bluuebunny/crossref_metadata_2025 huggingface dataset:
Disconnecting hippocampal projections to the anterior thalamus produces deficits on tests of spatial memory in rats
Authors: Warburton E. C. , Baird A. L. , Morgan A. , Muir J. L. , Aggleton J. P.
Published: March 2003

A disconnection procedure was used to test whether projections from the hippocampus to the anterior thalamic nuclei (AT), via the fimbria‐fornix (FX), form functional components of a spatial memory system. The behavioural effects of combined unilateral lesions in the AT and FX were compared when they were either in contralateral hemispheres (AT‐FX Contra) or the same hemisphere (AT‐FX Ipsi). Other groups received bilateral FX lesions and Sham surgeries. Expt 1 demonstrated that none of these lesions affected performance of an object recognition task, while performance of an object location task, which tests the subjects' preference for an object that has changed location, was impaired in the AT‐FX Contra and FX groups. In a T‐maze alternation task, however, the FX group was severely impaired while both the AT‐FX Ipsi and AT‐FX Contra lesion groups showed only a mild impairment. In order to test whether spared crossed projections might support spatial performance in the AT‐FX Contra group we then examined the effects of a combined AT‐FX Contra lesion coupled with transection of the hippocampal commissure. This combination of lesions produced a severe disruption in spatial memory performance in the water maze, radial arm maze and T‐maze, which was significantly greater than that produced by ipsilateral and contralateral AT‐FX lesions alone. These results support the notion that disconnection of the AT from their hippocampal inputs produces impairments on a range of spatial memory tasks, but indicate that there are an array of different routes that can subserve this function.
Regulation of GluR2 promoter activity by neurotrophic factors via a neuron‐restrictive silencer element
Authors: Brené Stefan , Messer Chad , Okado Haruo , Hartley Melissa , Heinemann Stephen F. , Nestler Eric J.
Published: March 2003

The AMPA glutamate receptor subunit GluR2, which plays a critical role in regulation of AMPA channel function, shows altered levels of expression in vivo after several chronic perturbations. To evaluate the possibility that transcriptional mechanisms are involved, we studied a 1254‐nucleotide fragment of the 5′‐promoter region of the mouse GluR2 gene in neural‐derived cell lines. We focused on regulation of GluR2 promoter activity by two neurotrophic factors, which are known to be altered in vivo in some of the same systems that show GluR2 regulation. Glial‐cell line derived neurotrophic factor (GDNF) and brain‐derived neurotrophic factor (BDNF) both induced GluR2 promoter activity. This was associated with increased expression of endogenous GluR2 immunoreactivity in the cells as measured by Western blotting. The effect of GDNF and BDNF appeared to be mediated via a NRSE (neuron‐restrictive silencer element) present within the GluR2 promoter. The response to these neurotrophic factors was lost upon mutating or deleting this site, but not several other putative response elements present within the promoter. Moreover, overexpression of REST (restrictive element silencer transcription factor; also referred to as NRSF or neuron restrictive silencer factor), which is known to act on NRSEs in other genes to repress gene expression, blocked the ability of GDNF to induce GluR2 promoter activity. However, GDNF did not alter endogenous levels of REST in the cells. Together, these findings suggest that GluR2 expression can be regulated by neurotrophic factors via an apparently novel mechanism involving the NRSE present within the GluR2 gene promoter.
Neural selectivity for hue and saturation of colour in the primary visual cortex of the monkey
Authors: Hanazawa Akitoshi , Komatsu Hidehiko , Murakami Ikuya
Published: March 2003

In the inferior temporal (IT) cortex of monkeys, which has been shown to play a critical role in colour discrimination, there are neurons sensitive to a narrow range of hues and saturation. By contrast, neurons in the retina and the parvocellular layer of the lateral geniculate nucleus (pLGN) encode colours in a way that does not provide explicit representation of hue or saturation, and the process by which hue‐ and saturation‐selectivity is elaborated remains unknown. We therefore tested the colour‐selectivity of neurons in the primary visual cortex (V1) and compared it with those of pLGN and IT neurons. Quantitative analysis was performed using a standard set of colours, systematically distributed within the CIE (Commission Internationale de l'Eclairage)‐xy chromaticity diagram. Selectivity for hue and saturation was characterized by analysing response contours reflecting the overall distribution of responses across the chromaticity diagram. We found that the response contours of almost all pLGN neurons were linear and broadly tuned for hue. Many V1 neurons behaved similarly; nonetheless, a considerable number of V1 neurons had clearly curved response contours and were selective for a narrow range of hues or saturation. The relative frequencies of neurons exhibiting various selectivities for hue and saturation were remarkably similar in the V1 and IT cortex, but were clearly different in the pLGN. Thus, V1 apparently plays a very important role in the conversion of colour signals necessary for generating the elaborate colour selectivity observed in the IT cortex.
Neurofilament protein distribution in the macaque monkey dorsolateral premotor cortex
Authors: Geyer Stefan , Zilles Karl , Luppino Giuseppe , Matelli Massimo
Published: March 2003

Regional and laminar distribution patterns of neurofilament proteins in the dorsolateral premotor cortex (PMd) were studied with monoclonal antibody SMI‐32 in five adult macaque monkeys and compared with the cytoarchitectonical features of the PMd. Our goal was to reveal whether the increasing functional diversity of the PMd which electrophysiological studies have unravelled over the last years is reflected on a structural level by differences in the neurochemical phenotype. Differences in size, shape and packing density of immunopositive layer III and V pyramidal cells define areas much more clearly than do differences in cytoarchitecture. The PMd can be subdivided into a rostral and a caudal part at a level slightly anterior to the genu of the arcuate sulcus. The extent of these two areas matches the two cytoarchitectonically defined areas F7 and F2, respectively. Within area F2, differences in layer V immunoreactive neurons define a dorsal (F2d) and a ventral (F2v) region. The border between areas F2d and F2v lies at the superior precentral dimple and cannot be detected cytoarchitectonically in Nissl‐stained sections. Neurofilament proteins are involved in the stabilization of the cytoskeleton of the axon and have been correlated with axonal size and conduction velocity of nerve fibres. This regional variability in the neurochemical phenotype of layer V within the caudal PMd may reflect a differential organization of the descending output from this part of the premotor cortex. It might also be related to differences in the motor control of voluntary arm and leg movements.
Developmental expression of amphiphysin in the retinotectal system of the chick: from mRNA to protein
Authors: Grabs Detlev , Bergmann Mathias , Rager Günter
Published: March 2003

The role of amphiphysin in clathrin‐mediated endocytosis of synaptic vesicles is well established. However, it is still uncertain if the protein is also involved in developmental mechanisms, e.g. axon outgrowth and synapse formation. To investigate the developmental changes in the expression of amphiphysin we used the retinotectal system of the chick, a highly ordered and easily accessible primary neuronal pathway. Reverse transcription polymerase chain reaction (RT‐PCR) of total RNA from chick retina and tectum revealed first transcripts for amphiphysin, dynamin and synaptotagmin at embryonic day 5 (E5) for both regions. Surprisingly, Western blots of the retina revealed an increase of protein expression for amphiphysin only after E11 in the retina and the tectum. Immunofluorescence for amphiphysin was not detectable before E10 in the developing chick retina, while other presynaptic proteins like synaptotagmin showed already intense signals in the inner and outer plexiform layers. Subsequently, amphiphysin immunoreactivity follows the expression of synaptotagmin and synaptic vesicle protein 2 (SV2) as seen in the retina and the tectum, and exhibits the same staining as the other proteins in the mature chick brain. Ultrastructural data revealed for the first time that amphiphysin is not only limited to conventional synapses but is also abundant in retinal ribbon terminals. Taken together our data reveal that: (i) there is a developmental delay between mRNA transcription and protein expression for key proteins involved in endocytosis; (ii) amphiphysin gets upregulated after synapse formation; and (iii) amphiphysin is present in the synaptic vesicle cycle in retinal ribbon synapses.
MPTP selectively induces haem oxygenase‐1 expression in striatal astrocytes
Authors: Fernandez‐Gonzalez Angeles , Pérez‐Otaño Isabel , Morgan James I.
Published: March 2003

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta with accompanying evidence of increased oxidative damage, deficits in mitochondrial function and iron deposition. Recently, haem oxygenase‐1 levels were reported to be elevated in PD brains. Because this enzyme is involved in the response to oxidative stress and is critical for cellular haem and iron homeostasis, it could play a role in the pathogenesis of PD. Therefore, we investigated the expression of haem oxygenase isoform 1 (HO‐1) in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD. MPTP triggered a relatively rapid and persistent increase in HO‐1 mRNA exclusively in the mouse striatum. In situ hybridization and immunohistochemistry showed HO‐1 to be localized to striatal astrocytes. The induction of HO‐1 by MPTP was blocked by selegiline and GBR‐12909, indicating the protoxin had to be metabolized by monoamine oxidase B and taken up by dopaminergic neurons to exert its action in astrocytes. MPTP did not alter the expression of other enzymes of haem synthesis or degradation nor were the levels of mRNA for haem or iron‐binding proteins changed. Thus, expression of HO‐1 was not part of a cellular program involving haem biosynthesis or homeostasis. In addition, heat shock proteins were not induced by MPTP. Thus, MPTP elicited a selective transcriptional response in striatal astrocytes. This response appears to be mediated by molecules released from affected dopaminergic nerve terminals in the striatum acting upon neighbouring astrocytes. This signalling pathway and its potential relevance to PD are discussed.
Galanin influences the mechanosensitivity of sensory endings in the rat knee joint
Authors: Heppelmann Bernd , Just Stefan , Pawlak Matthias
Published: March 2003

The aim of the present study was to examine the effect of galanin on group III and IV afferent nerve fibres (n = 53) innervating normal and acutely inflamed knee joints in rats. They responded to local mechanical stimulation, movements of the joint and i.a. injections of KCl close to the joint. Single i.a. bolus injections of galanin (0.1 mm, 0.2 mL) caused no direct responses of the units. In normal and acutely inflamed joints, about half of the units did not change the responses to knee joint rotation. A significant reduction of the responses to noxious movements was found in ∼ 40% of the units reaching a mean value of 57% in normal joints and 70% in inflamed joints compared with control movements. In ∼ 10% the responses increased to 143% in normal joints and 120% in inflamed joints. Injection of a galanin receptor antagonist (M35) doubled the responses to noxious movements in 36% of the units in normal joints and reduced it in 18% to 86% of the control movements, indicating a tonic release and influence on the mechanosensitivity of a proportion of primary afferents by galanin. In conclusion, these data further support the hypothesis that the mechanosensitivity of fine afferent nerve fibres is regulated by a mixture of different substances being released into the innervated tissue. Besides the action of several pro‐inflammatory peptides there seems to exist a tonic inhibitory system.
Cellular response to texture and form defined by motion in area 19 of the cat
Authors: Khayat Paul S. , Saint‐Amour Dave , Molotchnikoff Stéphane , Lepore Franco , Guillemot Jean‐Paul
Published: March 2003

The present study examined the neuronal sensitivity in area 19 of the cat to a motion‐defined bar and to texture. Sensitivity was tested in normal, lesioned (areas 17–18) and split‐chiasm cats using a kinematogram, as well as a textured bar drifting on a uniform light background and a light bar drifting on a stationary textured background. Texture density was varied. The results indicate that almost all cells of area 19 recorded in the three groups of cats responded to a motion‐defined bar or to its edges. Texture density influenced the responses in that the discharge rate increased as density decreased. However, the majority of cells were sensitive to the highest texture density kinematogram. Moreover, the neural responses of all cats were either independent of the density of the textured bar or background, or were modulated by it. These results show that cells in area 19 can signal the presence of a kinetic bar and that the density of either the textured bar, the background or both can influence figure–ground detection. The results are interpreted with respect to how various inputs influence the function of area 19.
Effects of scopolamine on a novel choice serial reaction time task
Authors: Higgs Suzanne , Deacon Robert M. J. , Rawlins J. Nicholas P.
Published: March 2003

Rats were trained on a novel attentional task adapted from the five‐choice serial reaction time test first developed by Carli et al. [1983; Behav. Brain. Res., 9, 361–80]. The novel task required rats to detect the occurrence of brief light flashes in one of two spatial locations following trial initiation by a lever press. Blank trials were interleaved with stimulus trials and the rat had to make a different response to indicate the absence of a light. Occasional light‐alone trials were also presented in which the visual stimulus appeared without forewarning. Pre‐exposure to food for 60 min prior to test increased response omissions for all trials and slowed correct response latency, but failed to significantly alter accuracy. A decrease in light‐stimulus duration (1–0.4 s) decreased accuracy, increased the reporting of blank trials and the number of light‐alone trial omissions. Scopolamine (0.03–0.1 mg/kg) and scopolamine methylbromide (0.1 mg/kg) failed to affect accuracy, but increased light‐alone trial omissions and lengthened correct response latency. The results confirm that the novel task is able to distinguish between motivational and attentional manipulations, and imply that scopolamine affected performance via nonattentional mechanisms.
Cloning and characterization of SDF‐1γ, a novel SDF‐1 chemokine transcript with developmentally regulated expression in the nervous system
Authors: Gleichmann Marc , Gillen Clemens , Czardybon Margarete , Bosse Frank , Greiner‐Petter Regine , Auer Johannes , Müller Hans Werner
Published: March 2003

The cytokines SDF‐1α and ‐1β are two alternatively spliced variants of the CXC (α) chemokines that are highly conserved among species. SDF‐1α was shown to function as a B‐cell maturation factor, a ligand for the CXCR4 (LESTR/fusin) chemokine receptor, thereby inhibiting replication of T cell‐tropic HIV‐1 strains and inducing cell death in human neuronal cell lines. In this report the cloning of the rat SDF‐1β cDNA and a new SDF‐1 isoform, SDF‐1γ, are presented. Using Northern blot analysis, the expression pattern of both isoforms was studied in different tissues and it is shown that during postnatal development of the central and peripheral nervous system SDF‐1β‐ and SDF‐1γ‐mRNA expression is inversely regulated. Whilst SDF‐1β‐mRNA is the predominant isoform in embryonic and early postnatal nerve tissue, SDF‐1γ‐mRNA is expressed at higher levels in adulthood. After peripheral nerve lesion a transient increase in SDF‐1β‐mRNA expression is observed. As revealed by in situ hybridization, neurons and Schwann cells are the main cellular sources of both SDF‐1β and SDF‐1γ mRNAs in the nervous system. Computer‐assisted analysis revealed that both transcripts encode secreted peptides with putative proteolytic cleavage sites which might generate novel neuropeptides.
Neurotrophin 3 potentiates glutamatergic responses of IHC afferents in the cochlea in vivo
Authors: Oestreicher E. , Knipper M. , Arnold A. , Zenner H. P. , Felix D.
Published: March 2003

Neurotrophins have traditionally been regarded as slow‐acting signals essential for neuronal survival and differentiation. Recent studies with neuronal slices, cultures and nerve ending preparations have shown that neurotrophins generate acute changes in nerve activity. Among the secondary sensory cells are the inner hair cells (IHC) and taste buds, cells which express the neurotrophic factors necessary for the survival of their innervating neurons. If in these cells neurotrophins acutely affect the nerve activity of their afferent neurons, as in the central nervous system (CNS), this may have important functional implications for the corresponding sensory transduction processes. The neurotrophin NT‐3 has been reported to be expressed in IHCs. We chose an in vivo application system for the microiontophoretic supply of NT‐3 in the subsynaptic region of the IHC. The effect of NT‐3 on spontaneous and evoked afferent cochlear nerve activities in adult guinea pig inner ear was studied. We observed that NT‐3 rapidly increases the spontaneous and glutamate‐evoked firing rate of IHC afferents. Moreover, firing induced by both N‐methyl‐ d‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) were specifically enhanced during the presence of NT‐3, a process which was selectively blocked by the tyrosine kinase receptor inhibitor K252a. Because we localized NT‐3 mRNA not only in IHCs but also in the spiral ganglion, we propose that similar to other sensory systems, afferent and autocrine neurotrophin activities may be responsible for survival of cochlear neurons. In addition, NT‐3 in IHCs may operate as a signal‐dependent, intrinsic neuromodulator and/or neuroprotector.
Characterization of calcium currents in functionally mature mouse spinal motoneurons
Authors: Carlin K. P. , Jiang Z. , Brownstone R. M.
Published: March 2003

Motoneurons integrate synaptic input and produce output in the form of trains of action potentials such that appropriate muscle contraction occurs. Motoneuronal calcium currents play an important role in the production of this repetitive firing. Because these currents change in the postnatal period, it is necessary to study them in animals in which the motor system is ‘functionally mature’, that is, animals that are able to weight‐bear and walk. In this study, calcium currents were recorded using whole‐cell patch‐clamp techniques from large (> 20 μm) ventral horn cells in lumbar spinal cord slices prepared from mature mice. Ninety percent (nine out of 10) of the recorded cells processed for choline acetyltransferase were found to be cholinergic, confirming their identity as motoneurons. A small number of motoneurons were found to have currents with low‐voltage‐activated (T‐type) characteristics. Pharmacological dissection of the high‐voltage‐activated current demonstrated ω‐agatoxin‐TK‐ (P/Q‐type), ω‐conotoxin GVIA‐ (N‐type), and dihydropyridine‐ and FPL‐64176‐sensitive (L‐type) components. A cadmium‐sensitive component of the current that was insensitive to these chemicals (R‐type) was also seen in these cells. These results indicate that the calcium current in lumbar spinal motoneurons from functionally mature mice is mediated by a number of different channel subtypes. The characterization of these calcium channels in mature mammalian motoneurons will allow for the future study of their modulation and their roles during behaviours such as locomotion.
Distinct expression patterns of Eph receptors and ephrins relate to the structural organization of the adult rat peripheral vestibular system
Authors: Matsunaga Tatsuo , Greene Mark I. , Davis James G.
Published: March 2003

Eph receptors and their ligands, termed ephrins, have been implicated in axon guidance, neuron–target interactions, regional compartmentalization, and synaptic functions in nervous systems. These activities of the Eph family molecules prompted us to investigate whether these molecules play roles in the maintenance, regeneration and plasticity in the mature peripheral vestibular system. Using reverse transcription‐polymerase chain reaction (RT‐PCR), Western blot and immunocytochemical analyses, we identified distinct and reciprocal expression patterns of full‐length isoforms of EphA5, EphA6, EphA7, EphB1, ephrin‐A2 and ephrin‐B1 that correlated with structural features of the peripheral vestibular system in adult rats. All of the Eph receptors and ephrins examined were localized in the cell bodies of vestibular ganglion neurons in vivo and in vitro, and were readily detected in their outgrowing neurites in vitro. In the utricle, these molecules were localized in distinct cellular and subcellular compartments corresponding to discrete features of utricular afferent innervation, e.g. defasciculation, branching and synapse formation. Taken together, these results identify the Eph receptors and ephrins as candidate molecular substrates for defining some aspects of the structural organization of the adult peripheral vestibular system.
The distribution and origin of the calretinin‐containing innervation of the nucleus accumbens of the rat
Authors: Bubser Michael , Scruggs Jennifer L. , Young Cheryl D. , Deutch Ariel Y.
Published: March 2003

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium‐binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium‐binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract‐tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin‐like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin‐immunoreactive fibres were seen in the core, where they were restricted to calbindin‐negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin‐rich regions of the accumbens. Conversely, injections of Fluoro‐gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin‐immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by ≈ 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.
Progesterone regulation of GABAA receptor plasticity in adult rat supraoptic nucleus
Authors: Fénelon Valérie S. , Herbison Allan E.
Published: March 2003

Marked plasticity in GABAA receptor signalling occurs in adult oxytocin neurons of the supraoptic nucleus (SON) through the modulation of GABAA receptor α subunits during pregnancy. The present studies were undertaken to examine the potential mechanisms underlying this plasticity. In vivo microdialysis experiments in conscious rats revealed that no significant changes in extracellular GABA concentrations occurred within the SON over the last two days of pregnancy and the time of parturition itself. In situ hybridization studies examined the effects of gonadal steroid manipulation upon the GABAA receptor subunits expressed by SON neurons (α1, α2, β2 and γ2 subunits) and demonstrated that cellular levels of the α1 subunit were increased following 8 days oestrogen and progesterone treatment. Estrogen alone or allopregnanolone, the progesterone derivative, had no effect on α1 subunit mRNA expression in the SON. Immunocytochemical experiments demonstrated progesterone receptors in many neural populations but not within the SON of late pregnant rats. These studies indicate that alterations in endogenous GABA release within the SON are unlikely to be responsible for the GABAA receptor plasticity exhibited by oxytocin neurons in late pregnancy. Rather, data demonstrate that the fluctuating concentrations of progesterone during pregnancy act indirectly on SON neurons to modulate α1 subunit mRNA expression. Together, these experiments provide evidence for the ligand‐independent induction of GABAA receptor plasticity in the adult brain by progesterone.
Coding for auditory space in the superior colliculus of the rat
Authors: Gaese B. H. , Johnen A.
Published: March 2003

Although the rat is often used to determine behavioural sound‐localization capabilities or neuronal computation of binaural information, the representation of auditory space in the rat brain has not been investigated so far. We obtained extracellular recordings from auditory neurons in the superior colliculus of anaesthetized rats and examined them for spatial tuning characteristics and topographical order. Many neurons (73%) showed significant tuning, with a single peak in the azimuth response profiles based on spike rates and response latencies. Best azimuth values from neurons in one SC were generally tuned to contralateral and rarely to frontal or ipsilateral directions. Tuning width was mostly broad; at supra‐threshold sound pressure levels (35 dB SPL), 55% of the units had a tuning width of > 120° in contralateral space. Additionally, tuning width increased with stimulation intensity. A significant but considerably scattered topographical order of best azimuth directions was observed in the deep layers of the superior colliculus with frontal directions being represented closer to the rostral pole. Tuned auditory units in the intermediate layers of the superior colliculus, however, showed no systematic spatial arrangement. This pattern was confirmed by analysing best azimuth directions from simultaneously recorded units. Our results indicate that the rat superior colliculus contains a representation of auditory space which is similar to that described for other small mammals.
Dendritic L‐type calcium currents in mouse spinal motoneurons: implications for bistability
Authors: Carlin K. P. , Jones K. E. , Jiang Z. , Jordan L. M. , Brownstone R. M.
Published: March 2003

The intrinsic properties of mammalian spinal motoneurons provide them with the capability to produce high rates of sustained firing in response to transient inputs (bistability). Even though it has been suggested that a persistent dendritic calcium current is responsible for the depolarizing drive underlying this firing property, such a current has not been demonstrated in these cells. In this study, calcium currents are recorded from functionally mature mouse spinal motoneurons using somatic whole‐cell patch‐clamp techniques. Under these conditions a component of the current demonstrated kinetics consistent with a current originating at a site spatially segregated from the soma. In response to step commands this component was seen as a late‐onset, low amplitude persistent current whilst in response to depolarizing–repolarizing ramp commands a low voltage clockwise current hysteresis was recorded. Simulations using a neuromorphic motoneuron model could reproduce these currents only if a noninactivating calcium conductance was placed in the dendritic compartments. Pharmacological studies demonstrated that both the late‐onset and hysteretic currents demonstrated sensitivity to both dihydropyridines and the L‐channel activator FPL‐64176. Furthermore, the α1D subunits of L‐type calcium channels were immunohistochemically demonstrated on motoneuronal dendrites. It is concluded that there are dendritically located L‐type channels in mammalian motoneurons capable of mediating a persistent depolarizing drive to the soma and which probably mediate the bistable behaviour of these cells.
Nitric oxide released by gastric mechanoreceptors modulates nicotinic activation of coeliac plexus neurons in the rabbit
Authors: Quinson N. , Niel J. P. , Miolan J. P.
Published: March 2003

The effects on the nicotinic activation of the coeliac plexus neurons of nitric oxide (NO) released within the coeliac plexus by gastric mechanoreceptors, in particular during gastroduodenal inhibitory reflex, were assessed. This study was performed in the rabbit on an in vitro preparation of the coeliac plexus connected to the stomach and the duodenum. The electrical activity of ganglionic neurons was recorded with intracellular recording techniques. Water‐filled balloons were used for gastric distensions and recording of duodenal motility. When a 10‐s train of pulses (20–40Hz) of supramaximal intensity was applied to the splanchnic nerves, gradual depression of nicotinic activation occurred. Gastric distension (50 mL, 7.5 min) modulated this depression phenomenon by inhibiting or facilitating the nicotinic activation. In the neurons impaled during the recording of duodenal motility, gastric distension triggered an inhibition of nicotinic activation concomitantly with a gastroduodenal inhibitory reflex organized by the coeliac plexus. If the gastric distensions were performed while the coeliac plexus was superfused by a NO scavenger, the nicotinic activation was unaffected and the gastroduodenal inhibitory reflex was abolished. Moreover, when the coeliac plexus was superfused with an inhibitor of nitric oxide synthase, gastric distensions were without effect on the nicotinic activation. These results demonstrate that NO released within the coeliac plexus by gastric mechanoreceptors, in particular during the gastroduodenal inhibitory reflex, modulates the central nicotinic activation of coeliac plexus neurons, so NO released within a prevertebral ganglion by gastric afferent fibres, in particular during the organization by this ganglion of a reflex regulating the gastrointestinal tract motility, also exerts a gating of the central inputs to the ganglionic neurons.
Cross‐modal plasticity of the corticothalamic circuits in rats enucleated on the first postnatal day
Authors: Négyessy László , Gál Viktor , Farkas Tamás , Toldi József
Published: March 2003

Reorganization of the reciprocal corticothalamic connections was studied as a possible anatomical substrate of the cross‐modal compensation of the missing visual input of the visual cortex by somatosensory‐evoked activities in neonatally enucleated rats. The use of quantitative retrograde tract‐tracing techniques revealed that the contribution of the lateral posterior thalamic nucleus (LP) is significantly increased following enucleation, while that of the dorsolateral geniculate and the lateral dorsal nuclei is decreased in the thalamocortical afferentation of a region in visual cortical area 17. In contrast with the control rats, a dense terminal arborization of afferents was labelled in the LP after the injection of anterograde tracer into the barrel cortex of the enucleated rats. The injection of anterograde tracer into the visual cortex also demonstrated a massive afferentation into the LP of the enucleated rats. Visual and somatosensory corticothalamic afferents exhibited similar ultrastructural features in the LP after enucleation, but their synaptic organizations differed as regards the diameter of the postsynaptic dendrites. Taken together with the previous observations, these results suggest a central role for the LP in the transmission of the somatosensory‐evoked activities to the visual cortex after early blindness.
Seizures induce widespread upregulation of cystatin B, the gene mutated in progressive myoclonus epilepsy, in rat forebrain neurons
Authors: D'amato Elena , Kokaia Zaal , Nanobashvili Avtandil , Reeben Mati , Lehesjoki Anna‐Elina , Saarma Mart , Lindvall Olle
Published: March 2003

Loss of function mutations in the gene encoding the cysteine protease inhibitor, cystatin B (CSTB), are responsible for the primary defect in human progressive myoclonus epilepsy (EPM1). CSTB inhibits the cathepsins B, H, L and S by tight reversible binding, but little is known regarding its localization and physiological function in the brain and the relation between the depletion of the CSTB protein and the clinical symptoms in EPM1. We have analysed the expression of mRNA and protein for CSTB in the adult rat brain using in situ hybridization and immunocytochemistry. In the control brains, the CSTB gene was differentially expressed with the highest levels in the hippocampal formation and reticular thalamic nucleus, and moderate levels in amygdala, thalamus, hypothalamus and cortical areas. Detectable levels of CSTB were found in virtually all forebrain neurons but not in glial cells. Following 40 rapidly recurring seizures evoked by hippocampal kindling stimulations, CSTB mRNA expression showed marked bilateral increases in the dentate granule cell layer, CA1 and CA4 pyramidal layers, amygdala, and piriform and parietal cortices. Maximum levels were detected at 6 or 24 h, and expression had reached control values at 1 week post‐seizures. The changes of mRNA expression were accompanied by transient elevations (at 6–24 h) of CSTB protein in the same brain areas. These findings demonstrate that seizure activity leads to rapid and widespread increases of the synthesis of CSTB in forebrain neurons. We propose that the upregulation of CSTB following seizures may counteract apoptosis by binding cysteine proteases.
Expression of novel antioxidant thioredoxin‐2 in the rat brain
Authors: Rybnikova Elena , Damdimopoulos Anastasios E. , Gustafsson Jan‐Åke , Spyrou Giannis , Pelto‐Huikko Markku
Published: March 2003

Thioredoxins are a class of small redox‐regulating proteins that have been implicated in the control of various aspects of cellular functions and seem to be one of the key regulators of signalling in the cellular responses to various stresses. Thioredoxin‐2 (Trx2) is a novel mammalian thioredoxin which, in contrast to previously known cytosolic thioredoxin (Trx1), has been localized to the mitochondria. Trx2 is abundantly expressed in skeletal muscle, heart and adrenal gland, as well as in some other peripheral tissues with high metabolic activity. Using in situ hybridization and immunohistochemistry, we have studied the distribution and regulation of Trx2 expression in the rat brain. Trx2 mRNA and protein are highly expressed in the neurons in several brain regions, including the olfactory bulb, frontal cortex, hippocampus, some hypothalamic and thalamic nuclei, cerebellum and numerous brainstem nuclei. In addition, the Trx2 mRNA expression in paraventricular hypothalamic nucleus and reticular thalamic nucleus was found to be sensitive to peripheral glucocorticoids, as dexamethasone treatment caused significant elevation of Trx2 mRNA level in this area. No changes in other brain areas were observed after dexamethasone treatment. These findings implicate a significant regulatory and/or protective function of Trx2 in the nervous system.
Participation of low‐threshold calcium spikes in excitatory synaptic transmission in guinea pig medial frontal cortex
Authors: De La Peña Elvira , Geijo‐Barrientos Emilio
Published: March 2003

We studied the activation of low‐threshold calcium spikes (LTS) by excitatory postsynaptic potentials in pyramidal neurons from guinea pig medial frontal cortex with intracellular recording. We used extracellular bicuculline and phaclofen and intracellular QX‐314 to block inhibitory synaptic potentials and sodium currents. Postsynaptic potentials were evoked by stimulation of layer I. We found that large (> 10–15 mV) excitatory synaptic potentials evoked from membrane potentials more negative than −75 mV were able to trigger LTS. The activation of LTS resulted in an increase of the rising slope or amplitude of the synaptic potentials depending on the size of the excitatory postsynaptic potential (EPSP). We used 100 μm NiCl2 to confirm the presence of LTS as part of the EPSPs. The N‐methyl‐d‐aspartate (NMDA) and non‐NMDA components of the excitatory synaptic potentials were isolated using (±)2‐amino‐5‐phosphonovaleric acid (APV; 50 μm) or 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX; 20 μm); both components could, independently, trigger an LTS. With recordings made with K+ acetate‐filled electrodes, we show that the activation of LTS was critical to allow excitatory synaptic potentials to reach the threshold of action potential firing; also, this amplification of synaptic responses produced the firing of more than a single action potential by the postsynaptic cell. These results demonstrate that in cortical pyramidal neurons the activation of low‐threshold calcium spikes results in the amplification of synaptic responses.
Protection against dopaminergic nigrostriatal cell death by excitatory input ablation
Authors: Takada M. , Matsumura M. , Kojima J. , Yamaji Y. , Inase M. , Tokuno H. , Nambu A. , Imai H.
Published: March 2003

The importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has recently been highlighted in the development of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is the major origin of excitatory, glutamatergic input to dopaminergic nigrostriatal neurons of which degeneration is well known to cause Parkinson's disease. Based on the concept that an excitatory mechanism mediated by glutamatergic neurotransmission underlies the pathogenesis of neurodegenerative disorders, we made an attempt to test the hypothesis that removal of the glutamatergic input to the nigrostriatal neurons by PPN lesions might prevent 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in the macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monkeys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were analysed by means of tyrosine hydroxylase immunohistochemistry. The present results revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP‐treated monkey group whose PPN had been lesioned, compared with the control, MPTP‐treated monkey group with the PPN intact. This clearly indicates that the onset of MPTP neurotoxicity is suppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ablation against nigrostriatal cell death defines evidence that nigral excitation driven by the PPN may be implicated in the pathophysiology of Parkinson's disease.
Increased rewarding properties of morphine in dopamine‐transporter knockout mice
Authors: Spielewoy Cécile , Gonon François , Roubert Christine , Fauchey Valérie , Jaber Mohamed , Caron Marc G. , Roques Bernard P. , Hamon Michel , Betancur Catalina , Maldonado Rafael , Giros Bruno
Published: March 2003

The activation of dopamine (DA) neurotransmission plays a crucial role in the behavioural responses to drugs of abuse. In particular, increased extracellular levels of DA within the mesolimbic pathway have been implicated in the rewarding and locomotor stimulatory properties of morphine. We investigated the behavioural responses to morphine in mice with a genetic disruption of the DA transporter (DAT), resulting in a constitutively high level of extrasynaptic DA. In the conditioned place preference test, DAT–/– mice exhibited a stronger rewarding response to morphine (5 mg/kg, s.c.) compared with control littermates. However, the same dose of morphine failed to increase locomotor activity in DAT–/– mice, whilst enhancing locomotion in DAT+/– and DAT+/+ animals. Morphine‐induced analgesia was unaffected in mutant mice, but the behavioural expression of naloxone‐induced withdrawal signs was blunted. In vivo voltammetry in the shell of the nucleus accumbens revealed that morphine was able to stimulate DA neurons in DAT–/– mice, resulting in the accumulation of higher extracellular DA levels compared with control animals. Morphine also induced a higher rate of c‐fos transcription in the shell of the nucleus accumbens in mutant mice. We conclude that morphine‐induced rewarding responses are firmly established in DAT mutant mice despite a DA transmission that is already tonically activated, and independently of any effect on locomotion. These particular behavioural responses to morphine may be associated with the action of the drug on DA release and c‐fos expression in the shell of the nucleus accumbens of DAT–/– mice.
Differential amygdala responses to winning and losing: a functional magnetic resonance imaging study in humans
Authors: Zalla Tiziana , Koechlin Etienne , Pietrini Pietro , Basso Gianpaolo , Aquino Patrick , Sirigu Angela , Grafman Jordan
Published: March 2003

The amygdala has been shown to respond to many distinct types of affective stimuli, including reward and punishment feedback in animals. In humans, winning and losing situations can be considered as reward and punishment experiences, respectively. In this study, we used functional magnetic resonance imaging (fMRI) to measure regional brain activity when human subjects were given feedback on their performance during a simple response time task in a fictitious competitive tournament. Lexical stimuli were used to convey positive ‘win’ or negative ‘lose’ feedback. The frequency of positive and negative trials was parametrically varied by the experimenters independently from the subjects' actual performance and unbeknownst to them. The results showed that the parametric increase of winning was associated with left amygdala activation whereas the parametric increase of losing was associated with right amygdala activation. These findings provide functional evidence that the human amygdala differentially responds to changes in magnitude of positive or negative reinforcement conveyed by lexical stimuli.
N‐methyl‐ d‐aspartate enhancement of the glycine response in the rat sacral dorsal commissural neurons
Authors: Le Xu Tian‐. , Dong Xian‐Ping , Wang Dian‐Shi
Published: March 2003

The effect of N‐methyl‐ d‐aspartate (NMDA) on the glycine (Gly) response was examined in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin‐perforated patch‐recording configuration under voltage‐clamp conditions. The application of 100 μm NMDA to SDCN neurons reversibly potentiated Gly‐activated Cl– currents (IGly) without affecting the Gly binding affinity and the reversal potential of IGly. A selective NMDA receptor antagonist, APV (100 μm), blocked the NMDA‐induced potentiation of IGly, whereas 50 μm CNQX, a non‐NMDA receptor antagonist, did not. The potentiation effect was reduced when NMDA was applied in a Ca2+‐free extracellular solution or in the presence of BAPTA AM, and was independent of the activation of voltage‐dependent Ca2+ channels. Pretreatment with KN‐62, a selective Ca2+–calmodulin‐dependent protein kinase II (CaMKII) inhibitor, abolished the NMDA action. Inhibition of calcineurin (CaN) further enhanced the NMDA‐induced potentiation of IGly. In addition, the GABAA receptor‐mediated currents were suppressed by NMDA receptor activation in the SDCN neurons. The present results show that Ca2+ entry through NMDA receptors modulates the Gly receptor function via coactivation of CaMKII and CaN in the rat SDCN neurons. This interaction may represent one of the important regulatory mechanisms of spinal nociception. The results also suggest that GABAA and Gly receptors may be subject to different intracellular modulatory pathways.
Dopamine‐independent action of cocaine on striatal and accumbal neurons
Authors: Kiyatkin Eugene A. , Rebec George V.
Published: March 2003

Increasing evidence suggests that dopamine (DA) mechanisms alone cannot fully explain the psychoemotional and behavioural effects of cocaine, including its ability to induce drug‐taking behaviour. Although it is known that cocaine, after intravenous administration or smoking, may reach brain levels high enough to inhibit Na+ transport, the role of this action remains unclear. To examine the contribution of local anaesthetic and DA mechanisms to changes in striatal and accumbal neuronal activity induced by cocaine, single‐unit recording was combined with iontophoresis in awake, unrestrained rats. Most spontaneously active and glutamate‐stimulated neurons were highly sensitive to brief cocaine applications (0–40 nA); cocaine‐induced inhibitions occurred at small ejection currents (0–5 nA), were dose‐dependent, highly stable during repeated applications and strongly dependent on basal activity rates. These neuronal responses remained almost unchanged after systemic administration of either a selective D1 antagonist (SCH‐23390, 0.2 mg/kg) or a combination of SCH‐23390 (1 mg/kg) and eticlopride (1 mg/kg), a D2 antagonist. Whereas SCH‐23390 alone had a weak attenuating effect, no effect and even a slight enhancement of responses to cocaine occurred in fast‐firing glutamate (GLU)‐stimulated units after the combined blockade of D1 and D2 receptors. Responses to cocaine were mimicked by iontophoretic procaine (0–40 nA), a short‐acting local anaesthetic with minimal effect on DA uptake. Procaine‐induced inhibitions occurred at the same low currents, had a similar time‐course, and were also strongly dependent on basal discharge rate. Our data support the existence of a DA‐independent mechanism for the action of cocaine involving a direct interaction with Na+ channels. Although further studies are required to clarify this mechanism and its interaction with other pharmacological and behavioural variables, a direct interaction with Na+ channels may contribute to changes in neuronal activity induced by self‐injected cocaine, thereby playing a role in mediating the psychoemotional and behavioural effects of this drug.
Transplanted CNS stem cells form functional synapses in vivo
Authors: Auerbach Jonathan M. , Eiden Maribeth V. , McKay Ron D. G.
Published: March 2003

An understanding of developmental mechanisms and new cell therapies can be achieved by transplantation into the nervous system. Multipotential stem cells have been isolated from the foetal and adult central nervous system (CNS). Immortalized and primary precursor cells integrate into the developing brain generating both neurons and glia as defined by immunological and morphological criteria. Here we show for the first time that in vitro‐expanded CNS precursors, upon transplantation into the brains of rats, form electrically active and functionally connected neurons. These neurons exhibit spontaneous and evoked postsynaptic events and respond to focal glutamate application. Donor cells were grafted into the foetal hippocampus, and the amplitude and frequency of spontaneous synaptic events were monitored in the grafted cells in area CA1 for the first month of postnatal life. The formation of synapses onto grafted neurons indicates that grafted CNS stem cells can be used to study synaptic development in vivo and has important implications for clinical cell replacement therapies.