bluuebunny/crossref_metadata_2025 huggingface dataset:
Met‐enkephalin immunoreactive neurons recruited by acute stress are innervated by axon terminals immunopositive for tyrosine hydroxylase and dopamine‐α‐hydroxylase in the anterolateral division of bed nuclei of the stria terminalis in the rat
Authors: Kozicz Tamás
Published: March 2003

The bed nuclei of the stria terminalis (BST) are highly heterogeneous forebrain structures, which play a central role in the regulation/modulation of stress responses. Studies using the inducible immediate early gene c‐fos as a marker of activated neurons have demonstrated significant stress‐induced neuronal activation in this limbic region. The BST also exhibit a dense network of dopamine and noradrenaline immunoreactive (ir) axon terminals. These catecholaminergic projections from various brainstem sources to the BST play an important role in a neurochemically mediated coordination of stress responses. In the anterolateral division of bed nuclei of the stria terminalis, the distribution of several Met‐enkephalin immunopositive perikarya overlaps with that of catecholaminergic axon terminals. Both monoaminergic and enkephalinergic structures have been postulated to play a role in the regulation/modulation of the central regulatory pathways of endocrine, behavioural and physiological responses during stress. Therefore the aims of this study were: (i) to study the possible involvement of dopaminergic fibre terminals in stress‐induced activation of BST perikarya; (ii) to investigate whether Met‐enkephalin‐immunoreactive neurons are recruited by acute volumen/osmotic challenge; and (iii), to demonstrate synaptic interactions between Met‐enkephalin‐ir neurons and fibre terminals immunopositive for dopamine or noradrenaline in the anterolateral division of the BST. From the results of this study we can conclude that depletion of dopamine in fibre terminals completely abolished stress‐induced activation of perikarya in the anterolateral division of BST. Furthermore, the innervation of stress‐induced Met‐enkephalin‐ir perikarya by dopaminergic fibre terminals in the oval nucleus of BST was demonstrated, whereas noradrenergic axons contacted enkephalinergic structures in the fusiform and subcomissural nuclei of BST. These interactions can be central in the modulatory control of the major stress regulatory pathway, the limbic hypothalamo–pituitary–adrenal axis.
CNS region‐specific regulation of glial glutamate transporter expression
Authors: Schlüter Karen , Figiel Maciej , Rozyczka Joanna , Engele Jürgen
Published: March 2003

The neuronal cell death associated with certain neurodegenerative disorders as well as acute brain injuries is in part due to the reduced expression of glial glutamate transporters and the subsequent accumulation of toxic extracellular glutamate concentrations. Extracellular factors previously found to potently stimulate the expression of the glial glutamate transporters, GLT‐1/EAAT2 and GLAST/EAAT1, in astroglial cultures of rat cerebral hemispheres are PACAP, TGFα, and EGF. In the present study, we sought to determine whether similar stimulatory influences apply for astroglia from other areas of the central nervous system (CNS). Immunoblot and real‐time RT‐PCR analysis of striatal astroglial cultures maintained for 72 h with PACAP, TGFα, or EGF revealed a prominent increase in GLT‐1 and GLAST expression. In apparent contrast, all factors completely failed to affect GLT‐1 and GLAST expression in astroglial cultures from the cerebellum, mesencephalon, and spinal cord between 36 h and 7 days. This failure was not due to the absence of functional recognition or transduction machineries for the extracellular factors as suggested by the additional observations that cerebellar, mesencephalic and spinal cord glia were capable of responding to stimulation with PACAP, TGFα, or EGF for 10 min with activation of CREB. Moreover, dibutyryl cyclic AMP (dbcAMP) potently promoted GLT‐1 and/or GLAST expression in mesencephalic, cerebellar and spinal cord glia, further indicating that extracellular factors regulate glial glutamate transporter expression throughout the CNS. Together these findings identify PACAP, TGFα and EGF as potent regulators of glutamate transporter expression in striatal glia. In addition, these findings provide evidence for a CNS region‐specific regulation of glial glutamate transport.
Somatic nociception activates NK1receptors in the nucleus tractus solitarii to attenuate the baroreceptor cardiac reflex
Authors: Boscan Pedro , Kasparov Sergey , Paton Julian F. R.
Published: March 2003

There is limited information regarding the integration of visceral and somatic afferents within the nucleus of the solitary tract (NTS). We studied the interaction of nociceptive and baroreceptive inputs in this nucleus in anin situarterially perfused, un‐anaesthetized decerebrate preparation of rat. At the systemic level, the gain of the cardiac component of the baroreceptor reflex was attenuated significantly by noxious mechanical stimulation of a forepaw. This baroreceptor reflex depression was mimicked by NTS microinjection of substance P and antagonized by microinjection of either bicuculline (a GABAAreceptor antagonist) or a neurokinin type 1 (NK1) receptor antagonist (CP‐99,994). The substance P effect was also blocked by a bilateral microinjection of bicuculline, at a dose that was without effect on basal baroreceptor reflex gain. Baroreceptive NTS neurons were defined by their excitatory response following increases in pressure within the ipsilateral carotid sinus. In 27 of 34 neurons the number of evoked spikes from baroreceptor stimulation was reduced significantly by concomitant electrical stimulation of the brachial nerve (P < 0.01). Furthermore, the attenuation of baroreceptor inputs to NTS neurons by brachial nerve stimulation was prevented by pressure‐ejection of bicuculline from a multi‐barrelled microelectrode (n = 8). In a separate population of 17 of 45 cells tested, brachial nerve stimulation evoked an excitatory response that was antagonized by blockade of NK1receptors. We conclude that nociceptive afferents activate NK1receptors, which in turn excite GABAergic interneurons impinging on cells mediating the cardiac component of the baroreceptor reflex.
Effects of long‐term treatment with dopamine receptor agonists and antagonists on terminal arbor size
Authors: Parish C. L. , Stanic D. , Drago J. , Borrelli E. , Finkelstein D. I. , Horne M. K.
Published: March 2003

This study demonstrates that pharmacological manipulation of the dopamine (DA) receptors can modulate the size of the axonal tree of substantia nigra pars compacta (SNpc) neurons in mice. Pharmacological blockade or genetic ablation of the D2 receptor (D2R) resulted in sprouting of DA SNpc neurons whereas treatment with a D2 agonist resulted in pruning of the terminal arbor of these neurons. Agents such as cocaine, that indirectly stimulate D2R, also resulted in reduced terminal arbor. Specific D1 agonists or antagonists had no effect on the density of DA terminals in the striatum. We conclude that the D2 receptor has a central role in regulating the size of the terminal arbor of nigrostriatal neurons. These findings have implications relating to the use of dopaminergic agonists in the management of Parkinson's disease and in controlling plasticity following injury, loss or transplantation of DA neurons.
Role of the paraventricular nucleus microenvironment in stress integration*
Authors: Herman James P. , Cullinan William E. , Ziegler Dana R. , Tasker Jeffrey G.
Published: March 2003

The hypothalamic paraventricular nucleus is the primary controller of hypothalamo‐pituitary–adrenocortical glucocorticoid release. In performing this function, the paraventricular nucleus summates a variety of information from both external and internal sources into a net secretory signal to the adrenal cortex. In this review, we will provide an overview of neuronal circuit mechanisms governing activation and inhibition of hypophysiotrophic neurons, highlight recent developments in our understanding of nonsynaptic mechanisms regulating paraventricular cellular activity, including dendritic neuropeptide release, direct steroid feedback, cytokine cascades and gaseous neurotransmission, and illustrate the capacity for hypophysiotrophic, neurohypophysial and preautonomic paraventricular effector pathways to work together in control of glucocorticoid release. The current state of knowledge reveals the paraventricular nucleus to be a dynamic entity, capable of integrating diverse classes of signals into control of adrenocortical activation.
Immune‐related mechanisms participating in resistance and susceptibility to glutamate toxicity
Authors: Schori Hadas , Yoles Eti , Wheeler Larry A. , Raveh Tal , Kimchi Adi , Schwartz Michal
Published: March 2003

Glutamate is an essential neurotransmitter in the CNS. However, at abnormally high concentrations it becomes cytotoxic. Recent studies in our laboratory showed that glutamate evokes T cell‐mediated protective mechanisms. The aim of the present study was to examine the nature of the glutamate receptors and signalling pathways that participate in immune protection against glutamate toxicity. We show, using the mouse visual system, that glutamate‐induced toxicity is strain dependent, not only with respect to the amount of neuronal loss it causes, but also in the pathways it activates. In strains that are genetically endowed with the ability to manifest a T cell‐dependent neuroprotective response to glutamate insult, neuronal losses due to glutamate toxicity were relatively small, and treatment with NMDA‐receptor antagonist worsened the outcome of exposure to glutamate. In contrast, in mice devoid of T cell‐dependent endogenous protection, NMDA receptor antagonist reduced the glutamate‐induced neuronal loss. In all strains, blockage of the AMPA/KA receptor was beneficial. Pharmacological (with α2‐adrenoceptor agonist) or molecular intervention (using either mice overexpressing Bcl‐2, or DAP‐kinase knockout mice) protected retinal ganglion cells from glutamate toxicity but not from the toxicity of NMDA. The results suggest that glutamate‐induced neuronal toxicity involves multiple glutamate receptors, the types and relative contributions of which, vary among strains. We suggest that a multifactorial protection, based on an immune mechanism independent of the specific pathway through which glutamate exerts its toxicity, is likely to be a safer, more comprehensive, and hence more effective strategy for neuroprotection. It might suggest that, because of individual differences, the pharmacological use of NMDA‐antagonist for neuroprotective purposes might have an adverse effect, even if the affinity is low.
Two major distinct subpopulations of neurokinin‐3 receptor‐expressing neurons in the superficial dorsal horn of the rat spinal cord
Authors: Ding Yu‐Qiang , Lu Chun‐Rong , Wang Hong , Su Chang‐Jun , Chen Liang‐Wei , Zhang Yuan‐Qiang , Ju Gong
Published: March 2003

This study was designed to provide evidence for elucidating the mechanisms of neurokinin‐3 receptor (NK3) in spinal pain modulation. First, colocalization of NK3 with the µ‐opioid receptor (MOR1) was studied in the spinal dorsal horn of the rat. Confocal microscopy showed that about 44% of NK3‐expressing neurons in laminae I and II were immunoreactive for MOR1, which corresponded to about 93% of the total population of MOR1‐containing neurons in these laminae. Second, the relationship between NK3/MOR1‐coexpressing neurons and those that express nitric oxide synthase (NOS) was examined by using a triple immunofluorescent staining method. About 37% of NK3‐immunoreactive neurons were also NOS‐immunoreactive, which constituted about 82% of NOS‐immunoreacitve neurons in the superficial laminae. However, no triple‐labelled neurons were detected. The present results indicate that there are two major distinct subpopulations of NK3‐expressing neurons in the superficial dorsal horn, which suggests that the involvement of NK3 receptor in spinal nociception could be mediated by two distinct mechanisms, i.e. opioid and nitric oxide.
The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats
Authors: Kole Maarten H. P. , Swan Laura , Fuchs Eberhard
Published: March 2003

Recent hypotheses on the action of antidepressants imply a modulation of excitatory amino acid transmission. Here, the effects of long‐term antidepressant application in rats with the drug tianeptine were examined at hippocampal CA3 commissural associational (c/a) glutamate receptor ion channels, employing the whole‐cell patch‐clamp technique. The drug's impact was tested by subjecting rats to daily restraint stress for three weeks in combination with tianeptine treatment (10 mg/kg/day). Whereas stress increased the deactivation time‐constant and amplitude of the N‐methyl‐d‐aspartate (NMDA) receptor‐mediated excitatory postsynaptic currents (EPSCs), it did not affect the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)/kainate receptor‐mediated EPSCs. Concomitant pharmacological treatment of stressed animals with tianeptine resulted in a normalized scaling of the amplitude ratio of NMDA receptor to AMPA/kainate receptor‐mediated currents and prevented the stress‐induced attenuation of NMDA‐EPSCs deactivation. Both paired‐pulse‐facilitation and frequency‐dependent plasticity remained unchanged. Both in control and stressed animals, however, tianeptine treatment strengthened the slope of the input‐output relation of EPSCs. The latter was mimicked by exposing hippocampal slices in vitro with 10 µm tianeptine, which rapidly increased the amplitudes of NMDA‐ and AMPA/kainate EPSCs. The enhancement of EPSCs could be blocked by the intracellular presence of the kinase inhibitor staurosporine (1 µm), suggesting the involvement of a postsynaptic phosphorylation cascade rather then presynaptic release mechanisms at CA3 c/a synapses. These results indicate that tianeptine targets the phosphorylation‐state of glutamate receptors at the CA3 c/a synapse. This novel signal transduction mechanism for tianeptine may provide a mechanistic resolution for its neuroprotective properties and, moreover, a pharmacological trajectory for its memory enhancing and/or antidepressant activity.
Convergence of parvocellular and magnocellular information channels in the primary visual cortex of the macaque
Authors: Vidyasagar T. R. , Kulikowski J. J. , Lipnicki D. M. , Dreher B.
Published: March 2003

We investigated whether responses of single cells in the striate cortex of anaesthetized macaque monkeys exhibit signatures of both parvocellular (P) and magnocellular (M) inputs from the dorsal lateral geniculate nucleus (dLGN). We used a palette of 128 isoluminant hues at four different saturation levels to test responses to chromatic stimuli against a white background. Spectral selectivity with these isoluminant stimuli was taken as an indication of P inputs. The presence of magnocellular inputs to a given cortical cell was deduced from its responses to a battery of tests, including assessment of achromatic contrast sensitivity, relative strengths of chromatic and luminance borders in driving the cell at different velocities and conduction velocity of their retino‐geniculo‐cortical afferents. At least a quarter of the cells in our cortical sample appear to receive convergent P and M inputs. We cannot however, exclude the possibility that some of these cells could be receiving a convergent input from the third parallel channel from the dLGN, namely the koniocellular (K) rather than the P channel. The neurons with convergent P and M inputs were recorded not only from supragranular and infragranular layers but also from the principal geniculate input recipient layer 4. Thus, our results challenge classical ideas of strict parallelism between different information streams at the level of the primate striate cortex.
Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy*
Authors: Davis Michael
Published: March 2003

Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA receptor‐linked mitogen activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist d‐cycloserine facilitates extinction after either systemic administration or intra‐amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because d‐cycloserine is a widely available and safe compound, d‐cycloserine or similar agents might be usefully combined with traditional extinction‐based approaches in the treatment of clinical fear.
Tactile motion activates the human middle temporal/V5 (MT/V5) complex
Authors: Hagen Matthew C. , Franzén Ove , McGlone Francis , Essick Greg , Dancer Christopher , Pardo José V.
Published: March 2003

The human middle temporal/V5 complex (hMT/V5) plays a central role in the perception of visual motion. This region is considered a unimodal visual area with little direct involvement of other sensory modalities. The current study uses H215O PET to test whether tactile motion influences the activity of hMT/V5. Regional cerebral blood flow (rCBF) within hMT/V5 was estimated in eight subjects in separate tactile motion and visual motion conditions, each contrasted with a resting, control. The tactile motion condition involved a brush stroked proximal‐to‐distal along the volar forearm and palm, while the subject attended to the stimulus with closed eyes. The visual motion condition consisted of low contrast, grey‐scale rings radiating at 15°/s from a central point, upon which the subject was instructed to fixate. The location of hMT/V5 was defined for each subject separately as the local maximum of rCBF change during the visual motion condition (vs. control). The average change in rCBF within spherical regions of interest at each peak revealed significant bilateral activation of hMT/V5 in the tactile motion condition contrasted with a second, independent set of control scans. Additionally, a single subject received a sufficient number of scans to perform a pixel‐wise, within‐subject analysis. His functional images were coregistered to his anatomical MRI. In this subject, tactile motion produced a significant increase in rCBF that directly overlapped a region activated by visual motion at the posterior continuance of the inferior temporal sulcus, consistent with the known location of hMT/V5. These results suggest involvement of the hMT/V5 complex in tactile motion processing.
Methamphetamine‐induced, suprachiasmatic nucleus‐independent circadian rhythms of activity and mPer gene expression in the striatum of the mouse
Authors: Iijima Michihiko , Nikaido Takato , Akiyama Masashi , Moriya Takahiro , Shibata Shigenobu
Published: March 2003

While the suprachiasmatic nucleus (SCN) coordinates the majority of daily rhythms, some circadian patterns of expression are controlled from outside of the SCN. These include responses to daily methamphetamine (MAP) injection, or daily restricted feeding. The mechanisms underlying these SCN‐independent circadian rhythms are unknown. A circadian oscillation in the expression of mPer1 and/or mPer2, mouse period, in the SCN is considered necessary to generate an SCN‐dependent circadian rhythm. Therefore, in this experiment, we examined the association between mPer gene expression and the MAP‐induced, SCN‐independent circadian rhythm. Acute injection of MAP caused an elevation of mPer1, mBmal1, and mNpas2 gene expression in the striatum and mPer1 in the liver. Daily MAP injection at a fixed time for 6 days shifted the rhythmic mPer1 and mPer2 expression in the striatum from a nocturnal to a diurnal rhythm, but failed to affect that in the SCN. Although lesion of the SCN ‘flattened’mPer gene oscillation in the striatum and liver, daily MAP injection caused both behavioural and mPer gene expression rhythms. Daily MAP injection at variable injection intervals (12–36 h) for 6 days, however, failed to produce mPer gene rhythm in the striatum. Daily repeated MAP signals may strengthen the oscillatory force of SCN‐independent circadian behavioural and molecular rhythms. The present results suggest that daily oscillation of mPer genes outside the SCN is closely associated with the regulation of SCN‐independent rhythms. Thus, the present experiment highlights strongly the important role of clock gene expression, in the brain, that underlies the circadian behavioural rhythm.
Lack of PSD‐95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway
Authors: Gardoni Fabrizio , Bellone Camilla , Viviani Barbara , Marinovich Marina , Meli Elena , Pellegrini‐Giampietro Domenico E. , Cattabeni Flaminio , Di Luca Monica
Published: March 2003

The PSD‐95 protein family organizes the glutamatergic postsynaptic density and it is involved in the regulation of the excitatory signal at central nervous system synapses. We show here that PSD‐95 deficiency by means of antisense oligonucleotides induces significant neuronal cell death within 24 h both in primary hippocampal cultures and in organotypic hippocampal slices. On the other hand, cultured cortical neurons are spared by PSD‐95 antisense toxicity until they reach a NR2A detectable protein level (24 days in vitro). The neurotoxic event is characterized by increased αCaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of αCaMKII association, we found increased GluR1 delivery to cell surface in cultured hippocampal neurons paralleled by AMPA‐dependent increase in [Na+]I levels. In addition, both CaMKII specific inhibitor KN‐93 and AMPA receptor antagonists CNQX and NBQX rescued neuronal survival to control values. On the other hand, both the NMDA channel blocker MK‐801 and Dantrolene, an inhibitor of calcium release from ryanodine‐sensitive endoplasmic reticulum stores, failed to have any effect on neuronal survival in PSD‐95 deficient neurons. Thus, our data provide clues that PSD‐95 reduced expression in neurons is responsible for neuronal vulnerability mediated by direct activation of αCaMKII transduction pathway in the postsynaptic compartment.
Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh‐2 and Lqh‐3
Authors:   Haijun Chen,, Lu SongQing , Leipold Enrico , Gordon Dalia , Hansel Alfred , Heinemann Stefan H.
Published: March 2003

The scorpion α‐toxins Lqh‐2 and Lqh‐3, isolated from the venom of the Israeli yellow scorpion Leiurus quinquestriatus hebraeus, were previously shown to be very potent in removing fast inactivation of rat skeletal muscle sodium channels (Chen et al., 2000). Here, we show that tetrodotoxin‐sensitive neuronal channels NaV1.2 and NaV1.7, which are mainly expressed in mammalian central and peripheral nervous systems, respectively, are differentially sensitive to these two toxins. rNaV1.2 and hNaV1.7 channels were studied with patch‐clamp methods upon expression in mammalian cells. While Lqh‐3 was about 100‐times more potent in removing inactivation in hNaV1.7 channels compared with rNaV1.2, Lqh‐2 was about 20‐times more active in the other direction. Site‐directed mutagenesis showed that the differences in the putative binding sites for these toxins, the S3‐4 linkers of domain 4, are of major importance for Lqh‐3, but not for Lqh‐2.
Persistent epileptiform activity induced by low Mg2+ in intact immature brain structures
Authors: Quilichini P. P. , Diabira D. , Chiron C. , Ben‐Ari Y. , Gozlan H.
Published: March 2003

We have determined the properties of seizures induced in vitro during the first postnatal days using intact rat cortico‐hippocampal formations (CHFs) and extracellular recordings. Two main patterns of activity were generated by nominally Mg2+‐free ACSF in hippocampal and cortical regions: ictal‐like events (ILEs) and late recurrent interictal discharges (LRDs). They were elicited at distinct developmental periods and displayed different pharmacological properties. ILEs were first observed in P1 CHFs 52 ± 7 min after application of low‐Mg2+ ACSF (frequency 1.5 ± 0.3 h‐1, duration 86 ± 3 s). There is a progressive age‐dependent maturation of ILEs characterized by a decrease in their onset and an increase in their frequency and duration. ILEs were abolished by d‐APV and Mg2+ ions. From P7, ILEs were followed by LRDs that appeared 89 ± 8 min after application of low‐Mg2+ ACSF (frequency ≈ 1 Hz, duration 0.66 s, amplitude 0.31 ± 0.03 mV). LRDs were no longer sensitive to d‐APV or Mg2+ ions and persisted for at least 24 h in low‐Mg2+ or in normal ACSF. ILEs and LRDs were synchronized in limbic and cortical regions with 10–40 ms latency between the onsets of seizures. Using a double chamber that enables independent superfusion of two interconnected CHFs, we report that ILEs and LRDs generated in one CHF propagated readily to the other one that was being kept in ACSF. Therefore, at a critical period of brain development, recurrent seizures induce a permanent form of hyperactivity in intact brain structures and this preparation provides a unique opportunity to study the consequences of seizures at early developmental stages.
Insulin‐induced hypoglycemia decreases single‐unit activity of serotonergic medullary raphe neurons in freely moving cats: relationship to sympathetic and motor output
Authors: Martín‐Cora Francisco J. , Fornal Casimir A. , Metzler Christine W. , Jacobs Barry L.
Published: March 2003

Serotonergic single‐unit activity during glucoregulatory challenges was studied in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) of freely moving cats. Systemic insulin administration (2–4 IU/kg, i.v.) suppressed neuronal activity by ≈ 40% in direct relationship to blood glucose levels and in inverse relationship to plasma catecholamine levels. NRO and NRP serotonergic neurons displayed a temporary recovery in unit activity in response to i.v. glucose administration (500 mg/kg), which temporarily reversed insulin‐induced hypoglycemia. The neuronal responses to insulin and subsequent glucose administration were also directly related to changes in integrated nuchal electromyographic activity. Serotonergic unit activity remained unchanged after glucose loading (500 mg/kg, i.v.), which produced a four‐fold increase in blood glucose. Thus, medullary serotonergic neurons appear to be sensitive to reductions, but not increases, in blood glucose. The observed inverse relationship between unit activity and plasma catecholamines does not support a postulated sympathoexcitatory role for these neurons. Instead, the parallel changes in single‐unit activity and integrated muscle activity support the hypothesis that the activity of medullary serotonergic neurons is linked to motor output. These neurons may modulate autonomic outflow, but only in relationship to their primary role in motor control. Finally, medullary serotonergic neurons may play a protective role in maintaining glucose homeostasis by disfacilitating the output of the somatomotor system, and hence diminishing muscle energy demands, when peripheral glucose availability is low.
Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism
Authors: Petit Jean‐Marie , Tobler Irene , Allaman Igor , Borbély Alexander A. , Magistretti Pierre J.
Published: March 2003

Replenishment of brain glycogen stores depleted during waking has been suggested to constitute one of the functions of sleep [Benington, J. H. & Heller H. C. (1995) Prog. Neurobiol., 45, 347]. We have tested the hypothesis that the level of expression of enzymes involved in glycogen metabolism could undergo variations throughout the sleep‐waking or rest‐activity cycle, and after 6 h of ‘gentle’ total sleep deprivation in mice. Specifically, we determined the variations in mRNAs coding for protein targeting to glycogen (PTG), glycogen synthase and glycogen phosphorylase, all considered as key regulators of glycogen metabolism. Glycogen synthase and glycogen phosphorylase mRNAs exhibited significant variations throughout the light‐dark cycle with a maximum at the middle of the light period and a minimum at the middle of the dark period. Following sleep deprivation, a two‐fold increase in PTG mRNA and a decrease of mRNAs encoding glycogen synthase and glycogen phosphorylase were observed. These transcriptional events have functional consequences as the activity of glycogen synthase was increased 2.5‐fold indicating a stimulating effect of sleep deprivation on glycogen synthesis. These results indicate that (i) expression of genes related to brain glycogen metabolism exhibit variations throughout the sleep‐waking or rest‐activity cycle and (ii) given the almost selective localization of glycogen to astrocytes, these cells might participate in the regulation of sleep.
Somatostatin receptor subtypes 2 and 4 affect seizure susceptibility and hippocampal excitatory neurotransmission in mice
Authors: Moneta D. , Richichi C. , Aliprandi M. , Dournaud P. , Dutar P. , Billard J. M. , Carlo A. S. , Viollet C. , Hannon J. P. , Fehlmann D. , Nunn C. , Hoyer D. , Epelbaum J. , Vezzani A.
Published: March 2003

We have investigated the role of somatostatin receptor subtypes sst2 and sst4 in limbic seizures and glutamate‐mediated neurotransmission in mouse hippocampus. As compared to wild‐type littermates, homozygous mice lacking sst2 receptors showed a 52% reduction in EEG ictal activity induced by intrahippocampal injection of 30 ng kainic acid (P < 0.05). The number of behavioural tonic–clonic seizures was reduced by 50% (P < 0.01) and the time to onset of seizures was doubled on average (P < 0.05). Seizure‐associated neurodegeneration was found in the injected hippocampus (CA1, CA3 and hilar interneurons) and sporadically in the ipsilateral latero‐dorsal thalamus. This occurred to a similar extent in wild‐type and sst2 knock‐out mice. Intrahippocampal injection of three selective sst2 receptor agonists in wild‐type mice (Octreotide, BIM 23120 and L‐779976, 1.5–6.0 nmol) did not affect kainate seizures while the same compounds significantly reduced seizures in rats. L‐803087 (5 nmol), a selective sst4 receptor agonist, doubled seizure activity in wild‐type mice on average. Interestingly, this effect was blocked by 3 nmol octreotide. It was determined, in both radioligand binding and cAMP accumulation, that octreotide had no direct agonist or antagonist action at mouse sst4 receptors expressed in CCl39 cells, up to micromolar concentrations. In hippocampal slices from wild‐type mice, octreotide (2 µm) did not modify AMPA‐mediated synaptic responses while facilitation occurred with L‐803087 (2 µm). Similarly to what was observed in seizures, the effect of L‐803087 was reduced by octreotide. In hippocampal slices from sst2 knock‐out mice, both octreotide and L‐803087 were ineffective on synaptic responses. Our findings show that, unlike in rats, sst2 receptors in mice do not mediate anticonvulsant effects. Moreover, stimulation of sst4 receptors in the hippocampus of wild‐type mice induced excitatory effects which appeared to depend on the presence of sst2 subtypes, suggesting these receptors are functionally coupled.
Speech processing activates visual cortex in congenitally blind humans
Authors: Röder Brigitte , Stock Oliver , Bien Siegfried , Neville Helen , Rösler Frank
Published: March 2003

Neurophysiological recordings and neuroimaging data in blind and deaf animals and humans suggest that perceptual functions may be organized differently after sensory deprivation. It has been argued that neural plasticity contributes to compensatory performance in blind humans, such as faster speech processing. The present study employed functional magnetic resonance imaging (fMRI) to map language‐related brain activity in congenitally blind adults. Participants listened to sentences, with either an easy or a more difficult syntactic structure, which were either semantically meaningful or meaningless. Results show that blind adults not only activate classical left‐hemispheric perisylvian language areas during speech comprehension, as did a group of sighted adults, but that they additionally display an activation in the homologueous right‐hemispheric structures and in extrastriate and striate cortex. Both the perisylvian and occipital activity varied as a function of syntactic difficulty and semantic content. The results demonstrate that the cerebral organization of complex cognitive systems such as the language system is significantly shaped by the input available.
The integrative role of the rat medullary subnucleus reticularis dorsalis in nociception
Authors: Monconduit L. , Desbois C. , Villanueva L.
Published: March 2003

Neurons within the medullary subnucleus reticularis dorsalis (SRD) of the rat convey selectively nociceptive information from all parts of the body. We have sought to define the neuronal networks that convey information from widespread noxious stimuli to the diffuse thalamocortical system and also modulate spinal outflow. The experiments, which were performed in rats, were designed to determine whether efferents from the SRD issue collaterals to the thalamus and spinal cord. Injections of the tracers fluorogold and tetramethylrhodamine‐labelled dextran were centred stereotaxically in two areas that receive dense projections from the SRD: the cervical spinal cord and the lateral ventromedial thalamus (VMl), respectively. In other experimental series, SRD neurons were characterized electrophysiologically and individually labelled in a Golgi‐like manner following juxtacellular iontophoresis of biotin–dextran. More than half reticulothalamic neurons within the SRD provided monosynaptic connections to the spinal cord. SRD neurons that responded to Aδ‐ or Aδ‐ and C‐fibre activation from any area of the body had axons that gave both ascending and descending collaterals. Because the SRD innervates several areas involved in motor processing and receives strong, direct influences from several cortical regions, it could provide a structural basis for the processing of nociceptive and motor activities.
Connexin29 expression, immunocytochemistry and freeze‐fracture replica immunogold labelling (FRIL) in sciatic nerve
Authors: Li Xinbo , Lynn B. D. , Olson C. , Meier C. , Davidson K. G. V. , Yasumura T. , Rash J. E. , Nagy J. I.
Published: March 2003

The recently discovered connexin29 (Cx29) was reported to be present in the central and peripheral nervous systems (CNS and PNS), and its mRNA was found in particular abundance in peripheral nerve. The expression and localization of Cx29 protein in sciatic nerve were investigated using an antibody against Cx29. The antibody recognized Cx29 in HeLa cells transfected with Cx29 cDNA, while nontransfected HeLa cells were devoid of Cx29. Immunoblotting of sciatic nerve homogenate revealed monomeric and possibly higher molecular weight forms of Cx29. These were distinguished from connexin32 (Cx32), which also is expressed in peripheral nerve. Double immunofluorescence labelling for Cx29 and Cx32 revealed only partial colocalization of the two connexins, with codistribution at intermittent, conical‐shaped striations along nerve fibers. By freeze‐fracture replica immunogold labelling (FRIL), Cx32 was found in gap junctions in the outermost layers of myelin, whereas Cx29‐immunogold labelling was found only in the innermost layer of myelin in close association with hexagonally arranged intramembrane particle (IMP) ‘rosettes’ and gap junction‐like clusters of IMPs. Although both Cx32 and Cx29 were detected in myelin of normal mice, only Cx29 was present in Schwann cell membranes in Cx32 knockout mice. The results confirm that Cx29 is a second connexin expressed in Schwann cells of sciatic nerve. In addition, Cx29 is present in distinctive IMP arrays in the inner most layer of myelin, adjacent to internodal axonal plasma membranes, where this connexin may have previously unrecognized functions.
5‐HT4 receptors exert a frequency‐related facilitatory control on dorsal raphé nucleus 5‐HT neuronal activity
Authors: Lucas Guillaume , Debonnel Guy
Published: March 2003

We investigated, using single‐unit recordings in chloral hydrate‐anaesthetized rats, the role of serotonin4 (5‐HT4) receptors in the control of dorsal raphé nucleus (DRN) 5‐HT neuron activity. About one‐half (36) of the 76 neurons recorded were affected by either the preferential 5‐HT4 agonist cisapride (500 and 1000 µg/kg, i.v.) or the selective 5‐HT4 antagonist, GR 125487 (200– 2000 µg/kg, i.v.). Responding neurons displayed a significantly higher mean basal firing rate (1.93 ± 0.1 Hz) than non‐responders (1.31 ± 0.1 Hz). The firing rate of responding 5‐HT neurons was enhanced dose‐dependently by cisapride (+47 and +94% at 500 and 1000 µg/kg, respectively), an effect abolished by GR 125487 (500 µg/kg) and reduced by the 5‐HT4 antagonist, SDZ 205557 (500 µg/kg, i.v). Conversely, GR 125487 induced a dose‐dependent inhibition of responders activity, which was almost completely suppressed at the dose of 2000 µg/kg. In a separate set of experiments, the selective 5‐HT4 agonist, prucalopride (500 µg/kg, i.v), increased the firing activity (+35%) of 5‐HT neurons displaying a high basal firing rate; subsequent injection of GR 125487 (500 µg/kg, i.v.) suppressed this effect. These results indicate that 5‐HT4 receptors exert both a tonic and a phasic, positive, frequency‐related control on DRN 5‐HT neuronal activity. The existence of such a control might open new avenues for therapeutic research in the antidepressant field.
Functional anatomy of chemical senses in the alert monkey revealed by positron emission tomography
Authors: Kobayashi Masayuki , Sasabe Tetsuya , Takeda Masaki , Kondo Yusuke , Yoshikubo Shin‐ichi , Imamura Kazuyuki , Onoe Hirotaka , Sawada Tohru , Watanabe Yasuyoshi
Published: March 2003

Functional imaging technique using positron emission tomography (PET) has made it possible to localize functional brain regions in the human brain by detecting changes in regional cerebral blood flow (rCBF). Performing PET studies in the monkey will aid in integrating monkey electrophysiological research with human PET studies. We examined changes in rCBF during olfactory or combined olfactory and gustatory (flavour) stimulation using PET in the alert rhesus monkey. Olfactory or flavour stimulation with acetic acid or apple increased rCBF in the prepyriform area, substantia innominata and amygdala. Besides these areas, flavour stimulation increased rCBF in the anterior insula and frontal operculum, orbitofrontal cortex, inferior frontal gyrus and cerebellum. Apple odour or flavour stimuli increased rCBF in the inferior occipital gyrus in addition to the above areas. These findings suggest that the increases of rCBF in response to neural activities in the primary olfactory and gustatory cortices are detectable by the use of PET. In addition, regions activated by apple stimuli suggest that higher brain function might be detected with PET in the alert monkey.
Kindling enhances kainate receptor‐mediated depression of GABAergic inhibition in rat granule cells
Authors: Behr Joachim , Gebhardt Christine , Heinemann Uwe , Mody Istvan
Published: March 2003

Several lines of evidence indicate a substantial contribution of kainate receptors to temporal lobe seizures. The activation of kainate receptors located on hippocampal inhibitory interneurons was shown to reduce GABA release. A reduced GABA release secondary to kainate receptor activation could contribute to an enhanced seizure susceptibility. As the dentate gyrus serves a pivotal gating function in the spread of limbic seizures, we tested the role of kainate receptors in the regulation of GABA release in the dentate gyrus of control and kindled animals. Application of glutamate (100 µm) in the presence of the NMDA receptor antagonist d‐APV and the AMPA receptor antagonist, SYM 2206 caused a slight depression of evoked monosynaptic inhibitory postsynaptic currents (IPSCs) in control, but a substantial decrease in kindled dentate granule cells. The observation that kainate receptor activation altered paired‐pulse depression and reduced the frequency of TTX‐insensitive miniature IPSCs without affecting their amplitude is consistent with a presynaptic action on the inhibitory terminal to reduce GABA release. In kindled preparations, neither glutamate (100 µm) nor kainate (10 µm) applied in a concentration known to depolarize hippocampal interneurons led to an increase of the TTX‐sensitive spontaneous IPSC frequency nor to changes of the postsynaptic membrane properties. Consistently, the inhibitory effect on evoked IPSCs was not affected by the presence of the GABAB receptor antagonist, CGP55845A, thus excluding a depression by an enhanced release of GABA acting on presynaptic GABAB receptors. The enhanced inhibition of GABA release following presynaptic kainate receptor activation favours a use‐dependent hyperexcitability in the epileptic dentate gyrus.
Selective lesions of basal forebrain cholinergic neurons produce anterograde and retrograde deficits in a social transmission of food preference task in rats
Authors: Vale‐Martínez Anna , Baxter Mark G. , Eichenbaum Howard
Published: March 2003

We examined the performance of Long‐Evans rats with 192 IgG‐saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB) or nucleus basalis magnocellularis/substantia innominata (NBM/SI), which removed cholinergic projections mainly to hippocampus or neocortex, respectively. We studied the effects of these lesions on anterograde and retrograde memory for a natural form of hippocampal‐dependent associative memory, the social transmission of food preference. In a study of anterograde memory, MS/VDB lesions did not affect the immediate, 24‐h or 3‐week retention of the task. In contrast, NBM/SI lesions severely impaired immediate and 24‐h retention. In a study of retrograde memory in which rats acquired the food preference 5 days or 1 day before surgery and they were tested 10–11 days after surgery, MS/VDB‐lesioned rats showed striking memory deficits for the preference acquired at a long delay (5 days) before surgery, although all lesioned rats exhibited poorer retention on both retest sessions than on their pretest performance. Subsequent testing of new anterograde learning in these rats revealed no disrupting effects of lesions on a standard two‐choice test. When rats were administered a three‐choice test, in which the target food was presented along with two more options, NBM/SI‐lesioned rats were somewhat impaired on a 24‐h retention test. These results provide evidence that NBM/SI and MS/VDB cholinergic neurons are differentially involved in a social memory task that uses olfactory cues, suggesting a role for these neurons in acquisition and consolidation/retrieval of nonspatial declarative memory.
Properties of place cell firing after damage to the visual cortex
Authors: Paz‐Villagràn Vietminh , Lenck‐Santini Pierre‐Pascal , Save Etienne , Poucet Bruno
Published: March 2003

Hippocampal place cells were recorded while rats with lesions of the striate visual cortex foraged for food pellets in a cylindrical arena. Compared to control rats, rats with striate damage had place cells whose firing was less well organized in space, according to a measurement of spatial coherence. More importantly, the spatial location of firing fields in rats with striate lesions was poorly controlled by three‐dimensional objects, unlike the fields of either normal sighted rats or early blind rats. These findings suggest a possible contribution of the striate visual cortex to the selection of cues used for anchoring place cell firing fields in space.
SHORT COMMUNICATION Learning‐induced reduction in post‐burst after‐hyperpolarization (AHP) is mediated by activation of PKC
Authors: Seroussi Yaron , Brosh Inbar , Barkai Edi
Published: March 2003

We studied the role of protein kinase C (PKC) and protein kinase A (PKA) in mediating learning‐related long lasting reduction of the post‐burst after‐hyperpolarization (AHP) in cortical pyramidal neurons. We have shown previously that pyramidal neurons in the rat piriform (olfactory) cortex from trained (TR) rats have reduced post‐burst AHP for 3 days after odour‐discrimination learning, and that this reduction is due to decreased conductance of calcium‐dependent potassium current. In the present study, we examined whether this long‐lasting reduction in AHP is mediated by second messenger systems. The broad‐spectrum kinase inhibitor, H7, increased the AHP in neurons from TR rats, but not in neurons from pseudo‐trained (pseudo‐TR) and naive rats. Consequently, the difference in AHP amplitude between neurons from TR and control animals was diminished. This effect was also obtained by application of the specific PKC inhibitor, GF‐109203x. The PKC activator, 1‐Oleoyl‐2‐acetyl‐sn‐glycerol (OAG), significantly reduced the AHP in neurons from naive and pseudo‐TR rats, but not in neurons from TR rats, so that the difference between the groups was abolished. The PKA‐specific inhibitor, H‐89, increased the AHP in neurons from all groups to a similar extent, and the difference in AHP amplitude between neurons from TR rats and neurons from controls was maintained. We suggest that while the post‐burst AHP in piriform cortex pyramidal neurons is modulated by both PKC and PKA, a PKC‐dependent process maintains the learning‐related reduction of the AHP in these cells.
Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice
Authors: Kopp Caroline , Albrecht Urs , Zheng Binhai , Tobler Irene
Published: March 2003

A limited set of genes, Clock, Bmal1, mPer1, mPer2, mCry1 and mCry2, has been shown to be essential for the generation of circadian rhythms in mammals. It has been recently suggested that circadian genes might be involved in sleep regulation. We investigated the role of mPer1 and mPer2 genes in the homeostatic regulation of sleep by comparing sleep of mice lacking mPER1 (mPer1 mutants) or a functional mPER2 (mPer2 mutants), and wild‐type controls (WT) after 6 h of sleep deprivation (SD). Our main result showed that after SD, all mice displayed the typical increase of slow‐wave activity (SWA; EEG power density between 0.75 and 4 Hz) in nonREM sleep, reflecting the homeostatic response to SD. This increase was more prominent over the frontal cortex as compared to the occipital cortex. The genotypes did not differ in the effect of SD on the occipital EEG, while the effect on the frontal EEG was initially diminished in both mPer mutants. Differences between the genotypes were seen in the 24‐h distribution of sleep, reflecting especially the phase advance of motor activity onset observed in mPer2 mutants. While the daily distribution of sleep was modulated by mPer1 and mPer2 genes, sleep homeostasis reflected by the SWA increase after 6‐h SD was preserved in the mPer mutants. The results provide further evidence for the independence of the circadian and the homeostatic components underlying sleep regulation.