Prospective Assessment of Hepcidin in Relation to Delayed or Immediate Graft Function in Patients Undergoing Kidney Transplantation.

BACKGROUND: Hepcidin is a peptide hormone that regulates iron homeostasis. Hepcidin may represent an early, predictive biomarker of acute kidney injury, another model of ischemia-reperfusion injury. Urinary hepcidin-25 has been shown to be elevated in patients who do not develop acute kidney injury. Creatinine is an unreliable indicator during acute changes in kidney; therefore, the aim of the study was to assess whether hepcidin could predict renal outcome in 31 consecutive patients undergoing kidney allograft transplantation. Serum hepcidin was evaluated before and after 1, 3, 6, and 10 days after kidney transplantation, using commercially available kits. Serum creatinine was assessed at the same time. METHODS: We found a significant decrease in serum hepcidin, as early as after 1 day after kidney transplantation. Before transplantation, serum hepcidin was related to creatinine. In patients with delayed graft function, there was no decrease in serum hepcidin. RESULTS: Our findings may have important implications for the clinical treatment of patients undergoing kidney transplantation. The "window of opportunity" is narrow in delayed graft function to distinguish between acute rejection and calcineurin inhibitors nephrotoxicity, and time is limited to introduce proper treatment after initiating insult. CONCLUSIONS: Hepcidin must be investigated as a potential early marker for delayed graft function, especially in the upcoming setting of early dialysis treatment or anti-rejection therapy and might contribute to early patient risk stratification.

Dopamine modulates temporal dynamics of feedforward inhibition in rat prefrontal cortex in vivo.

Midbrain dopamine (DA) neurons project to pyramidal cells and interneurons of the prefrontal cortex (PFC). At the microcircuit level, interneurons gate inputs to a network and regulate/pattern its outputs. Whereas several in vitro studies have examined the role of DA on PFC interneurons, few in vivo data are available. In this study, we show that DA influences the timing of interneuron firing. In particular, DA had a reductive influence on interneuron spontaneous firing, which in the context of the excitatory response of interneurons to hippocampal electrical stimulation, lead to a temporal focalization of the interneuron response. This suggests that the reductive influence of DA on interneuron excitability is responsible for filtering out weak excitatory inputs. The increase in the temporal precision of interneuron firing is a mechanism by which DA can modulate the temporal dynamics of feedforward inhibition in PFC circuits and can thereby influence cognitive information processing.

2-Deoxyglucose and NMDA inhibit protein synthesis in neurons and regulate phosphorylation of elongation factor-2 by distinct mechanisms.

Cerebral ischaemia is associated with brain damage and inhibition of neuronal protein synthesis. A deficit in neuronal metabolism and altered excitatory amino acid release may both contribute to those phenomena. In the present study, we demonstrate that both NMDA and metabolic impairment by 2-deoxyglucose or inhibitors of mitochondrial respiration inhibit protein synthesis in cortical neurons through the phosphorylation of eukaryotic elongation factor (eEF-2), without any change in phosphorylation of initiation factor eIF-2alpha. eEF-2 kinase may be activated both by Ca(2+)-independent AMP kinase or by an increase in cytosolic Ca2+. Although NMDA decreases ATP levels in neurons, only the effects of 2-deoxyglucose on protein synthesis and phosphorylation of elongation factor eEF-2 were reversed by Na(+) pyruvate. Protein synthesis inhibition by 2-deoxyglucose was not as a result of a secondary release of glutamate from cortical neurons as it was not prevented by the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine hydrogen maleate (MK 801), nor to an increase in cytosolic-free Ca2+. Conversely, 2-deoxyglucose likely activates eEF-2 kinase through a process involving phosphorylation by AMP kinase. In conclusion, we provide evidence that protein synthesis can be inhibited by NMDA and metabolic deprivation by two distinct mechanisms involving, respectively, Ca(2+)-dependent and Ca(2+)-independent eEF-2 phosphorylation.

ATP-induced inhibition of gap junctional communication is enhanced by interleukin-1 beta treatment in cultured astrocytes.

Nucleotides are signaling molecules involved in variety of interactions between neurons, between glial cells as well as between neurons and glial cells. In addition, ATP and other nucleotides are massively released following brain insults, including inflammation, and may thereby be involved in mechanisms of cerebral injury. Recent concepts have shown that in astrocytes intercellular communication through gap junctions may play an important role in neuroprotection. Therefore, we have studied the effects of nucleotides on gap junction communication in astrocytes. Based on measurement of intercellular dye coupling and recording of junctional currents, the present study shows that ATP (10-100 microM) induces a rapid and a concentration-dependent inhibition of gap junction communication in cultured cortical astrocytes from newborn mice. Effects of agonists and antagonists of purinergic receptors indicate that the inhibition of gap junctional communication by ATP mainly involves the stimulation of metabotropic purinergic 1 (P2Y(1)) receptors. Pretreatment with the pro-inflammatory cytokine interleukin-1beta (10 ng/ml, 24 h), which has no effect by itself on gap junctional communication, increases the inhibitory effect of ATP and astrocytes become sensitive to uridine 5'-triphosphate (UTP). As indicated by the enhanced expression of P2Y(2) receptor mRNA, P2Y(2) receptors are responsible for the increased responses evoked by ATP and UTP in interleukin-1beta-treated cells. In addition, the effect of endothelin-1, a well-known inhibitor of gap junctional communication in astrocytes was also exacerbated following interleukin-1beta treatment. We conclude that ATP decreases intercellular communication through gap junctions in astrocytes and that the increased sensitivity of gap junction channels to nucleotides and endothelin-1 is a characteristic feature of astrocytes exposed to pro-inflammatory treatments.

Endothelins regulate astrocyte gap junctions in rat hippocampal slices.

Gap junctional communication (GJC) is a typical feature of astrocytes proposed to contribute to the role played by these glial cells in brain physiology and pathology. In acutely isolated hippocampal slices from rat (P11-P19), intercellular diffusion of biocytin through gap junction channels was shown to occur between hundreds of cells immuno-positive for astrocytic markers studied in the CA1/CA2 region. Single-cell RT-PCR demonstrated astrocytic mRNA expression of several connexin (Cx) subtypes, the molecular constituent of gap junction channels, whereas immunoblotting confirmed that Cx43 and Cx30 are the main gap junction proteins in hippocampal astrocytes. In the brain, astrocytes represent a major target for endothelins (Ets), a vasoactive family of peptides. Our results demonstrate that Ets decrease the expression of phosphorylated Cx43 forms and are potent inhibitors of GJC. The Et-induced effects were investigated using specific Et receptor agonists and antagonists, including Bosentan (Tracleer trade mark ), an EtA/B receptor antagonist, and using hippocampal slices and cultures from EtB-receptor-deficient rats. Interestingly, the pharmacological profile of Ets effects did not follow the classical profile established in cardiovascular systems. The present study therefore identifies Ets as potent endogenous inhibitory regulators of astrocyte networks. As such, the action of these peptides on astrocyte GJC might be involved in the contribution of astrocytes to neuroprotective processes and have a therapeutic potential in neuropathological situations.

Mu opioid control of the N-methyl-D-aspartate-evoked release of [3H]-acetylcholine in the limbic territory of the rat striatum in vitro: diurnal variations and implication of a dopamine link.

Using an in vitro microsuperfusion procedure, the release of newly synthesized [(3)H]-acetylcholine (ACh), evoked by N-methyl-D-aspartate (NMDA) receptor stimulation, was investigated in striosome-enriched areas and matrix of the rat striatum. The role of micro-opioid receptors, activated by endogenously released enkephalin, on the NMDA-evoked release of ACh was studied using the selective micro-opioid receptor antagonist, beta-funaltrexamine. Experiments were performed 2 (morning) or 8 (afternoon) h after light onset, in either the presence or absence (alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis) of dopaminergic transmission. As expected, based on the presence of micro-opioid receptors in striosomes, beta-funaltrexamine (0.1 nM, 10 nM and 1 microM) enhanced the NMDA (1 mM+10 microM D-serine)-evoked release of ACh in striosome-enriched areas but not in the matrix. Interestingly, these responses were significantly more pronounced in afternoon than in morning experiments. In the presence of alpha-methyl-p-tyrosine, the NMDA-evoked release of ACh was increased with similar amplitude in morning and afternoon experiments. However, in this condition (without dopamine transmission), the facilitatory effects of beta-funaltrexamine on the NMDA-evoked release of ACh were suppressed totally in the morning and only partially in the afternoon. The selective micro-opiate agonist, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (1 microM, coapplied with NMDA), was without effect on the NMDA-evoked release of ACh but abolished both dopamine-dependent (morning) and dopamine-independent (afternoon) responses of beta-funaltrexamine (10 nM and 1 microM).Therefore, in the limbic territory of the striatum enriched in striosomes, the micro-opioid-inhibitory regulation of ACh release follows diurnal rhythms. While dopamine is required for this regulation in the morning and the afternoon, an additional dopamine-independent process is present only in the afternoon.

Heterogeneity of spike frequency adaptation among medium spiny neurones from the rat striatum.

The main neuronal population of the striatum is composed of the medium spiny neurones (MSNs). In fact several sub-populations of MSNs can be distinguished according to the striatal compartment (striosomes and matrix) to which they belong, their afferents and their sites of projection, their biochemical markers and their morphologies. However, these cells are generally described as an electrophysiological homogeneous population. Using brain slices from the rat and whole cell patch clamp recordings, we show that at P(15) 28% of the MSNs display a spike frequency adaptation. While the mean frequency adaptation ratio for non-adapting cells was 1.07+/-0.01 it reached 2.66+/-0.09 in adapting MSNs and the incidence of this frequency adaptation phenotype appeared to be stable during post-natal development. Single-cell RT-PCR analysis of mRNAs for mu opioid receptors, enkephalin and substance P precursors suggested that adapting MSNs are present in both striatal compartments as well as in the direct and indirect pathways of the matrix. Adapting neurones were also distinguished from non-adapting cells by a lower membrane time constant, a higher AP threshold, a reduced delay to the first spike and a higher initial firing rate. Micro-domains differing by their magnitude of adaptation could be distinguished within the spike frequency adaptation process.A subgroup of MSNs exists, showing a marked spike frequency adaptation together with other distinct properties, such as shorter delay to first spike and membrane time constant, and higher initial frequency and action potential threshold. In conclusion, when strong cortical inputs are delivered in coincidence, adapting MSNs could not only transmit faster the first AP but also exert a sort of cutoff of the transmission due to their spike frequency adaptation process.

[Primary pericardial sarcoma]. / Sarcome primitif du péricarde.

We present the case of a 50 years old male revealed by a recurrent pericardial effusion. The diagnosis of malignancy was confirmed by direct biopsy. The treatment consisted in surgical excision and chemotherapy. The patient was asymptomatic 17 months after surgery.

Basal ganglia and processing of cortical information: functional interactions between trans-striatal and trans-subthalamic circuits in the substantia nigra pars reticulata.

The substantia nigra pars reticulata (SNR), a major output station of basal ganglia, receives information from the cerebral cortex through three main pathways, i.e. a direct inhibitory trans-striatal pathway, an indirect excitatory trans-striatal pathway that involves the pallidum and the subthalamus and a direct excitatory trans-subthalamic pathway. In order to determine how cortical information flow originating from functionally distinct cortical areas and processed through the trans-striatal and trans-subthalamic pathways is integrated within the SNR, the responses induced by electrical stimulation of prefrontal, motor and auditory cortex in SNR cells were analyzed in anesthetized rats. Further confirming that direct striato-nigral pathways related to these functionally distinct cortical areas are organized in parallel channels, stimulation of the prefrontal, motor and auditory cortex induced an inhibitory response on distinct subpopulations of SNR cells. Within a given channel, the direct trans-striatal and the trans-subthalamic pathways converge on a large number of nigral cells. In addition, the present study reveals that nigral cells receiving an inhibitory input from a given cortical area through the direct trans-striatal pathway can also receive an excitatory input from a functionally distinct cortical area through the trans-subthalamic pathways. Such a convergence mainly occurred between the direct striato-nigral pathway issued from the auditory cortex and the trans-subthalamic pathways issued from the motor cortex. These data reveal the existence of a converging influence of trans-subthalamic and direct striato-nigral pathways not only within but also across channels. Within a given cortico-basal ganglia channel, the trans-subthalamic pathways likely contribute to the temporal shaping of the striato-nigral inhibition and thus of the disinhibition of the related nigral target nuclei in the thalamus and mesencephalon. Across channels, the specific interactions between trans-subthalamic and direct striato-nigral pathways could contribute to prevent inhibition of subpopulations of nigral cells implicated in competing functions.

Autoradiographic distribution of tachykinin NK2 binding sites in the rat brain: comparison with NK1 and NK3 binding sites.

The autoradiographic distribution of tachykinin NK(2) binding sites was determined in the adult rat brain using [(125)I]neurokinin A in the presence of either senktide (NK(3) agonist) and [Pro(9)]substance P (NK(1) agonist) or senktide and SR 140333 (NK(1) antagonist). Indeed, this radioligand labels two subtypes of NK(1) binding sites (which present a high affinity not only for SP but also for neurokinin A, neuropeptide K and neuropeptide gamma) as well as NK(3) binding sites. The distribution of NK(2) binding sites was also compared with those of NK(1) and NK(3) binding sites, these sites being labeled with [(125)I]Bolton and Hunter substance P and [(125)I]Bolton and Hunter eledoisin, respectively. In agreement with our results obtained with membranes from various brain structures, NK(2)-sensitive [(125)I]neurokinin A labeling was mainly observed in few structures including the dorsal and ventral hippocampus, the septum, the thalamus and the prefrontal cortex. The density of NK(2) binding sites was weak when compared with those of NK(1) and NK(3) binding sites. Marked differences were observed in the distributions of NK(1), NK(2) and NK(3) binding sites. These results are discussed taking into consideration differences or similarities between the distributions of NK(2)-sensitive [(125)I]neurokinin A binding sites and of their endogenous ligands (neurokinin A, neuropeptide K and neuropeptide gamma) but also local NK(2) agonist responses blocked by NK(2) antagonists. Insights on the roles of endogenous tachykinins in several brain functions are also discussed on the basis of the respective distributions of different neurokinin binding sites.

N-Methyl-D-aspartate receptor activation inhibits protein synthesis in cortical neurons independently of its ionic permeability properties.

Transient cerebral ischemia, which is accompanied by a sustained release of glutamate, strongly depresses protein synthesis. We have previously demonstrated in cortical neurons that a glutamate-induced increase in intracellular Ca(2+) is likely responsible for the blockade of the elongation step of protein synthesis. In this study, we provide evidence indicating that NMDA mobilizes a thapsigargin-sensitive pool of intracellular Ca(2+). Exposure of cortical neurons to NMDA, in the absence of external Ca(2+), produced a transient rise in intracellular Ca(2+) that was suppressed by pretreatment with thapsigargin. This rise in intracellular Ca(2+) did not result from an influx of Na(+) via reversal of the mitochondrial Na(+)/Ca(2+) exchanger since it persisted in a Na(+)-free medium or in the presence of CGP 37157, an inhibitor of the exchanger. Moreover, the NMDA-induced increase in intracellular Ca(2+) required the presence of D-serine, was blocked by D(-)-2-amino-5-phosphonopentanoic acid, but was not reduced in the presence of external Mg(2+). This unexpected non-ionotropic effect of NMDA was associated with an inhibition of protein synthesis that was also insensitive to the absence of external Ca(2+) or Na(+), or presence of Mg(2+). NMDA treatment resulted in an increase in the phosphorylation of eEF-2 in the absence or presence of external Ca(2+). The initiation step of protein synthesis was not blocked by NMDA since the phosphorylation of initiation factor eIF-2alpha subunit was not altered by NMDA treatment. In conclusion, we provide evidence indicating that NMDA can inhibit protein synthesis in cortical neurons through a process that involves the mobilization of intracellular Ca(2+) stores via a mechanism that is not linked to the ionic properties of NMDA receptors.

Generation of reactive oxygen metabolites by the varicose vein wall.

OBJECTIVES: to evaluate the content of lipid peroxidation products (expressed by the concentration of thiobarbituric acid-reactive substances; TBARS), the content of myeloperoxidase (MPO), and the localisation of xanthine oxidase (XO) in varicose veins (vv), varicose veins with superficial thrombophlebitis and unchanged saphenous veins. METHODS: varicose saphenous veins, varicose veins with superficial thrombophlebitis and normal saphenous veins obtained during varicose vein surgery on 36 patients as well as healthy saphenous veins from cadaver organ donors (control). Homogenates were prepared in which TBARS concentration and MPO content were determined. Immunohistochemical staining to detect XO was also performed. RESULTS: the highest concentration of TBARS occurred in vv with superficial thrombophlebitis, the lowest in donor vein. The highest content of MPO was observed in vv and slightly lower - in varicose veins with thrombophlebitis. A positive reaction for XO was seen in vv wall endothelium. Specimens of vv with thrombophlebitis revealed strong, intense staining in endothelium as well as in vasa vasorum. CONCLUSIONS: varicose veins, especially those complicated with superficial thrombophlebitis revealed increased free radical generation. Its sources might be neutrophils, and in vv complicated with superficial thrombophlebitis-xanthine oxidase.

[Peritoneal tuberculosis: 27 cases in the suburbs of northeastern Paris]. / Tuberculose péritonéale: 27 cas dans la banlieue nord-est de Paris.

SETTING: Peritoneal tuberculosis did not disappear from France during the 1990s. OBJECTIVE: To determine the characteristics of peritoneal tuberculosis in the north-eastern suburbs of Paris. METHOD: A retrospective study of cases diagnosed with peritoneal tuberculosis between 1990 and 1998 in five suburban hospitals in the north-east region of Paris. RESULTS: Twenty-seven cases of adult peritoneal tuberculosis were diagnosed. There were nine women and 18 men, with a mean age of 37.5 years, 88.9% of whom were foreign born. General and digestive symptoms--abdominal pain and/or ascites--were present in 96.3% of the cases. The mean delay in treatment was 30 days. Peritoneal involvement was isolated in 25.9% of cases, and associated with pulmonary tuberculosis in 40.7% or hepatic tuberculosis in 25.9%. Co-infection with HIV (human immunodeficiency virus) was present 14.8% of cases. Culture of ascites fluid, laparoscopy and/or laparotomy (n = 17), with directed biopsy, aided in the formal diagnosis of peritoneal tuberculosis in 59.2%. One relapse and one case of multiresistance were observed. The mean duration of treatment was 9 months (range 6-12 months). Three patients received treatment with corticosteroids, and 91.2% of the patients achieved cure without sequelae. CONCLUSION: Peritoneal tuberculosis is not rare in the Paris region. The diagnosis should be suspected in case with ascites and fever, and can be confirmed by laparoscopy with sampling for bacteriology and histology. The methods of treatment need to be standardised.

Brain macrophages inhibit gap junctional communication and downregulate connexin 43 expression in cultured astrocytes.

Astrocytes are typically interconnected by gap junction channels that allow, in vitro as well as in vivo, a high degree of intercellular communication between these glial cells. Using cocultures of astrocytes and neurons, we have demonstrated that gap junctional communication (GJC) and connexin 43 (Cx43) expression, the major junctional protein in astrocytes, are controlled by neuronal activity. Moreover, neuronal death downregulates these two parameters. Because in several brain pathologies neuronal loss is associated with an increase in brain macrophage (BM) density, we have now investigated whether coculture with BM affects astrocyte gap junctions. We report here that addition of BM for 24 h decreases the expression of GJC and Cx43 in astrocytes in a density-dependent manner. In contrast, Cx43 is not detected in BM and no heterotypic coupling is observed between the two cell types. A soluble factor does not seem to be involved in these inhibitions because they are not observed either in the presence of BM conditioned media or in the absence of direct contact between the two cell types by using inserts. These observations could have pathophysiological relevance as neuronal death, microglial proliferation and astrocytic reactions occur in brain injuries and pathologies. Because astrocyte interactions with BM and dying neurons both result in the downregulation of Cx43 expression and in the inhibition of GJC, a critical consequence on astrocytic phenotype in those situations could be the inhibition of gap junctions.

Costimulation of N-methyl-D-aspartate and muscarinic neuronal receptors modulates gap junctional communication in striatal astrocytes.

Cocultures of neurons and astrocytes from the rat striatum were used to determine whether the stimulation of neuronal receptors could affect the level of intercellular communication mediated by gap junctions in astrocytes. The costimulation of N-methyl-D-asparte (NMDA) and muscarinic receptors led to a prominent reduction of astrocyte gap junctional communication (GJC) in coculture. This treatment was not effective in astrocyte cultures, these cells being devoid of NMDA receptors. Both types of receptors contribute synergistically to this inhibitory response, as the reduction in astrocyte GJC was not observed after the blockade of either NMDA or muscarinic receptors. The involvement of a neuronal release of arachidonic acid (AA) in this inhibition was investigated because the costimulation of neuronal NMDA and muscarinic receptors markedly enhanced the release of AA in neuronal cultures and in cocultures. In addition, both the reduction of astrocyte GJC and the release of AA evoked by NMDA and muscarinic receptor costimulation were prevented by mepacrine, a phospholipase A(2) inhibitor, and this astrocyte GJC inhibition was mimicked by the exogenous application of AA. Metabolites of AA formed through the cyclooxygenase pathway seem to be responsible for the effects induced by either the costimulation of NMDA and muscarinic neuronal receptors or the application of exogenous AA because, in both cases, astrocyte GJC inhibition was prevented by indomethacin. Altogether, these data provide evidence for a neuronal control of astrocytic communication and open perspectives for the understanding of the modalities through which cholinergic interneurons and glutamatergic inputs affect local circuits in the striatum.

Cortical alpha 1-adrenergic regulation of acute and sensitized morphine locomotor effects.

The role of alpha1-adrenergic transmission was tested on locomotor effects of acute or repeated morphine (5 mg/kg, i.p.) administration. Prazosin, an alpha1-adrenergic antagonist, administered 30 min before morphine, either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (200 pmol/side) reduced the stimulatory influence of morphine on locomotion. The progressive increase of the locomotor response induced by repeated morphine injections was blocked by a prazosin pretreatment but not the behavioral sensitization on the test day. These data suggest that blockade of cortical alpha1-adrenergic receptors reduces the expression of acute and sensitized locomotor responses to morphine, but does not prevent the induction of behavioral sensitization.

Presence of NK2 binding sites in the rat brain.

Attempts were made to label tachykinin NK2 binding sites in the adult rat brain using [125I]neurokinin A (NKA) as ligand in the presence of NK1 and NK3 agonist or antagonist to avoid labelling of NK1 and NK3 binding sites, respectively. A high-affinity, specifically NK2-sensitive, [125I]NKA-binding, temperature-dependent, reversible, sensitive to GTPgammaS and correspondence to a single population of binding sites (K(D) and B(max) values: 2.2 nM and 7.3 fmol/mg protein) was demonstrated on hippocampal membranes. Competition studies performed with tachykinins and tachykinin-related compounds indicated that the pharmacological properties of these NK2-sensitive [125I]NKA binding sites were identical to those identified in the rat urinary bladder and duodenum. NKA, neuropeptide K, and neuropeptide gamma, as well as the potent and selective NK2 antagonists SR 144190, SR 48968 and MEN 10627, presented a nanomolar affinity for these sites. The regional distribution of these NK2-sensitive [125I]NKA binding sites differs markedly from those of NK1 and NK3 binding sites, with the largest labeling being found in the hippocampus, the thalamus and the septum. Binding in other brain structures was low or negligible. A preliminary autoradiographic analysis confirmed [125I]NKA selective binding in hippocampal CA1 and CA3 areas, particularly, and in several thalamic nuclei.

Sequential and opposite regulation of two outward K(+) currents by ET-1 in cultured striatal astrocytes.

In the brain, astrocytes represent a major target for endothelins (ETs), a family of peptides that can be released by several cell types and that have potent and multiple effects on astrocytic functions. Four types of K(+) currents (I(K)) were detected in various proportions by patch-clamp recordings of cultured striatal astrocytes, including the A-type I(K), the inwardly rectifying I(K IR), the Ca(2+)-dependent I(K) (I(K Ca)), and the delayed-rectified I(K) (I(K DR)). Variations in the shape of current-voltage relationships were related mainly to differences in the proportion of these currents. ET-1 was found to regulate with opposite effects the two more frequently recorded outward K(+) currents in striatal astrocytes. Indeed, this peptide induced an initial activation of I(K Ca) (composed of SK and BK channels) and a delayed long-lasting inhibition of I(K DR). In current-clamp recordings, the activation of I(K Ca) correlated with a transient hyperpolarization, whereas the inhibition of I(K DR) correlated with a sustained depolarization. These ET-1-induced sequential changes in membrane potential in astrocytes may be important for the regulation of voltage gradients in astrocytic networks and the maintenance of K(+) homeostasis in the brain microenvironment.

Dendritic arborizations of the rat substantia nigra pars reticulata neurons: spatial organization and relation to the lamellar compartmentation of striato-nigral projections.

The cerebral cortex provides a major source of inputs to the basal ganglia. As has been well documented, the topography of corticostriatal projections subdivides the striatum into a mosaic of functionally distinct sectors. How information flow from these striatal sectors remains segregated or not within basal ganglia output nuclei has to be established. Electrophysiologically identified neurons of the rat substantia nigra pars reticulata were labeled by juxtacellular injection of Neurobiotin, and the spatial organization of their dendritic arborizations was analyzed in relation to the projection fields of individual striatal sectors. Thirty-nine nigral neurons located in the projection territory of the distinct striatal sensorimotor sectors were reconstructed. The data show that the dendritic arborizations of nigral neurons conform to the geometry of striato-nigral projections. Like striatal projections, the arborizations formed a series of curved laminas enveloping a dorsolaterally located core. Although dendritic fields of the neurons lying in the laminae were flat, those located in the core were spherical or cylindrical, thereby conforming to the shape of the striatal projection fields. This remarkable alignment between the dendritic arborizations of nigral neurons and the projection fields from individual striatal districts supports the concept of a parallel architecture of the striato-nigral circuits. However, pars reticulata neurons usually extend part of their dendrites within adjacent striatal projection fields, thereby ensuring a continuum between channels. The extension of the dendritic arborizations within the striatal projection fields suggests that nigral neurons integrate the information that is relevant for the completion of the specific motor behavior they control.

Segregation and convergence of information flow through the cortico-subthalamic pathways.

Cortico-basal ganglia circuits are organized in parallel channels. Information flow from functionally distinct cortical areas remains segregated within the striatum and through its direct projections to basal ganglia output structures. Whether such a segregation is maintained in trans-subthalamic circuits is still questioned. The effects of electrical stimulation of prefrontal, motor, and auditory cortex were analyzed in the subthalamic nucleus as well as in the striatum of anesthetized rats. In the striatum, cells (n = 300) presenting an excitatory response to stimulation of these cortical areas were located in distinct striatal territories, and none of the cells responded to two cortical stimulation sites. In the subthalamic nucleus, both prefrontal and motor cortex stimulations induced early and late excitatory responses as a result of activation of the direct cortico-subthalamic pathway and of the indirect cortico-striato-pallido-subthalamic pathway, respectively. Stimulation of the auditory cortex, which does not send direct projection to the subthalamic nucleus, induced only late excitatory responses. Among the subthalamic responding cells (n = 441), a few received both prefrontal and motor cortex (n = 19) or prefrontal and auditory cortex (n = 10) excitatory inputs, whereas a larger number of cells were activated from both motor and auditory cortices (n = 48). The data indicate that the segregation of cortical information flow originating from prefrontal, motor, and auditory cortices that occurred in the striatum is only partly maintained in the subthalamic nucleus. It can be proposed that the existence of specific patterns of convergence of information flow from these functionally distinct cortical areas in the subthalamic nucleus allows interactions between parallel channels.