bluuebunny/crossref_metadata_2025 huggingface dataset:
Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase‐2 in brain endothelial cells and also upregulate their receptors
Authors: Cao Chunyu , Matsumura Kiyoshi , Shirakawa Noriyuki , Maeda Mitsuyo , Jikihara Ikuyo , Kobayashi Shigeo , Watanabe Yasuyoshi
Published: March 2003

Peripheral immunological insults induce interleukin (IL)‐1β and IL‐6 in the brain. To elucidate the mechanism(s) of fever evoked by these brain‐derived cytokines, and possible interactions between them, we examined in rats: (i) whether cyclooxygenase‐2 is responsible for fever evoked by central injection of these cytokines; (ii) if so, where in the brain cyclooxygenase‐2 is induced; (iii) where the receptors for these cytokines are located; and (iv) how the expression of these receptors is influenced by the cytokines. Intracerebroventricular injection of these cytokines evoked fever that was suppressed by a cyclooxygenase‐2 inhibitor. Brain endothelium was the site of cyclooxygenase‐2 induction by these cytokines. IL‐1 receptor (IL‐1R) was constitutively expressed in brain endothelium, and its mRNA was further upregulated by either cytokine. IL‐6R mRNA was constitutively expressed in the cerebral cortex, and was newly induced in as yet unidentified cells in brain blood vessels by either cytokine. Messenger RNAs for cyclooxygenase‐2, IL‐1R, and IL‐6R were often observed in the same blood vessels. These results suggest that COX‐2 induced in brain endothelium is, at least in part, involved in the fever evoked by these cytokines, and that one possible interaction between these two cytokines is mutual upregulation of their receptors in the endothelium or perivascular cells, resulting in augmentation of their actions.
Ontogenetic development of the diencephalic MCH neurons: a hypothalamic ‘MCH area’ hypothesis
Authors: Brischoux F. , Fellmann D. , Risold P. Y.
Published: March 2003

The ontogeny of rat diencephalic melanin‐concentrating hormone (MCH) neurons has been analysed, using the bromodeoxyuridine method to determine the period of birth of these neurons, and using in situ hybridization and immunohistochemistry to study their chemical differentiation. The spatiotemporal pattern of MCH neuron generation is complex, although it is broadly lateromedial with a peak between embryonic days (E) 12 and E13. The first expression of the MCH gene has been detected on E13 in neurons in the presumptive lateral hypothalamic area. But the adult‐like pattern was observed from E18. Medial‐most MCH neurons express the peptide CART (cocaine‐amphetamine‐regulated transcript) from E18, and the receptor neurokinin 3 (NK3) from between postnatal day (P) 0 and P5. These results are discussed and compared with data from the literature to better understand the organization of the ‘MCH‐containing area’.
Glutamate receptor targeting in the postsynaptic spine involves mechanisms that are independent of myosin Va
Authors: Petralia Ronald S. , Wang Ya‐Xian , Sans Nathalie , Worley Paul F. , Hammer Iii John A. , Wenthold Robert J.
Published: March 2003

Targeting of glutamate receptors (GluRs) to synapses involves rapid movement of intracellular receptors. This occurs in forms of synaptic upregulation of receptors, such as long‐term potentiation. Thus, many GluRs are retained in a cytoplasmic pool in dendrites, and are transported to synapses for upregulation, presumably via motor proteins such as myosins travelling along cytoskeletal elements that extend up into the spine. In this ultrastructural immunogold study of the cerebellar cortex, we compared synapses between normal rats/mice and dilute lethal mutant mice. These mutant mice lack myosin Va, which has been implicated in protein trafficking at synapses. The postsynaptic spine in the cerebellum lacks the inositol trisphosphate receptor (IP3R) ‐laden reticular tubules that are found in normal mice and rats (Takagishi et al., Neurosci. Lett., 1996, 215, 169). Thus, we tested the hypothesis that myosin Va is necessary for transport of GluRs and associated proteins to spine synapses. We found that these spines retain a normal distribution of (i) GluRs (delta 1/2, GluR2/3 and mGluR1α), (ii) at least one associated MAGUK (membrane‐associated guanylate kinase) protein, (iii) Homer (which interacts with mGluR1α and IP3Rs), (iv) the actin cytoskeleton, (v) the reticulum‐associated protein BiP, and (vi) the motor‐associated protein, dynein light chain. Thus, while myosin Va may maintain the IP3R‐laden reticulum in the spine for proper calcium regulation, other mechanisms must be involved in the delivery of GluRs and associated proteins to synapses. Other possible mechanisms include diffusion along the extrasynaptic membrane and delivery via other motors running along the spine's actin cytoskeleton.
Radial migration in the cerebral cortex is enhanced by signals from thalamus
Authors: Edgar Julia M. , Price David J.
Published: March 2003

The six layered cerebral cortex derives from cells that divide in the ventricular zone and migrate to their final destination in the cortical plate (future cortex). In the mouse, cortical layer III and IV neurons undergo their final mitotic division at around E16, at which time thalamic axons are beginning to enter the cortex. We used bromodeoxyuridine‐birthdating of cells in cortical slice cultures to show that the thalamus enhances the migration out of the ventricular zone of future layer III/IV cells. When cortical slices were cultured alone, less than 35% of cells born in vitro on E16 were present in the pial half of the slice after 48 h in culture. In contrast, when cortical slices were cocultured with thalamus, 69% of these cells were found in the pial half of the slice. Explants of other developing tissues did not mimic the effect of the thalamus. The thalamus had no obvious effect on cortical radial glial cells, cortical cell viability or maintenance of cortical slice structure. We found that most precursors born at a similar age but in vivo, shortly before cortical slices were isolated, migrated to the pial half of the cultured slices in the absence of a cocultured thalamic explant. Thus, E16 cortical slices cultured without thalamus permit migration of cells born in vivo and therefore already exposed to the thalamus. Our results indicate that the thalamus provides factors to E16‐born cortical precursors that enhance their directed migration out of the ventricular zone to the cortical plate.
Sensory enrichment after peripheral nerve injury restores cortical, not thalamic, receptive field organization
Authors: Florence S. L. , Boydston L. A. , Hackett T. A. , Lachoff H. Taub , Strata F. , Niblock M. M.
Published: March 2003

Sensory perception can be severely degraded after peripheral injuries that disrupt the functional organization of the sensory maps in somatosensory cortex, even after nerve regeneration has occurred. Rehabilitation involving sensory retraining can improve perceptual function, presumably through plasticity mechanisms in the somatosensory processing network. However, virtually nothing is known about the effects of rehabilitation strategies on brain organization, or where the effects are mediated. In this study, five macaque monkeys received months of enriched sensory experience after median nerve cut and repair early in life. Subsequently, the sensory representation of the hand in primary somatosensory cortex was mapped using multiunit microelectrodes. Additionally, the primary somatosensory relay in the thalamus, the ventroposterior nucleus, was studied to determine whether the effects of the enrichment were initiated subcortically or cortically. Age‐matched controls included six monkeys with no sensory manipulation after median nerve cut and regeneration, and one monkey that had restricted sensory experience after the injury. The most substantial effect of the sensory environment was on receptive field sizes in cortical area 3b. Significantly greater proportions of cortical receptive fields in the enriched monkeys were small and well localized compared to the controls, which showed higher proportions of abnormally large or disorganized fields. The refinements in receptive field size and extent in somatosensory cortex likely provide better resolution in the sensory map and may explain the improved functional outcomes after rehabilitation in humans.
Electrophysiological characterization of laminar synaptic inputs to the olfactory tubercle of the rat studied in vitro: modulation of glutamatergic transmission by cholinergic agents is pathway‐specific
Authors: Owen G. S. , Halliwell J. V.
Published: March 2003

We have exploited the complementary arrangement of afferents in a coronal slice (300–400 µm) of the rat olfactory tubercle (OT) maintained in vitro to investigate transmission in two separate synaptic pathways. We recorded extracellular responses within the OT dense cell layer in slices and stimulated either the outermost layer to activate primary olfactory fibres or deeper to activate secondary input. Superficial stimulation produced a synaptic potential with superimposed population spike. This interpretation was based on blockade by calcium removal from the bathing medium and the use of the glutamate antagonist DNQX (10 µm); the spike was found to be selectively suppressed by tetrodotoxin applied near the cells. The spike, but not the synaptic wave, was depressed by 12 mm Ca2+ and enhanced by 1 mm Ba2+ in the bathing medium. Deep stimulation to activate association and intrinsic fibres elicited a nerve volley followed by a later response, also blocked by Ca2+ removal or 10 µm DNQX. It was unaffected by high Ca2+ or Ba2+, hence resulting from synaptic and not action current flow. Removal of Mg2+ from the bathing medium revealed an NMDA component of synaptic transmission at both loci that was selectively blocked by D‐AP‐5. The deep synaptic response, only, was depressed by carbachol IC50 7 µm or muscarine IC50 13 µm. This depression was also induced by AChE inhibitors eserine or tacrine and was antagonized by 1 µm atropine or 5–10 µm clozapine. These results characterize transmission in the OT and demonstrate a role for muscarinic modulation of deeper synapses in the OT that is influenced by psychotherapeutic drugs.
Modulation of dendrodendritic interactions and mitral cell excitability in the mouse accessory olfactory bulb by vaginocervical stimulation
Authors: Otsuka Tomoko , Ishii Keiji , Osako Yoji , Okutani Fumino , Taniguchi Mutsuo , Oka Tatsuzo , Kaba Hideto
Published: March 2003

When female mice are mated, they form a memory to the pheromonal signal of their male partner. The neural changes underlying this memory occur in the accessory olfactory bulb, depend upon vaginocervical stimulation at mating and involve changes at the reciprocal synapses between mitral and granule cells. However, the action of vaginocervical stimulation on the reciprocal interactions between mitral and granule cells remains to be elucidated. We have examined the effects of vaginocervical stimulation on paired‐pulse depression of amygdala‐evoked field potentials recorded in the external plexiform layer of the accessory olfactory bulb (AOB) and the single‐unit activity of mitral cells antidromically stimulated from the amygdala in urethane‐anaesthetized female mice. Artificial vaginocervical stimulation reduced paired‐pulse depression (considered to be due to feedback inhibition of the mitral cell dendrites from the granule cells via reciprocal dendrodendritic synapses) recorded in the AOB external plexiform layer. As would be expected from this result, vaginocervical stimulation also enhanced the spontaneous activity of a proportion of the mitral cells tested. These results suggest that vaginocervical stimulation reduces dendrodendritic feedback inhibition to mitral cells and enhances their activity.
Δ9‐tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect
Authors: Valverde Olga , Noble Florence , Beslot Françoise , Daugé Valérie , Fournié‐Zaluski Marie‐Claude , Roques Bernard P.
Published: March 2003

Recent studies have suggested that cannabinoids might initiate the consumption of other highly addictive substances, such as opiates. In this work, we show that acute administration of Δ9‐tetrahydrocannabinol in mice facilitates the antinociceptive and antidepressant‐like responses elicited by the endogenous enkephalins protected from their degradation by RB 101, a complete inhibitor of enkephalin catabolism. This emphasizes the existence of a physiological interaction between endogenous opioid and cannabinoid systems. Accordingly, Δ9‐tetrahydrocannabinol increased the release of Met‐enkephalin‐like material in the nucleus accumbens of awake and freely moving rats measured by microdialysis. In addition, this cannabinoid agonist displaced the in vivo[3H]diprenorphine binding to opioid receptors in total mouse brain. The repetitive pretreatment during 3 weeks of Δ9‐tetrahydrocannabinol in mice treated chronically with morphine significantly reduces the naloxone‐induced withdrawal syndrome. However, this repetitive administration of Δ9‐tetrahydrocannabinol did not modify or even decrease the rewarding responses produced by morphine in the place preference paradigm. Taken together, these behavioural and biochemical results demonstrate the existence of a direct link between endogenous opioid and cannabinoid systems. However, chronic use of high doses of cannabinoids does not seem to potentiate the psychic dependence to opioids.
Glutamate transporter expression in astrocytes of the rat dentate gyrus following lesion of the entorhinal cortex
Authors: Hein C. , Horváth E. , Kugler P.
Published: March 2003

The glutamate transporters GLT‐1 and GLAST localized in astrocytes are essential in limiting transmitter signalling and restricting harmful receptor overstimulation. To show changes in the expression of both transporters following lesion of the entorhinal cortex (and degeneration of the glutamatergic tractus perforans), quantitative microscopic in situ hybridization (ISH) using alkaline‐phosphatase‐labelled oligonucleotide probes was applied to the outer molecular layer of the hippocampal dentate gyrus of rats (termination field of the tractus perforans). Four groups of rats were studied: sham‐operated controls, and animals 3, 14 and 60 days following unilateral electrolytic lesion of the entorhinal cortex. The postlesional shrinkage of the terminal field of the perforant path, ipsilateral to the lesion side, was determined and considered in the evaluation of quantitative ISH data. Statistical analysis revealed that ipsilateral to the lesion side there was a significant decrease of the GLT‐1 mRNA at every postlesional time‐point and of the GLAST mRNA at 14 and 60 days postlesion. The maximal decrease was ≈ 45% for GLT‐1 and ≈ 35% for GLAST. In the terminal field of the perforant path contralateral to the lesion side, no significant changes of ISH labelling were measured. The results were complemented by immunocytochemical data achieved using antibodies against synthetic GLT‐1 and GLAST peptides. In accordance with ISH results, there was an obvious decrease of GLT‐1 and GLAST immunostaining in the terminal field of the perforant path ipsilateral to the lesion side. From these data we conclude that, following a lesioning of the entorhinal cortex, the loss of glutamatergic synapses in the terminal field of the perforant path resulted in a strong downregulation of glutamate transporters in astrocytes. The decrease of synaptically released glutamate or of other neuronal factors could be involved in this downregulation.
Neurotoxicity of channel mutations in heterologously expressed α7‐nicotinic acetylcholine receptors
Authors: Lukas Ronald J. , Lucero Linda , Buisson Bruno , Galzi Jean‐Luc , Puchacz Elzbieta , Fryer John D. , Changeux Jean‐Pierre , Bertrand Daniel
Published: March 2003

Nicotinic acetylcholine receptors (nAChR) composed of chick α7 subunits mutated to threonine at amino acid valine‐251 in the putative channel‐lining M2 domain were expressed heterologously in several neuron‐like and non‐neuronal mammalian cell lines. Expression of mutant α7‐nAChR is toxic to neuron‐like cells of the human neuroblastoma cell lines SH‐SY5Y and IMR‐32, but not to several other cell types. Growth in the presence of the α7‐nAChR antagonist methyllycaconitine (MLA) protects against neurotoxicity, as does gradual downregulation of functional, mutant α7‐nAChR in surviving transfected SH‐SY5Y cells. Relative to wild‐type α7‐nAChR, functional α7‐nAChR mutants show a higher affinity for agonists, slower rates of desensitization, and sensitivity to dihydro‐β‐erythroidine (DHβE) as an agonist, but they retain sensitivity to MLA as a competitive antagonist. These findings demonstrate that expression of hyperfunctional, mutant forms of Ca2+‐permeable α7‐nAChR is toxic to neuron‐like cells.
Opposing effects of behavioural activity and light on neurons of the suprachiasmatic nucleus
Authors: Schaap Jeroen , Meijer Johanna H.
Published: March 2003

The mammalian circadian pacemaker is located in the suprachiasmatic nuclei. It can be shifted in phase by photic cues and by the behavioural activity of the animal. When presented together, light and behavioural activity attenuate each others' phase‐shifting effect. Still unclear is how behavioural activity affects the suprachiasmatic nuclei and how it interacts with photic information. Previously, we reported the occurrence of behaviourally induced suppressions of neuronal activity. The present study investigates the characteristics of these suppressions as a function of circadian time and, additionally, in the presence of photic cues. We performed long‐term multiunit activity recordings of neurons in freely moving rats and found that these suppressions of neuronal firing in the suprachiasmatic nucleus occurred at every phase of the circadian cycle. The magnitude of the suppressions showed a circadian variation, with larger suppressions during subjective day. When a light pulse was applied during a suppression, light and activity appeared to oppose each others' effects within the recorded population of neurons. The resulting discharge level appeared to be the sum of both responses. The opposing effects of light and activity were also found in single unit recordings, indicating that photic and behavioural stimuli interact at the level of a single neuron.
Lesions of the pedunculopontine tegmental nucleus reduce paradoxical sleep (PS) propensity: evidence from a short‐term PS deprivation study in rats
Authors: Deurveilher Samuel , Hennevin Elizabeth
Published: March 2003

Cholinergic neurons in the mesopontine tegmentum are thought to play a critical role in the generation of paradoxical sleep (PS). However, no study has yet examined whether lesions of these neurons cause deficits of PS in the rat. We describe here the effects of lesions of the pedunculopontine tegmental nucleus (PPT) on spontaneous PS and on PS propensity, expressed during and after a short period of PS deprivation. Lesions were induced by bilateral injections of ibotenate. PS deprivation was performed manually by gently waking rats each time they showed polygraphic signs of PS. Two weeks after lesions, an 8‐h baseline recording was performed; the following day, rats were PS deprived for 6 h and polygraphic recordings were then continued for 2 h, to examine recovery sleep. The same protocol was repeated 1 week later. Compared with controls and with rats with limited PPT lesions, rats bearing > 60% NADPH‐diaphorase‐positive cell loss within the PPT showed unaffected PS under baseline conditions. However, they made fewer attempts to enter PS during deprivation and they exhibited an attenuated rebound increase in PS time after deprivation. The number of PS attempts and the magnitude of PS rebound were negatively correlated with the percent loss of diaphorase‐positive neurons within the PPT. Thus, PS propensity that accumulated as a result of PS deprivation was reduced after extensive PPT lesions. In summary, although spontaneous PS was found to be unaltered, the PS deprivation procedure used in this study demonstrated the dysfunctioning of PS caused by PPT lesions.
Protective effect of harmaline and harmalol against dopamine‐ and 6‐hydroxydopamine‐induced oxidative damage of brain mitochondria and synaptosomes, and viability loss of PC12 cells
Authors: Kim Dong Hyun , Jang Yoon Young , Han Eun Sook , Lee Chung Soo
Published: March 2003

The present study elucidated the protective effect of β‐carbolines (harmaline, harmalol and harmine) against oxidative damage of brain mitochondria, synaptosomes and PC12 cells induced by either dopamine or 6‐hydroxydopamine. Harmaline, harmalol and antioxidant enzymes (superoxide dismutase/SOD and catalase) decreased the alteration of mitochondrial swelling and membrane potential induced by 200 µm dopamine or 100 µm 6‐hydroxydopamine. Deprenyl attenuated the dopamine‐induced mitochondrial dysfunction but did not reduce the effect of 6‐hydroxydopamine. While β‐carbolines inhibited the electron flow in mitochondria, they did not enhance the depressant effect of catecholamines. β‐Carbolines and antioxidant enzymes reversed the depression of synaptosomal Ca2+ uptake induced by 10 µm catecholamines. The compounds inhibited the catecholamine‐induced thioredoxin reductase inhibition, thiol oxidation and carbonyl formation in mitochondria and synaptosomes. β‐Carbolines decreased the reactive species‐induced deoxyribose degradation. Harmaline and harmalol reduced the catecholamine‐induced loss of the transmembrane potential and of cell viability in PC12 cells.β‐Carbolines alone did not show a significant cytotoxic effect on PC12 cells. The results suggest that β‐carbolines may attenuate the dopamine‐ or 6‐hydroxydopamine‐induced alteration of brain mitochondrial and synaptosomal functions, and viability loss in PC12 cells, by a scavenging action on reactive oxygen species and inhibition of thiol oxidation.
Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease
Authors: Sarna Justyna , Miranda Silvia R. P. , Schuchman Edward H. , Hawkes Richard
Published: March 2003

Niemann Pick disease is a family of autosomal recessive disorders characterized by cholesterol accumulation. The most common type is Niemann Pick type A/B (NPA/B), resulting from deficient acid sphingomyelinase activity, which leads to sphingomyelin and cholesterol accumulation. The neuropathology of NPA/B includes widespread neuronal degeneration. An acid sphingomyelinase knockout mouse model of NPA/B (ASMKO) has been developed by the targeted deletion of the acid sphingomyelinase gene. When cerebellar morphology was examined in the ASMKO mouse at postnatal day 60 (P60), a dramatic pattern of longitudinal stripes was revealed in which roughly half the Purkinje cells had died, leaving a highly stereotyped, bilaterally symmetrical array of stripes. Antizebrin II immunocytochemistry revealed that the absent Purkinje cells corresponded exactly to the zebrin II‐negative subset, leaving the zebrin II‐positive subset apparently intact. By P120, some of the zebrin II‐positive Purkinje cells had also been eliminated from the posterior vermis and hemispheres. By P180, all Purkinje cells had been lost from the anterior lobe. Finally at P240, almost all Purkinje cells had disappeared to leave a stereotyped distribution in lobules VI, IX–X and the flocculus and paraflocculus. The temporal pattern of Purkinje cell death demonstrates differential susceptibility of morphologically identical cells that appear to be linked to their molecular phenotypes.
Identification of a cis‐acting dendritic targeting element in the mRNA encoding the alpha subunit of Ca2+/calmodulin‐dependent protein kinase II
Authors: Blichenberg Arne , Rehbein Monika , Müller Reinhold , Garner Craig C. , Richter Dietmar , Kindler Stefan
Published: March 2003

In mammalian neurons a selected group of mRNAs, including the transcript encoding the alpha subunit of Ca2+/calmodulin‐dependent protein kinase II, is found in dendrites. The molecular mechanisms underlying extrasomatic RNA trafficking are not well described. It is thought that dendritic transcripts contain cis‐acting elements that direct their selective subcellular sorting. Here we report the identification of an extrasomatic targeting element in the 3′ untranslated region of the mRNA encoding the alpha subunit of Ca2+/calmodulin‐dependent protein kinase II. In primary hippocampal neurons, this 1200‐nucleotide‐spanning, cis‐acting element is sufficient to mediate dendritic localization of chimeric reporter transcripts. The trafficking signal does not share any striking sequence similarity with a previously characterized dendritic targeting element in transcripts encoding the microtubule‐associated protein 2. In dendrites of transfected primary neurons, recombinant RNAs form granules with an average diameter of 0.45 µm that may represent preferential RNA docking sites or multimolecular transport units. These findings imply that extrasomatic sorting of individual dendritic mRNAs involves at least partially distinct molecular mechanisms, as well as large trafficking complexes.
The Cav2.1/α1A (P/Q‐type) voltage‐dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells
Authors: Stephens Gary J. , Morris Neil P. , Fyffe Robert E.W. , Robertson Brian
Published: March 2003

The effects of voltage‐dependent calcium channel (VDCC) antagonists on spontaneous inhibitory postsynaptic currents (sIPSCs) in mouse Purkinje cells were examined using in vitro cerebellar slices. The inorganic ion Cd2+ reduced sIPSC amplitude and frequency. No additional block was seen with the Na+ channel antagonist tetrodotoxin (TTX) suggesting that all action potential‐evoked inhibitory GABA release was mediated by high‐voltage‐activated VDCCs. No evidence was found for involvement of Cav1/α1C and α1D (L‐type), Cav2.2/α1B (N‐type) or Cav2.3/α1E (R‐type) high‐voltage‐activated VDCCs or low‐voltage‐activated Cav3/α1G, α1H and α1I (T‐type) VDCCs in mediating presynaptic GABA release. Blockade of sIPSCs by 200 nmω‐agatoxin IVA implicated the Cav2.1/α1A (P/Q‐type) subtype of high‐voltage‐activated VDCCs in mediating inhibitory transmission. Inhibition by ω‐agatoxin IVA was similar to that seen with Cd2+ and TTX. Selective antibodies directed against the Cav2.1 subunit revealed staining in regions closely opposed to Purkinje cell somata. Cav2.1 staining was colocalized with staining for antibodies against glutamic acid decarboxylase and corresponded well with the pericellular network formed by GABAergic basket cell interneurons. Antibody labelling of Cav2.3 revealed a region‐specific expression. In the cerebellar cortex anterior lobe, Cav2.3 staining was predominantly somatodendritic; whilst in the posterior lobe, perisomatic staining was seen primarily. However, electrophysiological data was not consistent with a role for the Cav2.3 subunit in mediating presynaptic GABA release. No consistent staining was seen for other Cav (α1) subunits. Electrophysiological and immunostaining data support a predominant role for Cav2.1 subunits in mediating action potential‐evoked inhibitory GABA release onto mouse Purkinje cells.
Efferent axons in the avian auditory nerve
Authors: Köppl Christine
Published: March 2003

The sensory hair cells of the inner ear receive both afferent and efferent innervation. The efferent supply to the auditory organ has evolved in birds and mammals into a separate complex system, with several types of neurons of largely unknown function. In this study, the efferent axons in four different species of birds (chicken, starling, barn owl and emu) were examined anatomically. Total numbers of efferents supplying the cochlear duct (auditory basilar papilla and the vestibular lagenar macula) were determined; separate estimates of the efferents to the lagenar macula only were also derived and subtracted. The numbers for auditory efferents thus varied between 120 (chicken) and 1068 (barn owl). Considering the much larger numbers of hair cells in the basilar papilla, each efferent is predicted to branch extensively. However, pronounced species‐specific differences as well as regional differences along the tonotopic gradient of the basilar papilla were documented. Myelinated and unmyelinated axons were found, with mean diameters of about 1 µm and about 0.5 µm, respectively. This suggests two basic populations of efferents, however, they did not appear to be distinguished sharply. Evidence is presented that some efferents lose their myelination at the transition from central oligodendrocyte to peripheral Schwann cell myelin. Finally, a comparison of the four bird species evaluated suggests that the efferent population with smaller, unmyelinated axons is the phylogenetically more primitive one. A new population probably arose in parallel with the evolution and differentiation of the specialized hair‐cell type it innervates, the short hair cell.
Daily variation and appetitive conditioning‐induced plasticity of auditory cortex receptive fields
Authors: Kisley Michael A. , Gerstein George L.
Published: March 2003

Long‐term modification of cortical receptive field maps follows learning of sensory discriminations and conditioned associations. In the process of determining whether appetitive – as opposed to aversive – conditioning is effective in causing such plastic changes, it was discovered that multineuron receptive fields, when measured in rats under ketamine‐sedation, vary substantially over the course of a week, even in the absence of classical conditioning and electrode movement. Specifically, a simple correlation analysis showed that iso‐intensity frequency response curves of multiunit clusters and local field potentials recorded from auditory cortex are nonstationary over 7 days. Nevertheless, significant plastic changes in receptive fields, due to conditioned pairing of a pure tone and electrical stimulation of brain reward centres, are detectable above and beyond these spontaneous daily variations. This finding is based on a novel statistical plasticity criterion which compares receptive fields recorded for three days before and three days after conditioning. Based on a more traditional criterion (i.e. one day before and after conditioning), the prevalence of learning‐induced changes caused by appetitive conditioning appears to be comparable to that described in previous studies involving aversive conditioning.
A single administration of interleukin‐1 or amphetamine induces long‐lasting increases in evoked noradrenaline release in the hypothalamus and sensitization of ACTH and corticosterone responses in rats
Authors: Schmidt E. D. , Schoffelmeer A. N. M. , De Vries T. J. , Wardeh G. , Dogterom G. , Bol J. G. J. M. , Binnekade R. , Tilders F. J. H.
Published: March 2003

Single administration of the cytokine interleukin‐1β (IL‐1) or the psychostimulant amphetamine causes long‐term sensitization of the hypothalamus pituitary adrenal (HPA) axis, i.e. enhanced adrenocorticotropine hormone (ACTH) and corticosterone responses weeks later. HPA responses to these stimuli involve activation of hypothalamic corticotropin‐releasing hormone (CRH) neurons by noradrenergic projections to the paraventricular nucleus (PVN). In search of the underlying mechanisms, we studied the temporal pattern of HPA sensitization in relation to (1) the reactivity of noradrenergic projections to the PVN and (2) altered secretagogue production in hypothalamic CRH neurons. Single exposure to IL‐1 or amphetamine induced cross‐sensitization of ACTH and corticosterone responses 11 and 22 days later, but not after 42 days. Amphetamine‐induced HPA sensitization was not accompanied by increased costorage of arginine vasopressin (AVP) in CRH terminals, as found previously after IL‐1 pretreatment. The reactivity of noradrenergic terminals was assessed by measuring the electrically evoked release of [3H]‐noradrenaline from superfused PVN slices. Single administration of amphetamine and IL‐1 induced a long‐lasting (up to 22 days) increase (up to 165%) of evoked noradrenaline release. This indicates that single exposure to psychostimulants or to cytokines can induce a long‐lasting increase in stimulus–secretion coupling in brainstem noradrenergic neurons that innervate the PVN. This common, long‐lasting functional change may underlie, at least in part, IL‐1‐ and amphetamine‐induced HPA cross‐sensitization. In addition, increased AVP signalling by hypothalamic CRH neurons appears to play a role in IL‐1‐induced, but not in amphetamine‐induced, HPA sensitization.
Deficient long‐term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C β4 mutant mice
Authors: Miyata Mariko , Kim Hyun‐Taek , Hashimoto Kouichi , Lee Tae‐Kwan , Cho Sun‐Young , Jiang Huiping , Wu Yanping , Jun Kisun , Wu Dianqing , Kano Masanobu , Shin Hee‐Sup
Published: March 2003

Long‐term depression (LTD) at parallel fibre–Purkinje cell synapse of the cerebellum is thought to be a cellular substrate for motor learning. LTD requires activation of metabotropic glutamate receptor subtype 1 (mGluR1) and its downstream signalling pathways, which invariably involves phospholipase Cβs (PLCβs). PLCβs consist of four isoforms (PLCβ1–4) among which PLCβ4 is the major isoform in most Purkinje cells in the rostral cerebellum (lobule 1 to the rostral half of lobule 6). We studied mutant mice deficient in PLCβ4, and found that LTD was deficient in the rostral but not in the caudal cerebellum of the mutant. Basic properties of parallel fibre–Purkinje cell synapses and voltage‐gated Ca2+ channel currents appeared normal. The mGluR1‐mediated Ca2+ release induced by repetitive parallel fibre stimulation was absent in the rostral cerebellum of the mutant, suggesting that their LTD lesion was due to the defect in the mGluR1‐mediated signalling in Purkinje cells. Importantly, the eyeblink conditioning, a simple form of discrete motor learning, was severely impaired in PLCβ4 mutant mice. Wild‐type mice developed the conditioned eyeblink response, when pairs of the conditioned stimulus (tone) and the unconditioned stimulus (periorbital shock) were repeatedly applied. In contrast, PLCβ4 mutant mice could not learn the association between the conditioned and unconditioned stimuli, although their behavioural responses to the tone or to the periorbital shock appeared normal. These results strongly suggest that PLCβ4 is essential for LTD in the rostral cerebellum, which may be required for the acuisition of the conditioned eyeblink response.
Differentiation‐dependent sensitivity to cell death induced in the developing retina by inhibitors of the ubiquitin‐proteasome proteolytic pathway
Authors: Neves D. D. C. , Rehen S. K. , Linden R.
Published: March 2003

The effects of inhibitors of proteasome function were studied in the retina of developing rats. Explants from the retina of neonatal rats at postnatal day (P) 3 or P6 were incubated with various combinations of the proteasome inhibitor carbobenzoxyl‐leucinyl‐leucinyl‐leucinal (MG132), the protein synthesis inhibitor anisomycin, or the adenylyl cyclase activator forskolin. MG132 induced cell death in a subset of cells within the neuroblastic (proliferative) layer of the retinal tissue. The cells sensitive to degeneration induced by either MG132 or anisomycin, were birthdated by bromodeoxyuridine injections. This showed that the MG132‐sensitive population includes both proliferating cells most likely in their last round of cell division, and postmitotic undifferentiated cells, at a slightly earlier stage than the population, sensitive to anisomycin‐induced cell death. The results show that sensitivity to cell death induced by proteasome inhibitors defines a window of development in the transition from the cell cycle to the differentiated state in retinal cells.
Activation of glycogen synthase kinase 3 beta (GSK‐3β) by platelet activating factor mediates migration and cell death in cerebellar granule neurons
Authors: Tong Ning , Sanchez Joseph F. , Maggirwar Sanjay B. , Ramirez Servio H. , Guo Huang , Dewhurst Stephen , Gelbard Harris A.
Published: March 2003

Children with vertically acquired HIV‐1 can present with a rapidly progressive encephalopathy and neuronal apoptosis in the first 12–18 months of life. Furthermore, abnormal prenatal platelet activating factor (PAF) signalling may result in lissencephaly, a disorder of neuronal migration. PAF, produced from human immunodeficiency virus type 1 (HIV‐1) ‐infected brain‐resident macrophages, induces neuronal apoptosis in cultured cerebellar granule neurons (CGNs) in part by activating glycogen synthase kinase 3 beta (GSK‐3β). However, PAF can also inhibit migration of CGNs that are dispersed and allowed to reaggregate. Therefore, we investigated the biological effects following activation of GSK‐3β by PAF, and whether these effects were dependent on the culture conditions of the CGNs. We show here that activation of neuronal GSK‐3β by PAF is receptor‐specific, with similar kinetics of activation in both monolayer cultures of CGNs that have ceased to migrate and reaggregate cultures of CGNs that are actively migrating. However, PAF receptor activation in reaggregated CGNs inhibits neuronal migration and induces approximately half the level of neuronal apoptosis compared with PAF‐treated CGN cultures that have ceased to migrate. PAF‐mediated inhibition of neuronal migration in reaggregated CGNs or induction of apoptosis in CGNs that have ceased to migrate can be reversed by either PAF receptor antagonists, or the GSK‐3β inhibitors lithium or valproic acid, in a dose‐dependent manner. Abnormal PAF signalling that results in GSK‐3β overactivation may represent a common mechanism for pathological defects in neuronal migration in the prenatal period and neuronal apoptosis in the postnatal period.
Purely temporal figure–ground segregation
Authors: Kandil Farid I. , Fahle Manfred
Published: March 2003

Visual figure–ground segregation is achieved by exploiting differences in features such as luminance, colour, motion or presentation time between a figure and its surround. Here we determine the shortest delay times required for figure–ground segregation based on purely temporal features. Previous studies usually employed stimulus onset asynchronies between figure‐ and ground‐containing possible artefacts based on apparent motion cues or on luminance differences. Our stimuli systematically avoid these artefacts by constantly showing 20 × 20 ‘colons’ that flip by 90° around their midpoints at constant time intervals. Colons constituting the background flip in‐phase whereas those constituting the target flip with a phase delay. We tested the impact of frequency modulation and phase reduction on target detection. Younger subjects performed well above chance even at temporal delays as short as 13 ms, whilst older subjects required up to three times longer delays in some conditions. Figure–ground segregation can rely on purely temporal delays down to around 10 ms even in the absence of luminance and motion artefacts, indicating a temporal precision of cortical information processing almost an order of magnitude lower than the one required for some models of feature binding in the visual cortex [e.g. Singer, W. (1999), Curr. Opin. Neurobiol., 9, 189–194]. Hence, in our experiment, observers are unable to use temporal stimulus features with the precision required for these models.
Amphetamine and cocaine induce different patterns of c‐fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context
Authors: Uslaner Jason , Badiani Aldo , Norton Camille S. , Day Heidi E. W. , Watson Stanley J. , Akil Huda , Robinson Terry E.
Published: March 2003

In the dorsal striatum, there are two major populations of medium spiny projection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so‐called ‘direct pathway’. A second population is positive for enkephalin mRNA (ENK+), and these cells influence the substantia nigra indirectly, via the globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as amphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cells. However, this apparent selectivity appears to be a function of environmental context. We found that when given in the animal's home cage, amphetamine and cocaine increased expression of the IEG, c‐fos, almost exclusively in DYN+ cells. However, when given in a novel environment, amphetamine and cocaine increased c‐fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphetamine and cocaine increased c‐fos mRNA expression in the subthalamic nucleus when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determined by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimulant drug‐induced neuroplasticity.
Dopaminergic retinal cell differentiation in culture: modulation by forskolin and dopamine
Authors: Guimarães Marília Zaluar P. , Hokoç Jan Nora , Duvoisin Robert , Reis Ricardo A. M. , De Mello Fernando Garcia
Published: March 2003

We examined the effects of dopamine and cAMP on the differentiation of dopaminergic retinal cells in the chick retina, using an in vitro system and tyrosine hydroxylase immunocytochemistry. Tyrosine hydroxylase‐positive cells were detected in cultures prepared from embryonic day 10 retinas. These increased in number as a function of time in vitro and by treatment for 4 days with forskolin. Besides causing a 3.4‐fold increase in the tyrosine hydroxylase‐positive population, forskolin also caused these cells to developed morphogenetic features of more mature cells. As opposed to forskolin, cultures treated with dopamine exhibited a 55% reduction of the tyrosine hydroxylase‐positive cell population, as compared to untreated cultures. Quinpirole was able to mimic the dopamine effect. This dopamine effect could only be blocked by clozapine, whereas raclopride and eticlopride were ineffective. Our results suggest the existence of a narrow window during development when undifferentiated dopaminergic cells are capable of being influenced by specific signals, possibly via cAMP production. The data also indicate that dopamine may act as a regulatory factor limiting the tyrosine hydroxylase‐positive population in the retina.
Post‐weaning social isolation of rats leads to an abnormal gait
Authors: Roberts L. , Clarke K. A. , Greene J. R. T.
Published: March 2003

The purpose of this study was to further characterize the phenotype of rats that have experienced prolonged postweaning social isolation, a paradigm that produces changes relevant to neuropsychiatric disorders. At weaning, male Wistar rats from three litters were housed socially (n = 12) or in isolation (n = 13) for 10 weeks. Isolated rats could see, hear and smell other rats. A sophisticated analysis of gait revealed that the stride duration was increased in isolates (12%, P = 0.0024) as a result of increased stance duration (18%, P = 0.0005), but there was no difference in vertical reaction force or velocity. Adrenal glands were heavier in isolates (19%, P = 0.0047). There was no difference in cross‐sectional area of the brain or lateral ventricles anywhere along the anterior–posterior axis. All experiments and analysis were performed blind to housing condition. This is the first study to demonstrate that socially isolated rats have an abnormal gait. Further analysis, including pharmacological manipulation, is needed in order to understand the nature of the abnormality.
Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour
Authors: Hall Jeremy , Parkinson John A. , Connor Thomas M. , Dickinson Anthony , Everitt Barry J.
Published: March 2003

Pavlovian conditioned cues exert a powerful influence on instrumental actions directed towards a common reward, this is known as Pavlovian‐to‐instrumental transfer (PIT). The nucleus accumbens (NAcc) has been hypothesized to function as an interface between limbic cortical structures required for associative conditioning, like the amygdala, and response mechanisms through which instrumental behaviour can be selected and performed. Here we have used selective excitotoxic lesions to investigate the involvement of subnuclei of the amygdala as well as the core and shell regions of the nucleus accumbens on PIT in rats. Within the amygdala, selective lesions of the central nucleus (CeN), but not of the basolateral nucleus (BLA), abolished the PIT effect. In addition, selective lesions of the NAcc core, but not the NAcc shell, also abolished PIT. None of the lesions impaired the acquisition of Pavlovian food cup approaches or instrumental responding itself. These data demonstrate that the CeN and NAcc core are central components of the neural system mediating the impact of Pavlovian cues on instrumental responding. We suggest that this effect may depend upon the regulation of the dopaminergic innervation of the NAcc core by projections from the CeN to the ventral tegmental area.
DNA elements of the type 1 adenylyl cyclase gene locus enhance reporter gene expression in neurons and pinealocytes
Authors: Chan Guy C.‐K. , Lernmark Ulrika , Xia Zhengui , Storm Daniel R.
Published: March 2003

The Ca2+‐stimulated type 1 adenylyl cyclase (AC1) contributes to several forms of synaptic plasticity and is the only known neurospecific adenylyl cyclase. Furthermore, the protein and mRNA levels of AC1 undergo a circadian oscillation in the pineal gland, and AC1 may play a pivotal role in regulating nocturnal melatonin synthesis. To better understand the expression of AC1, we isolated mouse genomic DNA clones of AC1. The transcription and translation start regions of mouse AC1 share extensive homologies with the bovine counterpart. The upstream proximal region has potential binding sites for transcription factors, including the steroid receptor family, the E‐box factors, and Sp1. A 280‐bp fragment that contains the transcription start site directed reporter gene expression in cultured cortical neurons and pinealocytes functioning as a basal neuro‐ and pineal‐directed promoter. Interestingly, pinealocyte expression of the reporter gene was inhibited by increases in cAMP. This cAMP sensitivity may explain why AC1 mRNA in the pineal is low at night when cAMP is elevated and high during the day when cAMP signals drop. An adjacent 330‐bp fragment interacted specifically with nuclear factor(s) that we designate binary E‐box factor (BEF). Methylation interference and DNase I footprinting identified the BEF‐binding site sequence as 5′‐CCAAGGTCACGTGGC‐3′. When linked to the basal tissue‐directed promoter, this 15‐bp sequence further enhanced reporter expression in neurons and pinealocytes. We propose that this 15‐bp sequence may contribute to increased expression of AC1 in neurons and pinealocytes relative to other cells.