bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine transporter knock‐out mice are hypersensitive to 3‐nitropropionic acid‐induced striatal damage
Authors: Fernagut Pierre‐O. , Diguet Elsa , Jaber Mohamed , Bioulac Bernard , Tison François 
Published: March 2003

AbstractEvidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic ‘low‐dose’ (total dose, 340 mg/kg in 7 days) 3‐nitropropionic acid (3‐NP) intoxication in dopamine transporter knock‐out mice (DAT–/–) compared to wildtype (DAT+/+) mice. Systemic ‘low‐dose’ 3‐NP induced a significant impairment in a rotarod task only in DAT–/– mice. Histopathology also demonstrated a significant reduction of the striatal volume (−7%, P < 0.05), neuronal density (−12.5%, P < 0.001) and absolute number estimates of striatal neurons (−11.5%, P < 0.001) in DAT–/– compared to DAT+/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These findings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system.
Innervation of interneurons immunoreactive for VIP by intrinsically bursting pyramidal cells and fast‐spiking interneurons in infragranular layers of juvenile rat neocortex
Authors: Staiger Jochen F. , Schubert Dirk , Zuschratter Werner , Kötter Rolf , Luhmann Heiko J. ,   Karl Zilles
Published: March 2003

AbstractCortical columns contain specific neuronal populations with characteristic sets of connections. This wiring forms the structural basis of dynamic information processing. However, at the single‐cell level little is known about specific connectivity patterns. We performed experiments in infragranular layers (V and VI) of rat somatosensory cortex, to clarify further the input patterns of inhibitory interneurons immunoreactive (ir) for vasoactive intestinal polypeptide (VIP). Neurons in acute slices were electrophysiologically characterized using whole‐cell recordings and filled with biocytin. This allowed us to determine their firing pattern as regular‐spiking, intrinsically bursting and fast‐spiking, respectively. Biocytin was revealed histochemically and VIP immunohistochemically. Sections were examined for contacts between the axons of the filled neurons and the VIP‐ir targets. Twenty pyramidal cells and five nonpyramidal (inter)neurons were recovered and sufficiently stained for further analysis. Regular‐spiking pyramidal cells displayed no axonal boutons in contact with VIP‐ir targets. In contrast, intrinsically bursting layer V pyramidal cells showed four putative single contacts with a proximal dendrite of VIP neurons. Fast‐spiking interneurons formed contacts with two to six VIP neurons, preferentially at their somata. Single as well as multiple contacts on individual target cells were found. Electron microscopic examinations showed that light‐microscopically determined contacts represent sites of synaptic interactions. Our results suggest that, within infragranular local cortical circuits, (i) fast‐spiking interneurons are more likely to influence VIP cells than are pyramidal cells and (ii) pyramidal cell input probably needs to be highly convergent to fire VIP target cells.
Role of the dopamine D3 receptor in reactivity to cocaine‐associated cues in mice
Authors: Le Foll Bernard , Francès Henriette , Diaz Jorge , Schwartz Jean‐Charles , Sokoloff Pierre 
Published: March 2003

AbstractEnvironmental stimuli previously associated with drug effects can acquire secondary reinforcing properties, able to maintain drug‐seeking behaviour or induce relapse. We have used a classical Pavlovian conditioning procedure to assess the role of the dopamine D3 receptor (D3R) in the expression of drug‐conditioned responses. Mice repeatedly receiving cocaine in a particular environment distinct from home‐cages displayed hyperlocomotion after subsequent exposure to the drug‐paired environment. Cocaine‐conditioned hyperactivity was inhibited by BP 897 or SB‐277011‐A, D3R‐selective partial agonist and antagonist, respectively. D3R gene‐targeted mice showed a trend towards an increase in cocaine cue‐conditioned hyperactivity. BP 897 had no effect on reactivity to neutral or aversive cues. Cocaine‐conditioned mice had increased levels of D3R mRNA and binding in the nucleus accumbens (NAc), and transcripts of brain‐derived neurotrophic factor (BDNF), a factor controlling D3R expression, in the ventral tegmental area (VTA). Cocaine had no effects on D3R or BDNF genes when administered in home‐cages. Cocaine cue‐conditioned c‐fos expression was found in cortical areas, notably in the somatosensory cortex, where it was inhibited by BP 897, and in several regions belonging or linked to the limbic system. In conditioned mice, BP 897 inhibited c‐fos expression in VTA and activated it in amygdala. These results demonstrate a modulation of reactivity to cocaine cues by the D3R, the expression of which is elevated in the NAc by the repeated association of drug effects with a particular context, through a BDNF‐dependent mechanism. D3R‐selective partial agonist or antagonist inhibit cocaine cue‐conditioned activity possibly by normalizing exacerbated D3R function in the NAc, but our results also point to a possible participation of a pathway involving the VTA, amygdala and somatosensory cortex.
Maturation of postsynaptic nicotinic structures on autonomic neurons requires innervation but not cholinergic transmission
Authors: Kaiser Sergio , Blank Martina , Berg Darwin K. 
Published: March 2003

AbstractPostsynaptic development at the neuromuscular junction depends on nicotinic transmission and secreted components from the presynaptic motor nerve terminal. Similarly, secreted components and synaptic activity are both thought to guide development of glutamatergic synapses in the CNS. Nicotinic synapses on chick ciliary neurons are structurally complex: a large presynaptic calyx engulfs the postsynaptic neuron and overlays a series of discrete mats of receptor‐rich somatic spines tightly interwoven and folded against the soma. We used fluorescence imaging of α7‐containing nicotinic receptors and the spine constituent drebrin to monitor postsynaptic development. The results show that surgical disruption of the preganglionic input or removal of the ganglionic synaptic target tissue after synapses form in the ganglion does not disrupt the receptor‐rich spine mats. Similarly, removal of the target tissue even prior to synapse formation in the ganglion does not prevent subsequent formation of the receptor clusters and associated spine constituents. Postsynaptic development is arrested, however, if normal innervation is prevented by ablating the preganglionic neurons prior to synapse formation. In this case the neurons express reduced levels of nicotinic receptors and cytoskeletal components and organize them only into early‐stage clusters. Even low levels of residual innervation, however, can restore much of the normal postsynaptic receptor patterns. Chronic pharmacological blockade of cholinergic synaptic activity fails to replicate the effects of ablating the preganglionic nucleus. The results indicate that ciliary neurons are programmed to express postsynaptic components and can initiate clustering of α7‐containing receptors but need presynaptic guidance for maturation of the postsynaptic structure.
BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency–response curve of synaptic plasticity
Authors: Ikegaya Yuji , Ishizaka Yoko , Matsuki Norio 
Published: March 2003

AbstractRecent evidence shows that neurotrophins are not only involved in neuronal survival and differentiation during development but also in modulating synaptic strength in the mature brain. To understand how neurotrophins alter this synaptic modification, we have investigated the effect of brain‐derived neurotrophic factor (BDNF) on long‐term depression (LTD) at Schaffer collateral–CA1 synapses in rat hippocampal slices. The slices treated with BDNF for 5 min showed significantly less LTD in response to a 1‐Hz tetanus compared with controls but displayed normal LTD when the afferents were tetanized at 10 Hz. Because BDNF enhanced long‐term potentiation (LTP) induced by a 30‐Hz tetanus, the synaptic modification threshold (θm) as defined in the ‘BCM’ theory of Bienenstock Cooper & Monroe [Bienenstock et al. (1982), J. Neurosci., 2, 32–48] was not shifted. BNDF is likely to alter the capability of the plastic changes in synaptic efficacy, i.e. to produce an upward shift in the BCM curve. The suppressive effect of BDNF on LTD was prevented by either the tyrosine kinase (Trk) receptor inhibitor K252a or the phospholipase C inhibitor U73122. Thus, TrkB activation may attenuate LTD through phospholipase C signalling pathway.
Activation of dopamine D1‐like receptors excites LTS interneurons of the striatum
Authors: Centonze Diego , Bracci Enrico , Pisani Antonio , Gubellini Paolo , Bernardi Giorgio , Calabresi Paolo 
Published: March 2003

AbstractDopamine (DA) has a crucial role in the modulation of striatal neuron activity. Along with projection cells, striatal interneurons receive dense dopaminergic innervation from midbrain neurons, thus, also suggesting that these intrinsic cells represent a synaptic target for DA action in the striatum. In the present study, we investigated the effects of DA on low‐threshold spike (LTS) interneurons of the rat striatum, by means of in vitro whole‐cell patch‐clamp electrophysiological recordings. Dopamine depolarized LTS cells, a pharmacological effect prevented by D1‐ but not D2‐like DA receptor antagonists. The membrane depolarization produced by DA was sufficient to trigger action potential discharge in the recorded cells and was insensitive to tetrodotoxin and glutamate receptor antagonists. In addition, this pharmacological effect was mimicked by D1‐ but not D2‐like DA receptor agonists, implying the selective involvement of D1‐like receptors in this action.
Direction of cross‐modal information transfer affects human brain activation: a PET study
Authors: Kawashima Ryuta , Watanabe Jobu , Kato Takashi , Nakamura Akinori , Hatano Kentaro , Schormann Torsten , Sato Kazunori , Fukuda Hiroshi , Ito Kengo , Zilles Karl 
Published: March 2003

AbstractThe purpose of this study was to determine the functional organization of the human brain involved in cross‐modal discrimination between tactile and visual information. Regional cerebral blood flow was measured by positron emission tomography in nine right‐handed volunteers during four discrimination tasks; tactile–tactile (TT), tactile–visual (TV), visual–tactile (VT), and visual–visual (VV). The subjects were asked either to look at digital cylinders of different diameters or to grasp the digital cylinders with the thumb and index finger of the right hand using haptic interfaces. Compared with the motor control task in which the subjects looked at and grasped cylinders of the same diameter, the right lateral prefrontal cortex and the right inferior parietal lobule were activated in all the four discrimination tasks. In addition, the dorsal premotor cortex, the ventral premotor cortex, and the inferior temporal cortex of the right hemisphere were activated during VT but not during TV. Our results suggest that the human brain mechanisms underlying cross‐modal discrimination have two different pathways depending on the temporal order in which stimuli are presented.
Functional characterization of compound heterozygosity for GlyRα1 mutations in the startle disease hyperekplexia
Authors: Rea Ruth , Tijssen Marina A. , Herd Colin , Frants Rune R. , Kullmann Dimitri M. 
Published: March 2003

AbstractThe human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor α1 subunit (GlyRα1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non‐functional. Neither mutant affected the electrophysiological properties of wild type GlyRα1 when co‐expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyRα1‐mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic.
NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d‐2‐hydroxyglutaric aciduria
Authors: Kölker Stefan , Pawlak Verena , Ahlemeyer Barbara , Okun Jürgen G. , Hörster Friederike , Mayatepek Ertan , Krieglstein Josef , Hoffmann Georg F. , Köhr Georg 
Published: March 2003

AbstractThe inherited neurometabolic disease d‐2‐hydroxyglutaric aciduria is complicated by progressive neurodegeneration of vulnerable brain regions during infancy and early childhood, frequently presenting with hypotonia, epilepsy and psychomotor retardation. Here, we report that the pathogenetic role of the endogenously accumulating metabolite d‐2‐hydroxyglutarate (D‐2), which is structurally similar to the excitatory amino acid glutamate, is mediated by at least three mechanisms. (i) D‐2‐induced excitotoxic cell damage in primary neuronal cultures from chick and rat involved N‐methyl‐d‐aspartate (NMDA) receptor activation. Indeed, D‐2 activated recombinant NMDA receptors (NR1/NR2A, NR1/NR2B) but not recombinant alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole (AMPA) receptors in HEK293 cells. (ii) Fluorescence microscopy using fura‐2 as a calcium indicator and the oxidant‐sensitive dye dihydrorhodamine‐123 revealed that D‐2 disturbed intracellular calcium homeostasis and elicited the generation of reactive oxygen species. (iii) D‐2 reduced complex V (ATP synthase) activity of the mitochondrial respiratory chain, reflecting an impaired energy metabolism due to inhibition of ATP synthesis but without affecting the electron‐transferring complexes I–IV. Thus, D‐2 stimulates neurodegeneration by mechanisms well‐known for glutamate, NMDA or mitochondrial toxins. In conclusion, excitotoxicity contributes to the neuropathology of d‐2‐hydroxyglutaric aciduria, highlighting new neuroprotective strategies.
ERK activation and nuclear translocation in amyloid‐β peptide‐ and iron‐stressed neuronal cell cultures
Authors: Kuperstein Faina , Yavin Ephraim 
Published: March 2003

AbstractOxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe2+ (5 µm) and the amyloid beta (Aβ1−40) peptide (5 µm) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10‐fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase‐3 activity was elevated 5–6 fold, all indicative of oxidative cell stress. The combined presence of Aβ1−40 and Fe2+ resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe2+ nor that with Aβ1−40 alone caused similar changes. Addition of either deferroxamine (DFe, 25 µm), catalase (0.4 mg/mL) or N‐acetyl cysteine (0.5 mm) – the last two known as suppressants of oxidative stress – attenuated ERK activation and nuclear translocation. The mitogen‐activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in Aβ1−40 plus Fe2+ (Aβ1−40/Fe2+) ‐induced apoptotic death. The full peptide Aβ1−42 was very effective at 0.5 µm while the inverse peptide Aβ40−1 at 5 µm was ineffective. The acetyl‐amyloid‐β protein amide fragment 15–20 (V‐pep) known to be an Aβ aggregation inhibitor, prevented Aβ1−40/Fe2+‐induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the Aβ1−40/Fe2+‐induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.
Intranasal herpes simplex virus type 2 inoculation causes a profound thymidine kinase dependent cerebral inflammatory response in the mouse hindbrain
Authors: Boivin Guy , Coulombe Zoé , Rivest Serge 
Published: March 2003

AbstractThe herpes simplex virus (HSV) has the ability to replicate in the central nervous system (CNS), which may cause fatal encephalitis. The present study investigated the activity of the nuclear factor kappa B (NF‐κB) and the pattern of cytokine/chemokine gene expression across the brain of HSV‐infected mice and the role of the viral thymidine kinase (TK) in mediating these effects. Mice were killed 1–8 days after intranasal inoculation with either HSV‐2 TK‐competent or TK‐deficient clinical isolates. Animals infected with the TK‐competent virus exhibited first signs of infection at day 5 postinoculation, whereas severe signs of sickness were observed between day 6 and 8. A robust hybridization signal was found in the brain of these animals for the gene encoding the inhibitory factor κBα (IκBα, index of NF‐κB activity), toll‐like receptor 2 (TLR2), tumour necrosis factor α (TNF‐α) and monocyte chemoattractant protein‐1 (MCP‐1) in numerous regions of the pons and medulla. The levels of expression of these genes increased 4 days after the inoculation and peaked at day 6 within the endothelium of the brain capillaries and cells of myeloid origin. A robust signal for the TK gene and its encoding protein was detected selectively within the regions that exhibited expression of the immune molecules. In contrast, animals that received the TK‐deficient virus did not show any signs of sickness or cerebral inflammation or HSV replication within the cerebral tissue. The present data provide clear evidence that HSV‐2 has the ability to trigger a profound inflammatory response in a pattern that follows the viral TK‐dependent HSV replication in neurons. Such neurovirulence occurring in the hindbrain is proposed here to be directly responsible for neurodegeneration and to lead to the cerebral innate immune response, which in turn could play a key role in fatal HSV‐2‐induced encephalitis.
Brain afferents to the medullary dorsal reticular nucleus: a retrograde and anterograde tracing study in the rat
Authors: Almeida Armando , Cobos Angeles , Tavares Isaura , Lima Deolinda 
Published: March 2003

AbstractThe medullary dorsal reticular nucleus (DRt) was recently shown to belong to the supraspinal pain control system; neurons within this nucleus give origin to a descending projection that increases spinal nociceptive transmission and facilitates pain perception [Almeidaet al.(1999),Eur. J. Neurosci.,11, 110–122]. In the present study, the areas of the brain that may modulate the activity of DRt neurons were investigated by using of tract‐tracing techniques. Injection of a retrograde tracer into the DRt resulted in labelling in multiple areas of the brain. In the contralateral orbital, prelimbic, infralimbic, insular, motor and somatosensory cortices labelling was prominent, but a smaller ipsilateral projection from these same areas was also detected. Strong labelling was also noted in the central amygdaloid nucleus, bed nucleus of stria terminalis and substantia innominata. Labelled diencephalic areas were mainly confined to the hypothalamus, namely its lateral and posterior areas as well as the paraventricular nucleus. In the mesencephalon, the periaqueductal grey, red nucleus and deep mesencephalic nucleus were strongly labelled, whereas, in the brainstem, the parabrachial nuclei, rostroventromedial medulla, nucleus tractus solitarius, spinal trigeminal nucleus, and the parvocellular, dorsal, lateral and ventral reticular nuclei were the most densely labelled regions. All deep cerebellar nuclei were labelled bilaterally. These data suggest that the DRt integrates information from the somatosensory, antinociceptive, autonomic, limbic, pyramidal and extrapyramidal systems while triggering its descending facilitating action upon the spinal nociceptive transmission.
Localization of putative glutamatergic/aspartatergic neurons projecting to the supraoptic nucleus area of the rat hypothalamus
Authors: Csáki Á. , Kocsis K. , Kiss J. , Halász B. 
Published: March 2003

AbstractOxytocin and vasopressin neurosecretory neurons of the supraoptic nucleus receive a rich glutamatergic innervation. The nerve cells of this prominent structure express various ionotropic and metabotropic glutamate receptor subtypes and there is converging evidence that glutamate acts as an excitatory transmitter in the control of release of oxytocin and vasopressin synthesized in this cell group. The location of the glutamatergic neurons projecting to this hypothalamic region is unknown. The aim of the present investigation was to study this question. [3H]d‐aspartate, which is selectively taken up by high‐affinity uptake sites at presynaptic endings that use glutamate as a transmitter, and is transported back to the cell body, was injected into the supraoptic nucleus area. The neurons retrogradely labelled with [3H]d‐aspartate were detected autoradiographically. Labelled nerve cells were found in several diencephalic and telencephalic structures, but not in the brainstem. Diencephalic cell groups included the supraoptic nucleus itself, its perinuclear area, hypothalamic paraventricular, suprachiasmatic, ventromedial, dorsomedial, ventral premammillary, supramammillary and thalamic paraventricular nuclei. Within the telencephalon, labelled neurons were detected in the septum, amygdala, bed nucleus of the stria terminalis and preoptic area. The findings provide neuromorphological data on the location of putative glutamatergic neurons projecting to the supraoptic nucleus and its perinuclear area. Furthermore, they indicate that local putative glutamatergic neurons as well as several diencephalic and telencephalic structures contribute to the glutamatergic innervation of the cell group and thus are involved in the control of oxytocin and vasopressin release by neurosecretory neurons of the nucleus.