic transmission. These properties may be important in the control of neuronal activity within perirhinal cortex.
Evaluation of Affymetrix Gene Chip sensitivity in rat hippocampal tissue using SAGE analysis*
Authors: Evans Simon J. , Datson Nicole A. , Kabbaj Mohamed , Thompson Robert C. , Vreugdenhil Erno , De Kloet E. Ronald , Watson Stanley J. , Akil Huda
Published: March 2003

DNA microarrays are a powerful tool for monitoring thousands of transcript levels simultaneously. However, the use of DNA microarrays in studying the central nervous system faces several challenges. These include the detection of low‐abundance transcripts in highly complex tissue as well as estimating relatively low‐magnitude changes in transcript levels in response to experimental manipulation. Many transcripts important to brain function have low expression levels or are expressed in relatively few cells, making them difficult to detect in the complex background of brain tissue. The aim of the present study is to evaluate the sensitivity of Gene Chip detection of transcripts in brain by using results from serial analysis of gene expression (SAGE) studies. The results of this comparison indicate that Affymetrix Gene Chips, like SAGE, only reliably detect medium‐ to high‐abundance transcripts and that detection of low‐abundance transcripts, many of which have great relevance to biological function in brain, is inconsistent. Specifically, we estimate that Gene Chips reliably detect no more than 30% of the hippocampal transcriptome when using a gross hippocampal dissection as the source tissue. This report provides the first broad evaluation of Affymetrix Gene Chip sensitivity relevant to studying the brain.
Group I and II metabotropic glutamate receptors modulate respiratory activity in the lamprey
Authors: Bongianni Fulvia , Mutolo Donatella , Carfì Marco , Pantaleo Tito
Published: March 2003

The respiratory role of group I and II metabotropic glutamate receptors (mGluRs) was investigated in the in vitro lamprey brainstem preparation by analysing changes in respiratory activity induced by bath application of specific agonists (10 and 25 µm) and antagonists (500 µm). Respiratory responses reached their maximum within 10 or 15 min, without any obvious further changes during application periods of 60 min The broad‐spectrum mGluR agonist (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (ACPD) and the specific group I mGluR agonist (S)‐3,5‐dihydroxyphenylglycine (DHPG) caused dose‐dependent increases in respiratory frequency and peak vagal activity. DHPG at higher concentrations (50–100 µm) did not cause any further consistent change in respiratory variables. Two different agonists acting on group II mGluRs, i.e. (2S,3S,4S)‐CCG/(2S,1′S,2′S)‐2‐(carboxycyclopropyl)‐glycine (L‐CCG‐I) and (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine (DCG‐IV), were employed. At 10 µm DCG‐IV increased respiratory frequency, whilst L‐CCG‐I did not produce any significant effect. Both drugs increased respiratory frequency and peak vagal amplitude at 25 µm. The nonselective group I and II antagonist (S)‐α‐methyl‐4‐carboxyphenylglycine (MCPG) as well as the specific group I antagonist (RS)‐1‐aminoindan‐1,5‐dicarboxylic acid (AIDA) elicited reversible reductions in respiratory frequency. Blockade of group II mGluRs by (2S)‐α‐ethylglutamic acid (EGLU) increased both frequency and peak amplitude of vagal bursts. The results indicate that both group I and II mGluRs have an important modulatory role in the control of the lamprey pattern of breathing, probably through an action on the rhythm generating mechanisms. They support the view that these receptors are activated under physiological conditions and differentially affect the frequency and intensity of respiratory bursts.
Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone‐induced suppression
Authors: Karishma K. K. , Herbert J.
Published: March 2003

Treating adult male rats with subcutaneous pellets of dehydroepiandrosterone (DHEA) increased the number of newly formed cells in the dentate gyrus of the hippocampus, and also antagonized the suppressive of corticosterone (40 mg/kg body weight daily for 5 days). Neither pregnenolone (40 mg/kg/day), a precursor of DHEA, nor androstenediol (40 mg/kg/day), a major metabolite, replicated the effect of DHEA (40 mg/kg/day). Corticosterone reduced the number of cells labelled with a marker for neurons (NeuN) following a 28‐day survival period, and this was also prevented by DHEA. DHEA by itself increased the number of newly formed neurons, but only if treatment was continued throughout the period of survival. Subcutaneous DHEA pellets stimulated neurogenesis in a small number of older rats (≈ 12 months old). These results show that DHEA, a steroid prominent in the blood and cerebral environment of humans, but which decreases markedly with age and during major depressive disorder, regulates neurogenesis in the hippocampus and modulates the inhibitory effect of increased corticoids on both the formation of new neurons and their survival.