bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential responsiveness of rat striatal nerve endings to the mitochondrial toxin 3‐nitropropionic acid: implications for Huntington's disease
Authors: Marti Matteo , Mela Flora , Ulazzi Linda , Hanau Stefania , Stocchi Sara , Paganini Francesca , Beani Lorenzo , Bianchi Clementina , Morari Michele
Published: August 2003

Rat striatal synaptosomes and slices were used to investigate the responsiveness of different populations of nerve terminals to 3‐nitropropionic acid (3‐NP), a suicide inhibitor of the mitochondrial enzyme succinate dehydrogenase, and to elucidate the ionic mechanisms involved. 3‐NP (0.3–3 mm) stimulated spontaneous γ‐aminobutyric acid (GABA), glutamate and [3H]‐dopamine efflux but left unchanged acetylcholine efflux from synaptosomes. This effect was associated with a >70% inhibition of succinate dehydrogenase, as measured in the whole synaptosomal population. The facilitation was not dependent on extracellular Ca2+ but relied on voltage‐dependent Na+ channel opening, because it was prevented by tetrodotoxin and riluzole. 3‐NP also elevated spontaneous glutamate efflux from slices but in a tetrodotoxin‐insensitive way. To investigate whether energy depletion could change the responsiveness of nerve endings to a depolarizing stimulus, synaptosomes were pretreated with 3‐NP and challenged with pulses of KCl evoking ‘quasi‐physiological’ neurotransmitter release. 3‐NP potentiated the K+‐evoked GABA, glutamate and [3H]‐dopamine release but inhibited the K+‐evoked acetylcholine release. The 3‐NP induced potentiation of GABA release was Ca2+‐dependent and prevented by tetrodotoxin and riluzole whereas the 3‐NP‐induced inhibition of acetylcholine release was tetrodotoxin‐ and riluzole‐insensitive but reversed by glipizide, an ATP‐dependent K+ channel inhibitor. We conclude that the responsiveness of striatal nerve endings to 3‐NP relies on activation of different ionic conductances, and suggest that the selective survival of striatal cholinergic interneurons following chronic 3‐NP treatment (as in models of Huntington's disease) may rely on the opening of ATP‐dependent K+ channels, which counteracts the fall in membrane potential as a result of mitochondrial impairment.
Callosal connections of dorso‐lateral premotor cortex
Authors: Marconi B. , Genovesio A. , Giannetti S. , Molinari M. , Caminiti R.
Published: August 2003

This study investigated the organization of the callosal connections of the two subdivisions of the monkey dorsal premotor cortex (PMd), dorso‐rostral (F7) and dorso‐caudal (F2). In one animal, Fast blue and Diamidino yellow were injected in F7 and F2, respectively; in a second animal, the pattern of injections was reversed. F7 and F2 receive a major callosal input from their homotopic counterpart. The heterotopic connections of F7 originate mainly from F2, with smaller contingent from pre‐supplementary motor area (pre‐SMA, F6), area 8 (frontal eye fields), and prefrontal cortex (area 46), while those of F2 originate from F7, with smaller contributions from ventral premotor areas (F5, F4), SMA‐proper (F3), and primary motor cortex (M1). Callosal cells projecting homotopically are mostly located in layers II–III, those projecting heterotopically occupy layers II–III and V–VI. A spectral analysis was used to characterize the spatial fluctuations of the distribution of callosal neurons, in both F7 and F2, as well as in adjacent cortical areas. The results revealed two main periodic components. The first, in the domain of the low spatial frequencies, corresponds to periodicities of cell density with peak‐to‐peak distances of approximately 10 mm, and suggests an arrangement of callosal cells in the form of 5‐mm wide bands. The second corresponds to periodicities of approximately 2 mm, and probably reflects a 1‐mm columnar‐like arrangement. Coherency and phase analyses showed that, although similar in their spatial arrangements, callosal cells projecting to dorsal premotor areas are segregated in the tangential cortical domain.
Independence of visuotopic representation and orientation map in the visual cortex of the cat
Authors: Buzás Péter , Volgushev Maxim , Eysel Ulf T. , Kisvárday Zoltán F.
Published: August 2003

The representations of visual space and stimulus orientation were mapped in the cat primary visual cortex using electrophysiological recordings supplemented with intrinsic signal optical imaging. The majority of units displaced up to 600 µm laterally had overlapping RFs both in orientation domains and around singularities of the orientation map. Quantitative comparison of these units revealed only a weak, positive correlation between the difference in their preferred orientations and RF separations (area 17: r = 0.09; area 18: r = 0.15). The occurrence of nonoverlapping RFs could be accounted for by random RF position scatter rather than by orientation difference between the units. Monte Carlo analysis showed that our findings are compatible with a locally smooth and linear representation of visual space that is not coupled to the representation of stimulus orientation. An important functional implication of the above map relationships is that positional information captured by the retina is faithfully transmitted into the cortex.
Corticospinal neurons up‐regulate a range of growth‐associated genes following intracortical, but not spinal, axotomy
Authors: Mason M. R. J. , Lieberman A. R. , Anderson P. N.
Published: August 2003

The failure of some CNS neurons to up‐regulate growth‐associated genes following axotomy may contribute to their failure to regenerate axons. We have studied gene expression in rat corticospinal neurons following either proximal (intracortical) or distal (spinal) axotomy. Corticospinal neurons were retrogradely labelled with cholera toxin subunit B prior to intracortical lesions or concomitantly with spinal lesions. Alternate sections of forebrain were immunoreacted for cholera toxin subunit B or processed for mRNA in situ hybridization for ATF3, c‐jun, GAP‐43, CAP‐23, SCG10, L1, CHL1 or krox‐24, each of which has been associated with axotomy or axon regeneration in other neurons. Seven days after intracortical axotomy, ATF3, c‐jun, GAP‐43, SCG10, L1 and CHL1, but not CAP‐23 or krox‐24, were up‐regulated by layer V pyramidal neurons, including identified corticospinal neurons. The maximum distance between the lesion and the neuronal cell bodies that up‐regulated genes varied between 300 and 500 µm. However, distal axotomy failed to elicit changes in gene expression in corticospinal neurons. No change in expression of any molecule was seen in the neocortex 1 or 7 days after corticospinal axotomy in the cervical spinal cord. The expression of GAP‐43, CAP‐23, L1, CHL1 and SCG10 was confirmed to be unaltered after this type of injury in identified retrogradely labelled corticospinal neurons. Thus, while corticospinal neuronal cell bodies fail to respond to spinal axotomy, these cells behave like regeneration‐competent neurons, up‐regulating a wide range of growth‐associated molecules if axotomized within the cerebral cortex.
Induced down‐regulation of neuropeptide Y‐Y1 receptors delays initiation of kindling
Authors: Benmaamar Ramla , Pham‐Lê Bich‐Thuy , Marescaux Christian , Pedrazzini Thierry , Depaulis Antoine
Published: August 2003

Neuropeptide Y appears to modulate epileptic seizures differentially according to the receptor subtypes involved. In the hippocampus, neuropeptide Y expression and release are enhanced in different models of epileptogenesis. On the contrary, the expression of Y1 receptors is decreased and it has been shown that activation of these receptors has pro‐convulsant effects. The aim of our study was to investigate the role of Y1 receptors during hippocampal kindling epileptogenesis using (i) knock‐out mice lacking Y1 receptors and (ii) intrahippocampal infusion of Y1 antisense oligodeoxynucleotide in rats. Y1 knock‐out mice showed similar susceptibility to seizure induction and presented no difference in kindling development as compared with their control littermates. Conversely, local hippocampal down‐regulation of Y1 receptors during the first week of hippocampal kindling, induced by a local infusion of a Y1 antisense oligodeoxynucleotide, significantly increased seizure threshold intensity and decreased afterdischarge duration. A reverse effect was observed during the week following the infusion period, which was confirmed by a significant decrease in the number of hippocampal stimulations necessary to evoke generalized seizures. At the end of this second week, an up‐regulation of Y1 receptors was observed in kindled rats infused with the antisense as compared with the mismatch‐treated controls. Our results in the rat suggest that the down‐regulation of Y1 receptors in the hippocampus participates in the control of the initiation of epileptogenesis. The lack of an effect of the deficiency of Y1 receptors in the control of kindling development in Y1 knock‐out mice could be due to compensatory mechanisms.
Proton‐induced calcitonin gene‐related peptide release from rat sciatic nerve axons, in vitro, involving TRPV1
Authors: Fischer Michael J. M. , Reeh Peter W. , Sauer Susanne K.
Published: August 2003

We have shown previously that rat sciatic nerve axons in vitro express sensitivity to capsaicin and heat and responded to these stimuli with a Ca2+‐dependent and graded immunoreactive calcitonin gene‐related peptide release. Morphological evidence for stimulated vesicular exocytosis and for the vanilloid receptor TRPV1 in the axolemma of the unmyelinated nerve fibres has also been presented. Here we used solutions of low pH, high K+ or 47 °C to stimulate isolated desheathed sciatic nerves measuring immunoreactive calcitonin gene‐related peptide release. pH 6.1 increased immunoreactive calcitonin gene‐related peptide release by 31% over baseline and pH 5.2 and 4.3 caused a log‐linear concentration‐dependent increase of 137 and 265%, respectively. The effect of pH 3.4 was out of the linear range and not reversible. Stimulation in Ca2+‐free solutions and under increased intracellular Ca2+ buffering capacity strongly reduced the proton responses. The TRPV1 antagonists capsazepine and ruthenium red substantially reduced the effects of pH 5.2 but not pH 6.1. Combining a stimulus of 60 mm K+ with the subliminal pH 6.3 reduced the axonal immunoreactive calcitonin gene‐related peptide response by 88%. The noxious heat response at pH 6.3, however, was only reduced by 39%, suggesting a hidden sensitization to heat by low pH. This was supported by an effect of capsazepine to reduce the combined response to half, indicative of an involvement of TRPV1 in the sensitization but not in the axonal heat response itself that was found to be resistant to capsazepine. Axonal calcitonin gene‐related peptide release is thought to play a physiological role in activity‐dependent autoregulation of endoneurial blood flow. Axonal sensitivity to and sensitization by protons may be a pathophysiological mechanism involved in certain peripheral neuropathies.
Homer‐1a/Vesl‐1S enhances hippocampal synaptic transmission
Authors: Hennou Sonia , Kato Akihiko , Schneider Edith M. , Lundstrom Kenneth , Gähwiler Beat H. , Inokuchi Kaoru , Gerber Urs , Ehrengruber Markus U.
Published: August 2003

Homer/Vesl proteins are involved in regulating metabotropic glutamate receptors, synaptogenesis, dendritic spine development and axonal pathfinding. We investigated the potential modulation of glutamatergic synaptic transmission by the immediate early gene product Homer‐1a/Vesl‐1S and by the constitutively expressed long‐form Homer‐1c/Vesl‐1L in CA1 pyramidal cells from cultured rat hippocampal slices. Semliki Forest virus vector‐mediated overexpression of Homer‐1a enhanced alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor function, but did not detectably affect N‐methyl‐d‐aspartate (NMDA) receptor function and presynaptic glutamate release. Overexpression of Homer‐1c, by contrast, did not alter synaptic transmission. To corroborate our electrophysiological results obtained in slice cultures, we performed quantitative immunocytochemistry in cultures of dissociated hippocampal neurons. Homer‐1a also increased synaptic clustering of AMPA but not NMDA receptors, whereas Homer‐1c had no detectable effect. Our results show that Homer‐1a potentiates synaptic AMPA receptor function, supporting a critical role for Homer‐1a in hippocampal synaptic plasticity.
Vestibular response kinematics in posterior parietal cortex neurons of macaque monkeys
Authors: Klam François , Graf Werner
Published: August 2003

Perception of extrapersonal space is a fundamental requirement for accurate interaction with the environment and moving in it. Parietal cortical areas are thought to play an important role in this function. A significant sensory input to this area arrives from the vestibular system. We quantified neuronal responses in the ventral intraparietal area and the medial intraparietal area of awake head‐fixed macaque monkeys during classical vestibular sinusoidal stimulation protocols and with a newly developed random vestibular testing paradigm. The goal was to study more specifically the signal content of perietal vestibular neurons with respect to head movement kinematics. Traditional sinusoidal stimulation analysis revealed that about one‐third of the neurons responded in phase with either head position or head acceleration, besides classical head velocity tuning. Random vestibular stimulation revealed more complex signal profiles in the majority of neurons, although quantification of the kinematic variables that drove the neurons most effectively led to similar results to phase shift analysis. Thus, a majority of cells was principally driven by head velocity, and a minority by either acceleration or position. Nevertheless, random stimulation also revealed the simultaneous presence of all three kinematic response parameters (i.e. velocity, position and acceleration) in a majority of neurons. A minority of cells coded only two kinematic variables, i.e. head velocity coupled with either acceleration or position. Neurons coding only one kinematic variable were not found. We hereby demonstrate for the first time that central vestibular neurons carry several head movement kinematic variables simultaneously.
Encoding of direction and combination of movements by primate putamen neurons
Authors: Ueda Yasumasa , Kimura Minoru
Published: August 2003

To perform multiple movements in a preprogrammed order, the brain needs to compute both the visuospatial and temporal organization of such multiple movements. Previous studies revealed participation of the parietal and premotor areas in visuospatial processing, and of the supplementary motor and presupplementary motor areas in temporal structuring of multiple movements. In the basal ganglia, on the other hand, relatively little has been known about how the neuronal processing of the visuospatial and temporal structuring of multiple movements occurs. In the present study, monkeys performed combinations of hand movements, either a lever turn–lever turn or lever turn–button press. Combinations of the two movements were performed under visually instructed condition first, then under remembered condition. We found that activity of 43% (30/69) and 60% (42/69) of putamen neurons was selective to the preprogrammed combination of movements and to the direction of the first movement. The neurons preferring remembered condition were mainly observed in the dorsomedial part of the putamen, where most of neurons were also selective to both direction and combination of movements, while those in the ventrolateral part of the putamen were not selective to the instructed and remembered conditions. The results supported a hypothesis that the movement direction‐selective and the movement combination‐selective neuron activities in the striatum may play an indispensable role in the visuospatial and temporal organization of movements through the cortico‐basal ganglia loop system.
Decrease of adenosine A1 receptor density and of adenosine neuromodulation in the hippocampus of kindled rats
Authors: Rebola Nelson , Coelho Joana E. , Costenla Ana Rita , Lopes Luísa V. , Parada António , Oliveira Catarina R. , Soares‐da‐Silva Patrício , De Mendonça Alexandre , Cunha Rodrigo A.
Published: August 2003

Adenosine is a neuromodulator that has been proposed to be a major endogenous anticonvulsant acting via A1 receptors. We tested if implementation of kindling through stimulation of the amygdala affected A1 receptor‐mediated neuromodulation in hippocampal slices taken from rats 4 weeks after the last stage 5 seizure. The A1 receptor agonist, N6‐cyclopentyladenosine (CPA) (6–100 nm), inhibited field excitatory postsynaptic potential (fEPSP) slope with an EC50 of 19.1–19.5 nm in control and sham‐operated rats, but was less potent in kindled rats (EC50 = 42.7 nm). This might result from a decreased number of A1 receptors in hippocampal nerve terminal membranes, because A1 receptor immunoreactivity decreased by 28 ± 3% and the binding density of the A1 receptor agonist [3H]R‐PIA decreased from 1702 ± 64 to 962 ± 78 fmol/mg protein in kindled compared with control rats. The tonic inhibition of hippocampal synaptic transmission by endogenous adenosine was also lower in kindled rats, because A1 receptor blockade with 50 nm 1,3‐dipropyl‐8‐cyclopentyladenosine (DPCPX) enhanced fEPSP slope by 23 ± 3% and θ‐burst‐induced long‐term potentiation by 94 ± 4% in control rats but was virtually devoid of effects in kindled rats. The evoked release of adenosine from hippocampal slices or nerve terminals was 56–71% lower in kindled rats probably due to the combined decrease in the capacity of adenosine transporters and decreased release of adenosine 5′‐triphosphate (ATP), which was partially compensated by a higher extracellular catabolism of ATP into adenosine in kindled rats. These results indicate that, although adenosine might inhibit the onset of epileptogenesis, once kindling is installed, the efficiency of the adenosine inhibitory system is impaired.
GRP94 (94 kDa glucose‐regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury
Authors: Bando Yoshio , Katayama Taiichi , Kasai Kousuke , Taniguchi Manabu , Tamatani Michio , Tohyama Masaya
Published: August 2003

The 94 kDa glucose‐regulated protein (GRP94), the endoplasmic reticulum (ER) resident molecular chaperone, has a role in cell death due to endoplasmic reticulum stress (ER stress). Here, we report that expression of GRP94 was increased in human neuroblastoma cells (SH‐SY5Y (SY5Y) cells) exposed to hypoxia/reoxygenation (H/R). H/R mediated death of SY5Y cells was associated with the activation of major cysteine proteases, caspase‐3 and calpain, along with an elevated intracellular calcium concentration. Pretreatment with adenovirus‐mediated antisense GRP94 (AdGRP94AS) led to reduced viability of SY5Y cells after being subjected to H/R compared with wild‐type cells or cells with adenovirus‐mediated overexpression of GRP94 (AdGRP94S). These results indicate that suppression of GRP94 is associated with accelerated apoptosis and that expression of GRP94 (as a stress protein) suppresses oxidative stress‐mediated neuronal death and stabilizes calcium homeostasis in the ER. We also used gerbils with transient forebrain ischemia to study the role of GRP94 in vivo. Neurons with adenovirus‐mediated overexpression of GRP94 were resistant to ischemic damage. These results confirmed that GRP94 could suppress ischemic injury to neurons, suggesting that gene transfer of GRP94 into the brain may have therapeutic potential in the treatment of cerebrovascular disease.
Ca2+‐sensitive regulation of E‐type Ca2+ channel activity depends on an arginine‐rich region in the cytosolic II–III loop
Authors: Leroy Jérôme , Pereverzev Alexey , Vajna Rolf , Qin Ning , Pfitzer Gabriele , Hescheler Jürgen , Malécot Claire O. , Schneider Toni , Klöckner Udo
Published: August 2003

Ca2+‐dependent regulation of L‐type and P/Q‐type Ca2+ channel activity is an important mechanism to control Ca2+ entry into excitable cells. Here we addressed the question whether the activity of E‐type Ca2+ channels can also be controlled by Ca2+. Switching from Ba2+ to Ca2+ as charge carrier increased within 50 s, the density of currents observed in HEK‐293 cells expressing a human Cav2.3d subunit and slowed down the inactivation kinetics. Furthermore, with Ca2+ as permeant ion, recovery from inactivation was accelerated, compared to the recovery process recorded under conditions where the accumulation of [Ca2+]i was prevented. In a Ba2+ containing bath solution the Ca2+‐dependent changes of E‐type channel activity could be induced by dialysing the cells with 1 µm free [Ca2+]i suggesting that an elevation of [Ca2+]i is responsible for these effects. Deleting 19 amino acids in the intracellular II–III linker (exon 19) as part of an arginine‐rich region, severely impairs the Ca2+ responsiveness of the expressed channels. Interestingly, deletion of an adjacent homologue arginine‐rich region activates channel activity but now independently from [Ca2+]i. As a positive feedback‐regulation of channel activity this novel activation mechanism might determine specific biological functions of E‐type Ca2+ channels.
Rapamycin‐sensitive signalling in long‐term consolidation of auditory cortex‐dependent memory
Authors: Tischmeyer Wolfgang , Schicknick Horst , Kraus Michaela , Seidenbecher Constanze I. , Staak Sabine , Scheich Henning , Gundelfinger Eckart D.
Published: August 2003

New memories initially persist in a labile state and require protein synthesis‐dependent processes of consolidation for long‐term manifestation. Using differential conditioning to linearly frequency‐modulated tones (FMs) we have recently shown that post‐training injections of protein synthesis inhibitors into the auditory cortex of Mongolian gerbils interfere with long‐term memory for a number of days. Here, we have used rapamycin as a pharmacological tool to elucidate signalling pathways that control the synthesis of proteins required for persistent memory storage. In mammalian cells, inhibition of target of rapamycin (TOR)‐mediated pathways was shown to block the translation of distinct classes of mRNAs. Bilateral infusions of rapamycin into the gerbil auditory cortex shortly after FM discrimination training did not impair the maintenance of the newly acquired memory trace for 24 h, but caused profound retention deficits at 48 h after injection. Control experiments showed that the amnesic action is rapamycin‐dependent, confined to the context of memory formation, and suppressed by the antagonist FK506. These data indicate that, in the mammalian brain, activation of rapamycin‐sensitive signalling pathways contributes to long‐term consolidation of a cerebral cortex‐dependent form of memory. Moreover, the finding that rapamycin‐induced amnesia parallels only late effects of conventional protein synthesis inhibitors on FM discrimination memory implies that at least two different protein synthesis‐dependent processes control memory formation. Both are activated during or shortly after learning. Whereas one process is required for the initial maintenance of memory for about one day the second one is involved in the regulation of its long‐lasting persistence in conditioning to FMs.
Endogenous nitric oxide modulates GABAergic transmission to granule cells in adult rat cerebellum
Authors: Wall Mark J.
Published: August 2003

Nitric oxide (NO) is a gaseous neurotransmitter which plays an important role in neuronal signalling and plasticity throughout the brain. In the cerebellum, NO synthase (NOS) is expressed in parallel fibres and within the internal granule cell layer (IGL). During development there are changes in NOS concentration, distribution and activity within the IGL, suggesting NO may play a role in IGL function. Therefore, the actions of NO in the IGL were investigated. The similar actions of a range of NOS inhibitors and NO scavengers strongly suggested the presence of a tonic level of endogenous NO in the IGL. Both the neuronal and inducible forms of NOS appeared to be sources of this endogenous NO. The effects observed following a reduction in the concentration of endogenous NO were consistent with enhanced granule cell GABAA receptor activation. For example, a reduction in NO concentration led to an increase in the frequency of action potential‐dependent phasic GABAergic inhibitory postsynaptic currents (IPSCs) and produced a TTX‐insensitive GABAA receptor‐mediated current. A direct action of NO on Golgi cell membrane potential and input resistance accounted for the increase in the frequency of phasic GABA release. The mechanism underlying the tonic GABA current is unclear but does not appear to be via the modulation of GABA uptake or the activation of nicotinic acetylcholine receptors. NO is a potentially novel mechanism for tuning GABAergic signalling to granule cells and therefore modulating the throughput of an important cerebellar circuit.
Endocannabinoids contribute to short‐term but not long‐term mGluR‐induced depression in the hippocampus
Authors: Rouach Nathalie , Nicoll Roger A.
Published: August 2003

Activation of postsynaptic group 1 metabotropic glutamate receptors (mGluRs) by the agonist DHPG causes a long‐term depression (DHPG‐LTD) of excitatory transmission in the CA1 region of the hippocampus, as well as causing the release of endocannabinoids from pyramidal cells. As cannabinoid agonists cause a presynaptic inhibition at these synapses and DHPG‐LTD is thought to be expressed, at least in part, by a presynaptic mechanism, we examined the possibility that endocannabinoids mediated DHPG‐LTD. We find that antagonists of cannabinoid receptors reduce the acute depression induced by DHPG, but have no effect on the lasting depression. Furthermore, both the acute and the lasting effects of DHPG were unaffected in the CB1 knockout mouse. These findings suggest that endocannabinoids, acting on a non‐CB1 cannabinoid receptor, contribute to the acute depression but not to DHPG‐LTD. Presumably some other retrograde signalling mechanism is responsible for DHPG‐LTD.
Nigral GABAergic inhibition upon cholinergic neurons in the rat pedunculopontine tegmental nucleus
Authors: Saitoh Kazuya , Hattori Satoko , Song Wen‐Jie , Isa Tadashi , Takakusaki Kaoru
Published: August 2003

We investigated, in a midbrain parasagittal slice preparation of Wistar rats (postnatal day 9–17), the synaptic inhibition of neurons in the pedunculopontine tegmental nucleus (PPN), which was mediated by gamma (γ)‐amino‐butyric acid (GABA). Whole‐cell patch‐clamp recording was used, in combination with a single‐cell reverse transcription‐polymerase chain reaction amplification technique, to record synaptic potentials and to identify the phenotype of the recorded PPN neuron. In the presence of the ionotropic glutamate receptor antagonists, 6‐cyano‐2, 3‐dihydroxy‐7‐nitro‐quinoxaline‐2, 3, dione, and dl‐2‐amino‐5‐phosphonovaleric acid, single electrical stimuli were applied to the substantia nigra pars reticulata (SNr), one of the basal ganglia output nuclei. Stimulation of the SNr evoked inhibitory postsynaptic potentials (IPSPs) in 73 of the 104 neurons in the PPN. The IPSPs were abolished with a GABAA receptor antagonist, bicuculline. Inhibitory postsynaptic currents of the neurons were reversed in polarity at approximately −93.5 mV, which was close to the value of the equilibrium potential for chloride ions of −88.4 mV. Single‐cell reverse transcription‐polymerase chain reactions revealed that approximately 30% (9/32) of the PPN neurons that received inhibition from the SNr expressed detectable levels of choline acetyltransferase mRNA. These findings show that output from the SNr regulates the activity of cholinergic PPN neurons through GABAA receptors.
Selective up‐regulation of the growth arrest DNA damage‐inducible gene Gadd45 alpha in sensory and motor neurons after peripheral nerve injury
Authors: Befort Katia , Karchewski Laurie , Lanoue Christopher , Woolf Clifford J.
Published: August 2003

The growth arrest and DNA damage‐inducible gene 45 alpha (Gadd45a) was one of 240 genes found previously by high density oligonucleotide microarray analysis to be regulated in the rat L4 and L5 dorsal root ganglia 3 days after transection of the sciatic nerve (>four‐fold up‐regulation). The Gadd45a mRNA expression profile investigated by northern blot, RNase protection assay and in situ hybridization in the rat shows negligible constitutive mRNA levels in embryonic, neonatal or adult intact dorsal root ganglia. Within 24 h of a sciatic nerve injury, a very large induction is found that persists for as long as regeneration of injured fibres is prevented by peripheral nerve ligation. When axons are allowed to regrow following sciatic nerve crush injury, Gadd45a expression is terminated at later time points, when levels of other markers of injury return towards normal. Colocalization with activating transcription factor 3‐LI and c‐jun mRNA implies that all peripherally injured primary sensory and motor neurons express Gadd45a mRNA. Injury to the central axons of dorsal root ganglion neurons produces only a minimal induction of Gadd45a while peripheral inflammation is without effect. Gadd45a is a specific marker of the presence of peripheral axonal injury in adult primary sensory and motor neurons.
GABA and GABAA receptors at hippocampal mossy fibre synapses
Authors: Bergersen Linda , Ruiz Arnaud , Bjaalie Jan G. , Kullmann Dimitri M. , Gundersen Vidar
Published: August 2003

Anatomical and electrophysiological evidence has raised the possibility that corelease of GABA and glutamate occurs at hippocampal mossy fibre synapses which, however, lack the vesicular GABA transporter VGAT. Here, we apply immunogold cytochemistry to show that GABA, like glutamate, has a close spatial relation to synaptic vesicles in rat mossy fibre terminals, implying that a mechanism exists to package GABA in synaptic vesicles. We also show that GABAA and AMPA receptors are colocalized at mossy fibre synapses. The expression of GABA and GABAA receptors is, however, weaker than in inhibitory synapses. Electrical stimuli that recruit mossy fibres evoke monosynaptic GABAA receptor‐mediated signals in post‐synaptic targets that show marked frequency‐dependent facilitation and sensitivity to group II metabotropic receptors, two features that are characteristic of mossy fibre transmission. These results provide further evidence for GABA and glutamate cotransmission at mossy fibre synapses, although paired pre‐ and post‐synaptic recordings will be required to determine the role of GABA at this unusual synapse.
An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus of adult female rat
Authors: Perez‐Martin Margarita , Azcoitia Iñigo , Trejo Jose Luis , Sierra Amanda , Garcia‐Segura Luis M.
Published: August 2003

Interdependence between estradiol and insulin‐like growth factor‐I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin‐like growth factor‐I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin‐like growth factor‐I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5‐bromo‐2‐deoxyuridine and were killed 24 h after the last injection. The total number of 5‐bromo‐2‐deoxyuridine‐positive neurons was significantly increased in animals treated with insulin‐like growth factor‐I, compared with rats treated with vehicles, while rats treated with both insulin‐like growth factor‐I and estradiol showed a higher number of 5‐bromo‐2‐deoxyuridine‐positive neurons than rats treated with insulin‐like growth factor‐I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin‐like growth factor‐I on the number of 5‐bromo‐2‐deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin‐like growth factor‐I in the dentate gyrus, and that estradiol and insulin‐like growth factor‐I have a cooperative interaction to promote neurogenesis. The interaction between insulin‐like growth factor‐I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.
Recurrent rectal cancer. The pre‐irradiated primary tumour: can more radiotherapy be given?
Authors: Glimelius B.
Published: August 2003

Local recurrence of rectal cancer after combined radiation and adequate surgery is fortunately rare. It is difficult to manage and most patients have disseminated disease. The treatment possibilities were reviewed based upon a literature search and our own experience. In patients who have already had pre‐ or postoperative radiotherapy to a dose of about 50 Gy over five weeks or 25 Gy in one week, it is possible to re‐irradiate those who develop recurrence up to at least 30 Gy externally over three weeks. In addition, intra‐operative radiotherapy (IORT) or brachytherapy may be given. This strategy may give benefit but cure is not possible unless the recurrence is surgically resectable. There is, however, little information on secondary radiotherapy in these pre‐irradiated patients.
Multi‐modality approach in curative local treatment of early rectal carcinomas
Authors: Hershman M. J. , Myint A. Sun , Makin C. A.
Published: August 2003

Objective  Despite recent advances, surgery remains the mainstay for the management of rectal carcinoma. The conventional surgical treatment for low rectal carcinoma is total mesorectal excision. This results in either abdomino‐perineal excision of the rectum (APER) with permanent colostomy or low anterior resection (LAR) usually with a covering stoma. Local resection is an alternative treatment option and this could be offered either using manual trans‐anal resection (TAR) or transanal endoscopic microsurgery (TEM) if the tumour is situated higher.

Patients  Patient selection is an important factor if local resection is used. No further treatment is necessary for T1 tumours with clear surgical resection margins. Conventional radical surgery should be offered for T1 tumours with close resection margins (<1 mm) or T2 tumours with higher risk of lymph node metastases. Patients were treated by postoperative chemo‐radiotherapy or radiotherapy, if further radical surgery was not considered appropriate or if the patient refused further surgery. Using this approach, we describe our experience of 100 patients treated from January 1992 to June 2002.

Results  Only 13 patients had surgery alone and 87 patients had radiotherapy either pre‐operative (33 patients), postoperative (25 patients) or radical radiotherapy alone (29 patients). Local recurrence occurred in 10% of patients and salvage surgery was offered in over half (6 patients) of these patients. At median follow up of 33 months (range 3–120 months), the overall survival was 77% reflecting the fact that the majority of these patients were elderly with coexisting medical problems. However, cancer specific survival was 96%. More importantly, only 9 patients had colostomies and colostomy‐free survival in our cohort of patients from Liverpool was 91%.

Conclusion  We concluded that in selected patients, who were not medically fit (ASA 111 or above) or those who were unable to accept a permanent colostomy, local treatment could be offered with curative intent using a multimodality approach. In our experience, relapses can be salvaged effectively and we recommend a long‐term close follow up policy.
Adjuvant therapy for rectal cancer – the transatlantic view
Authors: Minsky B. D.
Published: August 2003

In North America there are two conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumour is T3 and/or N1–2, this is followed by postoperative combined modality therapy. The second, for patients with ultrasound T3 or clinical T4 disease, is pre‐operative combined modality therapy followed by surgery and postoperative chemotherapy.

Pre‐operative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of this approach compared with postoperative therapy include less acute toxicity and enhanced sphincter preservation. Recently completed randomized trials in the US and Germany will provide a definitive answer to this theory. In contrast to the combined modality approach to pre‐operative therapy a number of European centres advocate an intensive short course of radiation (5 Gy × 5 followed one week later by surgery). The only randomized trial which has revealed a significant advantage in survival is the Swedish Rectal Cancer Trial. The Dutch CKVO 95–04 TME trial did not confirm a survival advantage and two metanalyses report conflicting results. Due to selection bias, it is not possible accurately to compare the local recurrence and survival results of intensive short course radiation with conventional pre‐operative combined modality therapy. The intensive short course radiation approach is not used in North America due to its higher toxicity and lack of sphincter preservation. In the Dutch trial the 5‐year local recurrence was 12% with TME and was significantly decreased to 6% with pre‐operative radiation. The 5‐year local recurrence rate in the 324 patients with stage III disease who underwent a TME alone with negative margins was 20%. Therefore, despite TME surgery, radiation therapy is still a necessary component in the adjuvant management of rectal cancer.
Rectal cancer and ulcerative colitis: does it change the therapeutic approach?
Authors: Remzi F. H. , Preen M.
Published: August 2003

Objective  The aim of this study was to examine the incidence of coexisting colorectal cancer in ulcerative colitis in a population of patients undergoing ileal pouch anal anastomosis. The frequency of rectal cancer in this population, surgical intervention, general outcomes and cancer recurrence are described.

Methods  Data on 1850 patients undergoing restorative proctocolectomy from 1983 to 2001 were reviewed. Information was gathered from data in the department's pelvic pouch database, as well as pathology and surgical reports. Follow‐up questionnaires routinely sent to patients as part of the database were included in the analysis to determine current functional status. Mean follow‐up period was 7.5 years after surgery.

Results  Seventy patients had coexisting colorectal cancer at time of IPAA. 7 (10%) of cancers were incidental. Pre‐operative duration of disease was 18.6 years. Twenty‐six of the cancers were rectal cancers. The most common form of anastomosis in the rectal cancers was mucosectomy, especially in pre‐operatively known rectal cancer or low lying dysplasia. Preferred surgical technique for rectal cancer in mucosal ulcerative colitis (UC) included high ligation of mesenteric vessels with radical colectomy and taped occlusion of the rectum with irrigation of the rectal stump with Turnbull solution prior to mucosectomy. Patients with Stage 3 cancers received postoperative chemotherapy. Post‐operative radiation therapy was not commonly recommended. Five of 70 patients were deceased from metastatic colon cancer; 55 patients were confirmed alive with good to excellent pouch function with a follow‐up range of 1–17 years.

Conclusion  Restorative proctocolectomy with ileal pouch anal anastomosis is a successful surgical approach for patients with coexisting colorectal cancer in UC. When the appropiate surgical technique is used in patients with colon or rectal cancer, along with adjuvant chemotherapy when appropriate, prognosis and function is very good.
Total mesorectal excision for rectal cancer – what can be achieved by a national audit?
Authors: Wibe A. , Eriksen M T. , Syse A. , Myrvold H E. , Søreide O. ,   on behalf of The Norwegian Rectal Cancer Group
Published: August 2003

Objective  The results of rectal cancer surgery in Norway have been poor. In a national audit for the period 1986–88, 28% of the patients developed local recurrence (LR) following treatment with a curative intent. Five‐year overall survival was 55% for patients younger than 75 years. The aim of this study is to report how an initiative focusing on better surgery can improve the prognosis for rectal cancer patients on a national level.

Methods  In 1994, the Norwegian Rectal Cancer Group was founded. The aim of this initiative was to improve the surgical standard by implementing total mesorectal excision (TME) on a national level and to evaluate the results. A number of courses were arranged to teach the surgeons the TME technique, and pathologists were trained to increase the standard of both macroscopic and microscopic assessment of specimens. A rectal cancer registry was established, and all surgical departments treating rectal cancer were invited to transfer their clinical data to this registry. Each department regularly receives its own results together with the national average for comparison and quality control.

Results  The Rectal Cancer Registry includes all patients with rectal cancer diagnosed since November 1993. From then until December 1999, 5382 patients had a tumour located within 16 cm from the anal verge, and 3432 patients underwent rectal resection with a curative intent. Of these, 9% had adjuvant radiotherapy, and 2% were given chemotherapy. There was a rapid implementation of the new technique, as 78% underwent TME in 1994, increasing to 96% in 1998. After 39 months mean follow‐up the rate of local recurrence was 8%, and 5‐year overall survival was 71% for patients younger than 75 years.

Conclusions  An optimized surgical technique (TME) for rectal cancer can reduce the rate of local recurrence and increase overall survival. This improved surgical treatment can be implemented on a national level within a few years. Specialization of surgeons, feedback of results and a separate rectal cancer registry are thought to be major contributors to the improved treatment.
Surgery for locally recurrent rectal cancer
Authors: Wiggers T. , Mannaerts G. H. H. , Marinelli A. W. K. S. , Martijn H. , Rutten H. J. T.
Published: August 2003

After the diagnosis of a locally recurrent rectal cancer, imaging is the first step to estimate the extent and location of the local tumour growth and the presence or absence of distant metastases. The aim of the treatment is a R0 resection (microscopically tumour free circumferential margin) by multimodality treatment consisting of pre‐operative radiation, extended resection and intra‐operative radiotherapy by either electron beam irradiation or with high dose rate brachytherapy. Filling the pelvic cavity with vital tissue such as an omentoplasty should considered carefully. With this treatment the overall three‐year survival rate of a group of 33 patients was 60% with a local control rate of 73%. The combination of chemotherapy as a radiosensitizer resulted in an increase of R0 resections by 20%. Introduction of TME surgery and pre‐operative radiotherapy has created a new situation with limited possibilities due to dose‐accumulation toxicity of the radiotherapy and extensive scarring of the tissues making estimation of the extent of the tumour growth more difficult. The prevention of local recurrence by proper selection of primary cases, the training of experienced surgeons and the optimal use of pre‐operative radiotherapy is the way forward to improve results.
Ultralow anterior resection with intersphincteric dissection –what is the limit of safe sphincter preservation?
Authors: Tiret E. , Poupardin B. , McNamara D. , Dehni N. , Parc R.
Published: August 2003

Introduction  In the treatment of low rectal cancer, the possibility of sphincter preserving surgery is increased by partial sphincteric resection which may allow an oncologically safe resection margin in some patients who would traditionally have been treated by abdominoperineal resection. The aim of this study is to evaluate the morbidity, mortality and the oncological and functional results of intersphincteric resection to determine whether the technique may be considered a safe means of sphincter preservation.

Methods  Between May 1992 and December 1999, 26 patients (mean age 55 years, range 28–82) with adenocarcinoma of the rectum had partial sphincteric resection by an abdominal approach with a colonic J‐pouch anal anastomosis. The mean distance between the tumour and the anal verge 4.25 (range 3.1–5.25) cm. Four tumours were T1, 14 T2 (3 N+), 7 T3 (3 N+), and 1 T4 (N+). Neoadjuvant radiotherapy was used in 10 patients. The distal resection margin was positive in one patient who then proceeded to safe abdominoperineal resection (APR). In the remaining patient the mean distal resection margin on the fixed specimen was 1.6 (range 0.3–3.5) cm.

Results  There were no deaths. Morbidity was 30% with an anastomotic leak rate of 11%. At mean follow‐up of 39 (range 11–93) months the local recurrence rate was 3.4%. Functional results were evaluated in 25 patients at mean follow‐up of 27 (8–66) months: 65% had 0–2 bowel motions per 24 h, 31% had 3–5 and 4% between 6 and 9. Nine patients (36%) had nocturnal defecation. Continence was normal in 50% with 23% reporting incontinence to gas and 27% reporting minor episodes of incontinence. None had major incontinence and 85% considered their outcome satisfactory.

Conclusion  This study supports the current literature indicating that partial sphincteric resection is an oncologically and functionally safe alternative to abdominoperineal resection for some selected low rectal tumours.