bluuebunny/crossref_metadata_2025 huggingface dataset:
SHORT COMMUNICATION Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids
Authors: Szabo Bela , Siemes Sabine , Wallmichrath Ilka
Published: March 2003

It was shown recently that Δ9‐tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch‐clamp technique. GABAA receptor‐mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212‐2 (10−6 and 10−5 m). The CB1 cannabinoid receptor antagonist SR141716A (10−6 m) prevented the inhibition produced by WIN55212‐2 (10−5 m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212‐2 (10−5 m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212‐2 (10−5 m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.
Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task
Authors: Kempermann G. , Gage F. H.
Published: March 2003

A number of reports have indicated that adult neurogenesis might be involved in hippocampal function. While increases in adult neurogenesis are paralleled by improvements on learning tasks and learning itself can promote the survival of newly generated neurons in the hippocampus, a causal link between learning processes and adult hippocampal neurogenesis is difficult to prove. Here, we addressed the related question of whether the baseline level of adult neurogenesis is predictive of performance on the water maze task as a test of hippocampal function. We used ten strains of recombinant inbred mice, based on C57BL/6, which are good learners and show high baseline levels of neurogenesis, and DBA/2, which are known to be poor learners and which exhibit low levels of adult neurogenesis. Two of these strains, BXD‐2 and BXD‐8, showed a 26‐fold difference in the number of newly generated neurons per hippocampus. Over all strains, including the parental strains, there was a significant correlation between the number of new neurons generated in the dentate gyrus and parameters describing the acquisition of the water maze task (slope of the learning curves). Similar results were seen when the parental strains were not included in the analysis. There was no correlation between adult hippocampal neurogenesis and probe trial performance, performance on the rotarod, overall locomotor activity, and baseline serum corticosterone levels. This result supports the hypothesis that adult neurogenesis is involved in specific aspects of hippocampal function, particularly the acquisition of new information.
SHORT COMMUNICATION Selective enhancement of spatial learning under chronic psychosocial stress
Authors: Bartolomucci Alessandro , De Biurrun Gabriel , Czéh Boldizsár , Van Kampen Marja , Fuchs Eberhard
Published: March 2003

The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic‐hypothalamus‐pituitary‐adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal‐dependent and hippocampal‐independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal‐dependent task, whereas no stress‐induced effect was found in the hippocampal‐independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.
Recovery following peripheral destruction of olfactory neurons in young and adult mice
Authors: Ducray Angélique , Bondier Jean‐Robert , Michel Germaine , Bon Karine , Propper Alain , Kastner Anne
Published: March 2003

Olfactory neurons (ON) which are located in the olfactory epithelium are responsible of odorous molecule detection. A unique feature of these cells is their continuous replacement throughout life due to the proliferation and differentiation of local neural precursors, the basal cells. Thus, experimental destruction of all ON induces a stimulation of basal cell division followed by tissue regeneration. The fact that ON precursors display such proliferative and neurogenic activity in adults makes these cells particularly attractive as a potential tool for nervous system repair. However, basal cell proliferation and, thus, ON production, decrease in relation to age; mostly during the first months of life. Therefore, we aimed to seek whether the ability of ON precursors to yield new functional ON in regenerative conditions was consequently impaired in adult. ZnSO4 intranasal perfusion administered to young (1 month) and adult (6 months) mice leads in a few days to total ON destruction and to hyposmia. Tissue and function restoration occurred in the following weeks in both mice groups and was preceded by a transient peak of cell division. In adults, although neurogenesis in the impaired olfactory epithelium was less efficient than in young mice, neural precursors retain their ability to provide new functional ON as indicated by the butanol detection recovery. This was achieved more rapidly than total ON regeneration, suggesting that a reduced number of reconnected ON may be sufficient for odor discrimination.
Evaluation of GluR2 subunit involvement in AMPA receptor function of neonatal rat hypoglossal motoneurons
Authors: Essin K. , Nistri A. , Magazanik L.
Published: March 2003

AMPA receptors (AMPAr) mediate fast synaptic responses to glutamate and, when they lack the GluR2 subunit, are strongly Ca2+ permeable and may increase intracellular Ca2+ levels. Because hypoglossal motoneurons possess restricted ability to buffer internal Ca2+ and are vulnerable to Ca2+ excitotoxicity, we wondered if, in these cells, any significant Ca2+ influx could be generated via AMPAr activity. Using whole cell patch‐clamp recording from neonatal rat hypoglossal motoneurons, we tested the AMPAr properties conferred by GluR2 subunits, namely Ca2+ permeability, current rectification and sensitivity to pentobarbital or to the subunit‐specific channel blockers, IEM‐1460 and IEM‐1925. We recorded membrane currents generated by the agonist, kainate, and compared them with those obtained from hippocampal pyramidal neurons (expressing GluR2‐containing AMPAr) and from striatal giant aspiny or hippocampal interneurons (with GluR2‐lacking AMPAr). Ca2+ vs. Na+ permeability of motoneuron AMPAr was relatively low (0.25 ± 0.05), although higher than that of pyramidal neurons. With intracellularly applied spermine, significant inward rectification was absent from motoneurons. These data indicated the prevalence of functional GluR2 subunits. However, the sensitivity of motoneuron AMPAr to pentobarbital did not differ from that of GluR2‐lacking AMPAr on interneurons. Motoneurons possessed sensitivity to IEM‐1460 (IC50 = 90 ± 10 µm) approximately 10‐fold lower than striatal interneurons, although 10‐fold higher than hippocampal pyramidal cells. IEM‐1925 also reduced the amplitude of excitatory synaptic currents in brainstem slice motoneurons. We hypothesize that hypoglossal motoneuron AMPAr (moderately Ca2+ permeable because they contain few GluR2 subunits) may contribute to intracellular Ca2+ rises especially if persistent AMPAr activation (or the pathological GluR2 down‐regulation) occurs.
Corticofugal modulation of midbrain sound processing in the house mouse
Authors: Yan Jun , Ehret Günter
Published: March 2003

An understanding of the neural mechanisms responsible for auditory information processing is incomplete without a careful examination of substantial descending pathways. This study focuses on the functional role of corticofugal projections. Our work with the house mouse reveals that the focal electrical stimulation of the primary auditory cortex leads to profound changes in auditory response properties in the central nucleus of the inferior colliculus of the midbrain. Cortical stimulation does not impact on the collicular best frequencies when the best frequencies of stimulated cortical neurons and recorded collicular neurons are similar. Rather, collicular best frequencies are shifted toward the stimulated cortical best frequencies when cortical and collicular frequencies are different. Such a shift is unrelated to the differences in minimum thresholds between cortical and collicular neurons. In addition to frequency‐specific shifts in collicular best frequencies, cortical stimulation elevates collicular minimum thresholds and reduces both dynamic ranges and response magnitudes if cortical and collicular best frequencies are different. If cortical and collicular best frequencies are similar but minimum thresholds are different, collicular minimum thresholds are shifted toward the stimulated cortical thresholds; dynamic ranges and response magnitudes may either increase or decrease in this scenario. Our results suggest that the corticofugal adjustment has a centre–surround organization with regard to both cortical best frequencies and cortical minimum thresholds. The midbrain processing of sound components in the centre of cortical feedback is largely enhanced while processing in the surround is suppressed.
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

Evidence 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

Cortical 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

Environmental 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

Postsynaptic 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

Recent 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

Dopamine (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

The 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

The 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

The 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

Oxidative 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

The 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

The 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

Oxytocin 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.
Comparison of neuronal density and subfield sizes in the hippocampus of CD95L‐deficient (gld), CD95‐deficient (lpr) and nondeficient mice
Authors: Kovac Adam D. , Grammig Jo , Mahlo Jacqueline , Steiner Barbara , Roth Karl , Nitsch Robert , Bechmann Ingo
Published: March 2003

During brain development, the majority of neurons undergo programmed cell death. It is now clear that caspases are involved in this process of selective induction of neuronal apoptosis, yet the signals for this caspase activation remain undefined. As an upstream activator of these enzymes, the death receptor CD95 (Fas, APO1) was recently shown on neurons in the cornu ammonis (CA)2 and CA3 hippocampal subfields of early postnatal mice and rats. In vitro, cortical neuroblast cells are susceptible to CD95 ligand (CD95L, FasL, APO‐1 L)‐induced apoptosis. It was therefore suggested that the CD95/CD95L system is involved in neuronal apoptosis during hippocampal development. We therefore performed a blinded study comparing field size and neuronal density in the hippocampi of p20 CD95‐deficient (lpr), CD95L‐deficient (gld) and C57 mice. Whereas field sizes did not differ significantly between these strains, paired Mann–Whitney analyses revealed an increased number of neurons in the CA2 regions of CD95‐deficient mice (P = 0.008), and minor, yet at 1% nonsignificant, differences between gld, lpr and C57 strains in the CA1 and CA3 regions. However, joint comparison of the three strains using the Kruskal–Wallis test rendered all differences insignificant. We conclude that the CD95/CD95L system is either not involved, or can be replaced by alternate mechanisms in the control of neuronal populations during hippocampal development.
Nicotine withdrawal syndrome: behavioural distress and selective up‐regulation of the cyclic AMP pathway in the amygdala
Authors: Tzavara Eleni T. , Monory Krisztina , Hanoune Jacques , Nomikos George G.
Published: March 2003

Nicotine addiction is a major public health issue. The use of laboratory animal models is a crucial tool in research aiming at understanding the pathophysiological mechanisms of nicotine dependence and at proposing new therapies. In rodents, cessation of nicotine exposure or administration of the nicotinic antagonist mecamylamine induces a nicotine withdrawal syndrome. Antagonist‐precipitated withdrawal from other abused drugs such as opiates or cannabinoids has been associated with region‐specific modifications of the activity of the cyclic AMP pathway. Here we show that mecamylamine‐precipitated nicotine withdrawal in the rat is characterized by an increase in thigmotaxis (time spent in the periphery of an open field) that may be indicative of behavioural distress and can be associated with a selective up‐regulation of adenylyl cyclase activity in the amygdala, a region implicated in the regulation of negative affect in response to aversive stimuli, including withdrawal. Adenylyl cyclase activity that is increased during precipitated nicotine withdrawal is stimulated by calcium/calmodulin, as is also the case for opioid and cannabinoid abstinence. This suggests that directly or indirectly mediated increases in the activity of the cyclic AMP pathway could constitute a possible common molecular mechanism underlying neuroadaptive changes following abstinence from different abused drugs.
Spatial learning is unimpaired in mice containing a deletion of the alpha‐synuclein locus
Authors: Chen Philip E. , Specht Christian G. , Morris Richard G. M. , Schoepfer Ralf
Published: March 2003

α‐Synuclein belongs to a family of structurally related proteins expressed highly in the brain and is the major component of filamentous deposits present in a range of neurodegenerative diseases (synucleinopathies). It has been implicated in learning and memory, yet the physiological role of this protein is still unclear. It was recently found that a subpopulation of C57BL/6J mice carries a chromosomal deletion of the α‐synuclein locus, often unknown to the experimenter. As genetically engineered mice are often backcrossed with C57BL/6J animals for learning and memory experiments, we studied the importance of α‐synuclein in spatial learning tasks by examining the performance of α‐synuclein–/– mice in the hidden platform reference memory version of the watermaze. Our data show that α‐synuclein–/– mice had no significant impairment in performance during training or probe trials, compared with wild‐type littermates. Therefore, we conclude that α‐synuclein is not essential for this type of spatial learning.
Auditory activation of ‘visual’ cortical areas in the blind mole rat (Spalax ehrenbergi)
Authors: Bronchti Gilles , Heil Peter , Sadka Ronen , Hess Andreas , Scheich Henning , Wollberg Zvi
Published: March 2003

The mole rat (Spalax ehrenbergi) is a subterranean rodent whose adaptations to its fossorial life include an extremely reduced peripheral visual system and an auditory system suited for the perception of vibratory stimuli. We have previously shown that in this blind rodent the dorsal lateral geniculate nucleus, the primary visual thalamic nucleus of sighted mammals, is activated by auditory stimuli. In this report we focus on the manifestation of this cross‐modal compensation at the cortical level. Cyto‐ and myeloarchitectural analyses of the occipital area showed that despite the almost total blindness of the mole rat this area has retained the organization of a typical mammalian primary visual cortex. Application of the metabolic marker 2‐deoxyglucose and electrophysiological recording of evoked field potentials and single‐unit activity disclosed that a considerable part of this area is activated by auditory stimuli. Previous neuronal tracing studies had revealed the origin of the bulk of this auditory input to be the dorsal lateral geniculate nucleus which itself receives auditory input from the inferior colliculus.
Upregulation of neurokinin‐1 receptor expression in rat spinal cord by an N‐terminal metabolite of substance P
Authors: Velázquez Rubén A. , McCarson Kenneth E. , Cai Yongjiu , Kovács Katalin J. , Shi Qiuying , Evensjö Maria , Larson Alice A.
Published: March 2003

Chronic inflammatory conditions are associated with an upregulation of both substance P (SP) and neurokinin‐1 (NK‐1) receptors in the dorsal spinal cord. These receptors have been implicated in hyperalgesia as well as stress‐induced analgesia. On the basis of the release of SP during chronic pain, and its rapid metabolism, we tested the hypothesis that SP metabolites regulate the synthesis of either SP or NK‐1 receptors in the spinal cord. We measured expression of preprotachykinin mRNA and NK‐1 receptor mRNA following intrathecally administered substance P(1–7) (SP1–7), the major metabolite of SP in rat, and following capsaicin, a compound known to induce release of endogenous SP. SP(1–7) and capsaicin each increased NK‐1 receptor mRNA in the spinal cord (6 h) followed by an increase in NK‐1 receptor‐immunoreactivity (24 h and 1 week). D‐SP(1–7), a d‐isomer and antagonist of SP(1–7), did not mimic the effect of SP(1–7), indicating stereoselectivity. Instead, D‐SP(1–7) prevented the upregulation of NK‐1 receptor immunoreactivity that was induced by capsaicin injected intrathecally, suggesting that the effect of capsaicin is also mediated by SP N‐terminal metabolites. In contrast, the decrease in SP synthesis produced by capsaicin was not dependent on SP metabolites as SP(1–7) failed to decrease either preprotachykinin mRNA content in dorsal root ganglia (6 h) or SP immunoreactivity in the lumbar spinal cord (24 h and 1 week). In addition, the effects of capsaicin on SP synthesis were not prevented by D‐SP(1–7). Thus, SP metabolites, at times and doses that are antinociceptive, appear to enhance SP‐mediated signal transduction by upregulating NK‐1 receptor expression without affecting SP synthesis.
Peripheral GABAergic inhibition of spider mechanosensory afferents
Authors: Panek Izabela , French Andrew S. , Seyfarth Ernst‐August , Sekizawa Shin‐ichi , Torkkeli Päivi H.
Published: March 2003

Spider mechanosensory neurons receive an extensive network of efferent synapses onto their sensory dendrites, somata and distal axonal regions. The function of these synapses is unknown. Peripheral synapses are also found on crustacean stretch‐receptor neurons but not on mechanosensory afferents of other species, although inhibitory GABAergic synapses are a common feature of centrally located axon terminals. Here we investigated the effects of GABA receptor agonists and antagonists on one group of spider mechanosensory neurons, the slit sense organ VS‐3, which are accessible to current‐ and voltage‐clamp recordings. Bath application of GABA activated an inward current that depolarized the membrane and increased the membrane conductance leading to impulse inhibition. VS‐3 neuron GABA receptors were activated by muscimol and inhibited by picrotoxin but not bicuculline, and their dose–response relationship had an EC50 of 103.4 µm, features typical for insect ionotropic GABA receptors. Voltage‐ and current‐clamp analysis confirmed that, while the Na+ channel inhibition resulting from depolarization can lead to impulse inhibition, the increase in membrane conductance (i.e. ‘shunting’) completely inhibited impulse propagation. This result argues against previous findings from other preparations that GABA‐mediated inhibition is caused by a depolarization that inactivates Na+ conductance, and it supports those findings that assign this role to membrane shunting. Our results show that GABA can rapidly and selectively inhibit specific mechanoreceptors in the periphery. This type of peripheral inhibition may provide spiders with a mechanism for distinguishing between signals from potential prey, predators or mates, and responding with appropriate behaviour to each signal.
Brain temperature fluctuation: a reflection of functional neural activation
Authors: Kiyatkin Eugene A. , Brown P. Leon , Wise Roy A.
Published: March 2003

Although it is known that relatively large increases in local brain temperature can occur during behaviour and in response to various novel, stressful and emotionally arousing environmental stimuli, the source of this heat is not clearly established. To clarify this issue, we monitored the temperature in three brain structures (dorsal and ventral striatum, cerebellum) and in arterial blood at the level of the abdominal aorta in freely moving rats exposed to several environmental challenges ranging from traditional stressors to simple sensory stimuli (cage change, tail pinch, exposure to another male rat, a female rat, a mouse or an unexpected sound). We found that brain temperature was consistently higher than arterial blood temperature, and that brain temperature increased prior to, and to a greater extent than, the increase in blood temperature evoked by each test challenge. Thus, the local metabolic consequences of widely correlated neural activity appear to be the primary source of increases in brain temperature and a driving force behind the associated changes in body temperature.
Neurotensin phase‐shifts the firing rate rhythm of neurons in the rat suprachiasmatic nuclei in vitro
Authors: Meyer‐Spasche Alert , Reed Helen E. , Piggins Hugh D.
Published: March 2003

The suprachiasmatic nuclei (SCN) of the hypothalamus house the main mammalian circadian pacemaker. Cell bodies in the rat SCN contain the neuropeptide neurotensin (NT), and two NT receptor types, NTS1 and nts2. Because the role of NT in the circadian rhythm processes is unknown, we studied the phase‐shifting effects of NT on the firing rate rhythm of rat SCN neurons in vitro. Additionally, the NT receptor antagonists SR142948a and SR48692 were used to try and block any NT‐induced phase shifts. To elucidate the second messenger pathway responsible for mediating the phase‐resetting actions of NT, we utilized the phospholipase C (PLC) and protein kinase A (PKA) inhibitors U‐73122 and KT5720, respectively. Application of NT during the projected day resulted in a large advance in the time of peak in FRR, whereas treatments during the projected night had no effect. Both NT receptor antagonists blocked the NT‐induced phase shifts, as did the PLC inhibitor U‐73122. The PKA inhibitor KT5720 had no influence on the magnitude of the phase shift caused by NT during the middle of the projected day. These results provide the first evidence that NT may play a role in regulating the rat circadian pacemaker, using NTS1 and nts2 receptors presumably coupled to PLC.
AMPA receptor activation induces GABA release from neurons migrating tangentially in the intermediate zone of embryonic rat neocortex
Authors: Poluch Sylvie , König Norbert
Published: March 2003

In the intermediate zone of the embryonic rodent neocortex, neurons migrating tangentially from the basal ganglia express both functional amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors and γ‐aminobutyric acid (GABA). To test the hypothesis of GABA release triggered by AMPA receptor activation, we used whole‐hemisphere cultures prepared from rat embryos (day 15). We observed a marked decrease in the number of detectable GABA‐positive cells in the intermediate zone after exposure to T‐AMPA. This effect was blocked by coapplying GYKI 53655, an AMPA receptor antagonist. The decrease in GABA immunolabelling induced by T‐AMPA did not require extracellular calcium. In contrast, it was abolished after sodium substitution by choline, or after coapplication of nipecotic acid, a GABA transporter inhibitor. Exposure to high potassium reduced the number of detectable GABA‐positive cells. These results are compatible with carrier‐mediated GABA release consecutive to sodium influx. GABA released from neurons migrating tangentially in the intermediate zone after AMPA receptor activation may influence neighbouring elements including radially migrating postmitotic neurons, proliferating progenitors and possibly the tangential cells themselves.
Layer‐specific thalamocortical innervation in organotypic cultures is prevented by substances that alter neural activity
Authors: Anderson Gillian , Price David J.
Published: March 2003

Cortical layer IV is the major target of thalamocortical axons and many previous studies have shown that the development of this layer‐specific innervation can be modelledin vitroby organotypic cocultures of thalamus and cortex. The mechanisms causing thalamic axons to terminate in layer IV are unknown. We used thesein vitromodels to test the possibility that neural activity plays a part in this termination process by adding substances that raise or lower levels of neural activity to the cocultures. We found that addition of tetrodotoxin or 2‐amino‐5‐phosphonovalerate, to block activity, or potassium, to raise it, all interfered with termination in layer IV. These findings suggest that termination in layer IV requires neural activity at an appropriate level in the thalamocortical system. They also add support to recent findings that show that the importance of neural activity in development may extend to an earlier period than thought previously, to include the correct targeting of axons as well as the later refinement of connections.