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1.	Bengzon, J, et al. (author) Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling 1993 In: Neuroscience. - 0306-4522. ; 53:2, s. 433-446 Journal article (peer-reviewed)abstract Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.
2.	Cardell, M., et al. (author) High resolution immunogold analysis reveals distinct subcellular compartmentation of protein kinase Cγ and δ in rat Purkinje cells 1997 In: Neuroscience. - 0306-4522. ; 82:3, s. 709-725 Journal article (peer-reviewed)abstract High resolution immunogold cytochemistry was used to investigate the subcellular distribution of protein kinase Cγ and δ in Purkinje cells of the rat cerebellum. Postembedding incubation with an antibody raised to a peptide sequence near the C-terminus of protein kinase Cγ resulted in strong labelling along the dendrosomatic plasma membrane. A quantitative analysis indicated that this labelling reflected the existence of two pools of protein kinase Cγ; one membrane associated pool and one cytoplasmic pool located within 50 nm of the plasma membrane. The labelling along the plasma membrane showed a pronounced and abrupt increase when moving from the cell body into the axon initial segment. Gold particles signalling protein kinase Cγ were also enriched in putative Purkinje axon terminals in the dentate nucleus. The only organelle showing a consistent immunolabelling for protein kinase Cγ was the Golgi apparatus where the gold particles were restricted to the trans face. Protein kinase Cγ immunoreactivity also occurred in the Purkinje cell spines, with an enrichment in or near the postsynaptic density. Antibodies to protein kinase Cδ produced a very different labelling pattern in the Purkinje cells. Most of the gold particles were associated with rough endoplasmic reticulum, particularly with those cisternae that were located close to the nucleus or in the nuclear indentations. No significant protein kinase C5 immunolabelling was detected at the plasma membrane or in Purkinje cell spines. The present data point to a highly specific compartmentation of the two major protein kinase C isozyme in Purkinje cells and suggest that these isozymes act on different substrates and hence have different regulatory functions within these neurons.
3.	Dahlqvist, Per, et al. (author) Effects of postischemic environment on transcription factor and serotonin receptor expression after permanent focal cortical ischemia in rats 2003 In: Neuroscience. - 1873-7544 .- 0306-4522. ; 119:3, s. 643-652 Journal article (peer-reviewed)abstract Housing rats in an enriched environment improves functional outcome after ischemic stroke, this may reflect neuronal plasticity in brain regions outside the lesion. Which components of the enriched environment that are of greatest importance for recovery after brain ischemia is uncertain. We have previously found that enriched environment and social interaction alone both improve functional recovery after focal cerebral ischemia, compared with isolated housing with voluntary wheel-running. In this study, the aim was to separate components of the enriched environment and investigate the effects on some potential mediators of improved functional recovery; such as the inducible transcription factors nerve growth factor-induced gene A (NGFI-A) and NGFI-B, and the glucocorticoid and serotonin systems. After permanent middle cerebral artery occlusion, rats were divided into four groups: individually housed with no equipment (deprived group), individually housed with free access to a running wheel (running group), housed together in a large cage with no equipment (social group) or in a large cage furnished with exchangeable bars, chains and other objects (enriched group). mRNA expression of inducible transcription factors, serotonin and glucocorticoid receptors was determined with in situ hybridisation 1 month after cerebral ischemia. Rats housed in enriched or social environments showed significantly higher mRNA expression of NGFI-A and NGFI-B in cortical regions outside the lesion and in the CA1 (cornu ammonis region of the hippocampus), compared with isolated rats with or without a running wheel. NGFI-A and NGFI-B mRNA expression in cortex and in CA1 was significantly correlated to functional outcome. 5-Hydroxytryptamine receptor 1A (5-HT1A) mRNA expression and binding, as well as 5-HT2A receptor mRNA expression were decreased in the hippocampus (CA4 region) of the running wheel rats. Mineralocorticoid receptor gene expression was increased in the dentate gyrus amongst wheel-running rats. No group differences were found in plasma corticosterone levels or mRNA levels of glucocorticoid receptor, corticotropin-releasing hormone, 5-HT2C or c-fos. In conclusion, we have found that social interaction is a major component of the enriched environment regarding the effects on NGFI-A and NGFI-B expression. These transcription factors may be important mediators of improved functional recovery after brain infarctions, induced by environmental enrichment. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.
4.	Dahlqvist, Per, et al. (author) Environmental enrichment alters nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression after middle cerebral artery occlusion in rats 1999 In: Neuroscience. - 1873-7544 .- 0306-4522. ; 93:2, s. 527-535 Journal article (peer-reviewed)abstract Housing rats in an enriched environment after focal brain ischemia improves functional outcome without changes in infarct volume, suggesting neuroplastic changes outside the lesion. In this study, permanent occlusion of the middle cerebral artery was followed by housing in an enriched or a standard environment. Nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression were determined by in situ hybridization two to 30 days after middle cerebral artery occlusion. Stroke induced a decrease in nerve growth factor-induced gene A messenger RNA expression in cortical areas outside the ischemic lesion and in the CA1 subregion of the hippocampus two to three days after ischemia. This decrease was more prolonged with environmental enrichment, lasting until 20 days. However, 30 days after focal cerebral ischemia, environmental enrichment increased nerve growth factor-induced gene A expression compared to standard housing. A reduction of hippocampal glucocorticoid receptor (type II) messenger RNA two to 12 days after stroke in standard housed rats was restored by environmental enrichment. These data suggest that improved functional outcome induced by environmental enrichment after middle cerebral artery occlusion is associated with dynamically altered expression of nerve growth factor-induced gene A messenger RNA in brain regions outside the ischemic lesion, and sustained levels of hippocampal glucocorticoid receptor messenger RNA expression.
5.	Duan, W M, et al. (author) Addition of allogeneic spleen cells causes rejection of intrastriatal embryonic mesencephalic allografts in the rat 1997 In: Neuroscience. - 0306-4522. ; 77:2, s. 599-609 Journal article (peer-reviewed)abstract To address the importance of antigen-presenting cells for the survival of intracerebral neural allografts, allogeneic spleen cells were added to the graft tissue before transplantation. Dissociated embryonic, dopamine-rich mesencephalic and adult spleen tissues were prepared from either inbred Lewis or Sprague-Dawley rats. A mixture of neural and spleen cells was sterotaxically transplanted into the right striatum of adult Sprague-Dawley rats. Controls were neural allografts without addition of allogeneic spleen cells and syngeneic neural grafts with or without the addition of syngeneic spleen cells. Six weeks after transplantation, brain sections were processed immunocytochemically for tyrosine hydroxylase, specific for grafted dopamine neurons, and a bank of markers for various components in the immune and inflammatory responses. The neural allografts which were mixed with allogeneic spleen cells were rejected. In these rats, there were high levels of expression of major histocompatibility complex class I and II antigens, intense cellular infiltration including macrophages and activated microglial cells, and a presence of cluster of differentiation 4- and 8-immunoreactive cells in the graft sites. Moreover, there were increased levels of intercellular adhesion molecule-1, tumour necrosis factor-alpha and interleukin-6 in and around the grafts which were undergoing rejection. In contrast, syngeneic neural grafts survived well regardless of whether they were mixed with syngeneic spleen cells or not, and control neural allografts also exhibited unimpaired survival. No significant difference was observed in the number of grafted dopamine neurons among these three latter groups. The levels of expression of the different markers for inflammation and rejection were generally lower in these grafts than in implants of combined allogeneic neural and spleen cells. In summary, intrastriatal neural allografts, which normally survive well in our animal model, were rejected if allogeneic spleen cells from the same donor were added to the graft tissue. The added spleen cells caused strong host immune and inflammatory responses. The study gave support to the notion that immunological privilege of the brain does not provide absolute protection to immunogenetically histoincompatible neural grafts.
6.	Duan, W M, et al. (author) Immune reactions following systemic immunization prior or subsequent to intrastriatal transplantation of allogeneic mesencephalic tissue in adult rats 1995 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 64:3, s. 41-629 Journal article (peer-reviewed)abstract We have previously found that dissociated mesencephalic tissue, which differs from the host at both major histocompatibility complex and non-major histocompatibility complex gene loci, can survive stereotaxic transplantation to the striatum of adult rats. We have now studied the outcome of intrastriatal neural allografts in rats that were systemically immunized by an orthotopic skin allograft either prior or subsequent to intracerebral implantation surgery. Dissociated mesencephalic tissue from Lewis rat embryos was stereotaxically injected into the dopamine-depleted striatum of hemi-parkinsonian Sprague-Dawley rats. One group was immunized by an orthotopic allogeneic skin graft of the same genetic origin as the neural graft, six weeks before the neural transplantation (the pre-immunized group). Another group was post-immunized by an orthotopic skin allograft, six weeks after the neural transplantation (the post-immunized group). A control group of rats was not challenged by a skin allograft. Marked behavioural recovery was observed in six of seven rats in the control group, in six of eight rats in the post-immunized group, and in none of the pre-immunized rats. Tyrosine hydroxylase-immunopositive cells were found in rats from the two behaviourally compensated groups, but not in the pre-immunized group. The immune responses were evaluated by OX-18 (monoclonal antibody against major histocompatibility complex class I antigen), OX-6 (major histocompatibility complex class II antigen), OX-42 (microglia and macrophages), glial fibrillary acidic protein (astrocytes), OX-8 (cytotoxic T-lymphocytes) and W3/25 (helper T-lymphocytes) immunocytochemistry. All the neural allografts in the pre-immunized group were rejected, leaving scars only. There were more intense immune responses to the allografts in the post-immunized group than the control group, in terms of immunocytochemically higher expression of major histocompatibility complex class I and II antigens and more intense cellular reactions consisting of macrophages, activated microglia and astrocytes, in addition to CD8- and CD4-positive lymphocytes. In summary, the results show the following: (i) systemic pre-immunization leads to complete rejection of intrastriatal neural allografts, implying that the status of the host immune system before transplantation determines the outcome for intrastriatal neural allografts; (ii) established intrastriatal neural allografts can survive for at least six weeks after systemic immunization, in spite of increased host immune responses in and around the allografts; (iii) there are no marked immune reactions against intrastriatal neural allografts 13 weeks after implantation in rats which have not been systemically immunized by a skin allograft; (iv) pre-immunized rats may provide a very useful animal model to investigate the role of inflammatory lymphokines in immune rejection and to test alternative immunosuppressive drugs.
7.	Duan, W M, et al. (author) Sequential intrastriatal grafting of allogeneic embryonic dopamine-rich neuronal tissue in adult rats : will the second graft be rejected? 1993 In: Neuroscience. - 0306-4522. ; 57:2, s. 74-261 Journal article (peer-reviewed)abstract An important issue in clinical neural grafting is whether a second instriatial allograft can survive well in a patient who has received an allograft before. In this study, the survival, immunogenicity and function of intrastriatal grafts of allogeneic or syngeneic embryonic dopamine-rich tissue in rats which had previously received either an intrastriatal allo- or syn-graft or sham injections were examined. The first graft tissue was taken from inbred Lewis or Sprague-Dawley rat embryos and grafted into an intact striatum of adult Sprague-Dawley rats subjected to a unilateral 6-hydroxydopamine lesion on the contralateral side. Eight weeks after the first transplantation, either allogeneic or syngeneic tissue was grafted as dissociated tissue into the dopamine depleted striatum. The function of the second grafts was assessed by rotational asymmetry at two different time points, i.e. eight and 14 weeks after the second transplantation. There were significant reductions of rotational asymmetry in all groups over time, but no significant difference between groups. Tyrosine hydroxylase immunocytochemistry was used to assess dopamine cell survival and graft size. Statistical analysis revealed no significant differnce in the mean number of tyrosine hydroxylase immunoreactive cells or the mean volume of the second grafts placed on the right side (lesioned side) between groups. Monoclonal antibodies were used to evaluate cellular immune reactions and the major histocompatibility complex class I and class II expression in and around grafts. No major histocompatibility complex class I expression was seen in any of the graft combinations. The expression of the major histocompatibility complex class II antigens was generally higher in patches in and around the second allograft of rats which had previously received an allograft than that in and around any other type of grafts. However, the expression of the major histocompatibility complex class II antigens was low throughout the grafts and did not appear as marked perivascular infiltrates. All the major histocompatibility complex class II positive cells displayed a microglia-like morphology, supported by the parallel microglia and macrophage-specific OX-42 immunostaining. The results show that there is no marked on-going immune reactions in or around the implantation site in any group fourteen weeks after a second transplantation. It may be concluded, therefore, that sequential allografting, using stereotaxic implantation of dissociated embryonic neural tissue into the striatal parenchyma, is possible to perform without a major risk of graft rejection, provided that an atraumatic technique is used.
8.	Edström, A., et al. (author) Axonal outgrowth and neuronal apoptosis in cultured adult mouse dorsal root ganglion preparations : Effects of neurotrophins, of inhibition of neurotrophin actions and of prior axotomy 1996 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 75:4, s. 1165-1174 Journal article (peer-reviewed)abstract Dorsal root ganglia (L4 and L5) with attached spinal roots and nerve stumps were isolated from young adult mice and cultured in a layer of extracellular matrix material (matrigel). Within one day, a large number of axons grew out from the cut ends of the nerve and the dorsal root. The average outgrowth length was more than doubled by nerve growth factor, which also strongly increased the number of fibres, showing extensive branching. There was also a significant outgrowth stimulation by neurotrophin-3, but no observable effect by brain-derived neurotrophic factor. In preparations isolated and cultured six days after peripheral nerve transection in vivo, there was an increase in both the outgrowth length (about 1.5- to 2-fold) and in the number of axons. Stimulation of axonal outgrowth, which concerned outgrowth from both the peripheral nerve and the dorsal root, could be further enhanced by the addition of nerve growth factor to the culture. K-252a, a selective inhibitor of neurotrophin receptor-associated tyrosine kinase activity, did not affect either the normal outgrowth or the increased outgrowth in pre-axotomized preparations, at a concentration which abolished the stimulating effects by exogenous nerve growth factor and neurotrophin-3. Under the culturing conditions used, spontaneous apoptosis occurred, but none of the neurotrophins tested, nor K-252a, affected the number of apoptotic neuronal cells analysed by nick-labelling DNA breaks at the end of a 48-h culturing period. Altogether, the present data suggest that for most dorsal root ganglia neurons, signalling through the trk receptors does not influence the apoptosis in vitro and is not required for either the spontaneous axonal outgrowth in matrigel or the increased outgrowth which occurs after prior axotomy in vivo.
9.	Ekström, P., et al. (author) Intracellular staining of physiologically identified photoreceptor cells and hyperpolarizing interneurons in the teleost pineal organ 1988 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 25:3, s. 1061-1070 Journal article (peer-reviewed)abstract The directly photosensory pineal organ of the rainbow trout functions primarily as a luminance detector. Its neutral output reflects the level of ambient illumination in an almost linear fashion over several orders of magnitude. It may thus transmit information about the daily light-dark cycle to central projection targets in the brain, and exert an important control over putative central oscillators. We have studied single neural elements in the explanted pineal organ of the rainbow trout by combining intracellular recording with intracellular injections of either the fluorescent dye Lucifer Yellow CH or the electron dense marker horseradish peroxidase. After physiological characterization, dye was injected, and the pineal organs were processed for fluorescence or electron microscopy. Horseradish peroxidase-injected cells were selected with light microscopy, and were serially sectioned for electron microscopy. By examining the entire series of ultrathin sections of several labeled cells the following results were obtained. (1) Intensity-graded hyperpolarization that was elicited by light stimuli of all wavelengths could be either purely monophasic at all light intensities, or monophasic at low and intermediate light intensities but with an initial peak transient at response saturation. These two types of responses could be demonstrated to emanate from photoreceptor cells. (2) In addition, an interneuron that responded to light stimulation with intensity-graded hyperpolarizations that decreased in amplitude at high light intensities was identified by analysis of serial ultrathin sections. This interneuron was situated in close opposition to a photoreceptor-like element and another interneuron, both of which contained transcellularly transferred horseradish peroxidase. Transcellular transfer of horseradish peroxidase was repeatedly observed, although in the majority of cases only single cells were labeled. Intracellular injection of Lucifer Yellow CH consistently revealed dye-coupling between photoreceptors and between (inter)neurons. The numbers of labeled elements varied between two and eight cells, after intracellular injection of one cell. The present results indicate that the net neural output of the pineal organ is the result of a relatively complicated neural circuitry, encompassing different types of photoreceptors, interneurons and projection neurons. Electrical coupling between photoreceptors, between neurons, and between photoreceptors and neurons may provide spatial signal averaging. The very slow photoreceptor responses to photic stimulation may provide temporal signal averaging. These two averaging mechanisms might together minimize responses to rapid spatial and temporal changes in the ambient illumination, and thus minimize fluctuations in the neural output of the pineal organ that would be irrelevant to the monitoring of the circadian changes in the photic environment.
10.	Ferrand-Drake, M., et al. (author) Mitochondrial permeability transition induced DNA-fragmentation in the rat hippocampus following hypoglycemia 1999 In: Neuroscience. - 0306-4522. ; 90:4, s. 1325-1338 Journal article (peer-reviewed)abstract In the present study the time-course of DNA fragmentation following insulin-induced hypoglycemia was examined. In situ localization of DNA breaks were studied by the terminal deoxynucleotidyl transferase-mediated biotin- deoxyuridine triphosphate nick-end labelling method, and the temporal profile of DNA-fragmentation by agarose gel electrophoresis. Cell nuclei displayed terminal deoxynucleotidyl transferase-deoxyuridine triphosphate nick-end labelling within 3 h of recovery following 30 min of a hypoglycemic insult, and DNA from the hippocampus displayed oligonucleosomal fragmentation. Ultrastructural examination of the dentate granule cells showed mitochondrial swelling during the acute phase of the hypoglycemic insult, which preceded the DNA fragmentation seen in the recovery phase. Cyclosporin A but not tacrolimus, prevented mitochondrial swelling and subsequent DNA fragmentation. We conclude that during severe energy deprivation following hypoglycemia, mitochondrial swelling occurs due to mitochondrial permeability transition and that factors are released, which upon recovery can activate processes leading to DNA fragmentation and cell death.
11.	Ferrand-Drake, M., et al. (author) The time-course of DNA fragmentation in the choroid plexus and the CA1 region following transient global ischemia in the rat brain. The effect of intra-ischemic hypothermia 1999 In: Neuroscience. - 0306-4522. ; 93:2, s. 537-549 Journal article (peer-reviewed)abstract The time-course of DNA fragmentation in the CA1 region of the hippocampus and the choroid plexus was studied following induction of transient forebrain ischemia under lethal normothermic (37°C), or sublethal hypothermic (33°C) conditions. Oligonucleosomal- and high-molecular-weight DNA fragmentation were analysed by conventional agarose gel electrophoresis and pulsed-field gel electrophoresis, respectively. DNA breaks were visualized by the terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridinetriphosphate nick-end labeling method. At 48h of recovery following normothermic ischemia, in situ labeling of DNA breaks were widespread in medial CA1 and high-molecular-weight DNA cleavage was seen. In contrast, at the same time-point in lateral CA1, many pyknotic but few cells displaying in situ labeling of DNA breaks were observed. Major oligonucleosomal DNA fragmentation was not seen until 72h of recovery. Following hypothermic ischemia, DNA fragmentation was absent in CA1. DNA fragmentation was seen in the choroid plexus at 24h of recovery following normothermic ischemia, which was diminished by 48h of recovery.In conclusion, oligonucleosomal and high-molecular-weight DNA fragmentation at 10-50 kilobase pairs, occur in CA1 after morphological signs, and acidophilia signifying neurodegeneration appear. DNA fragmentation and cell death in the choroid plexus precede neuronal death in CA1 and may play a causative role.
12.	Freedman, J, et al. (author) Vasoconstrictor effects in spinal cord of the substance P antagonist [D-Arg, D-Trp7,9 Leu11]-substance P (Spantide) and somatostatin and interaction with thyrotropin releasing hormone 1988 In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 27:1, s. 267-278 Journal article (peer-reviewed)abstract The present study was undertaken to investigate the possible effects of Spantide [D-Arg1, D-Trp7,9 Leu11]-substance P, a substance P antagonist, and of somatostatin on spinal cord blood flow. The experiments were performed with the laser-doppler technique on the L1 spinal cord segment exposed by laminectomy. The effect of Spantide was also studied in the rat with the [14C]iodoantipyrine technique. In addition, experiments were performed on rabbit skeletal muscle in vivo after administration of Spantide to the local vasculature. In the experiments on spinal cord, approximately the same doses were employed as those earlier shown to be "neurotoxic". When the vehicle alone (0.9% saline) was administered intrathecally, a slight decrease of brief duration was noted in the blood flow. Spantide, however, caused a dose-dependent decrease, where 2 micrograms caused an immediate drop of the blood flow to approx. 20% of its normal value. A total circulatory arrest was found in several animals. In most cases, the flow was gradually normalized, whereas the effect persisted for up to 60 min in others. Virtually the same effect was exerted by somatostatin. The experiments using the iodoantipyrine technique confirmed the effect of Spantide. Here, the high resolution of this method showed that the gray matter was affected preferentially, with a complete ischemic state or a drastically reduced flow in 4 out of 5 animals 10 min after 2 micrograms of Spantide; one animal was unaffected, and this animal did not show any signs of motor impairment. The vasoconstriction of Spantide was not affected by simultaneous injections with substance P. However, after i.v. pretreatment with thyrotropin-releasing hormone, at a dose that previously has been reported to be protective against the neurodegenerative effects of Spantide, blood flow was markedly increased as compared to Spantide alone. Results from the experiments using intravital microscopy flow studies in the rabbit tenuissimus muscle revealed that Spantide at the doses used had no vasoconstrictor effect in the skeletal muscle of this species. The results suggest that previous demonstrations of motor impairment and "neurotoxic" actions of intrathecally injected substance P antagonists and somatostatin may be related to a marked decrease in spinal cord blood flow. Counteraction of the effect of Spantide by thyrotropin-releasing hormone may be explained by its effect to increase blood flow.
13.	Hornfelt, M., et al. (author) Involvement of axonal phospholipase A2 activity in the outgrowth of adult mouse sensory axons in vitro 1999 In: Neuroscience. - 0306-4522. ; 91:4, s. 1539-1547 Journal article (peer-reviewed)abstract The effect on axonal outgrowth of inhibition of phospholipase A2 activity was studied in a recently developed in vitro model, where dorsal root ganglia with attached spinal roots and nerve stumps from young adult mice were cultured in an extracellular matrix material (Matrigel). The phospholipase A2 inhibitors 4-bromophenacyl bromide and oleyloxyethyl phosphorylcholine dose-dependently reduced axonal outgrowth from the sciatic nerve stump. A similar inhibitory effect was seen when only the cut nerve end was exposed to the inhibitors in a compartmental culture system. The local effect of phospholipase A2 inhibition was further investigated on axons established in culture, using time-lapse recording. Exposure to phospholipase A2 inhibitors caused the retraction of filopodia extensions and a reduction in growth cone motility within a few minutes. After removal of inhibition, normal growth cone motility and axonal growth were regained. Nerve cell bodies and axons, in contrast to Schwann cells, showed immunoreactivity after staining with an antiserum against secretory phospholipase A2, and elevated levels of the enzyme could be detected after culture for 24 h. The immunoreactive protein was of approximately 170,000 molecular weight (phospholipase A2-170) as determined by sodium dodecyl sulphate- polyacrylamide gel electrophoresis and immunoblotting. The localization of phospholipase A2-170 in axons growing into the Matrigel was also demonstrated by use of a whole-mount technique. The results of this study show the importance of continuous phospholipase A2 activity for growth cone motility and axonal outgrowth in the mammalian peripheral nerve, and suggest the involvement of an axonally localized enzyme.
14.	Hu, B. R., et al. (author) Alterations of Ca2+/calmodulin-dependent protein kinase II and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia 1995 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 68:4, s. 1003-1016 Journal article (peer-reviewed)abstract The change in the subcellular distribution of Ca2+/calmodulin-dependent protein kinase II was studied in the rat hippocampus following normothermic and hypothermic transient cerebral ischemia of 15 min duration. A decrease in immunostaining of Ca2+/calmodulin-dependent protein kinase II was observed at 1 h of reperfusion which persisted until cell death in the CA1 region. In the CA3 and dentate gyrus areas immunostaining recovered at one to three days of reperfusion. The Ca2+/calmodulin-dependent protein kinase II was translocated to synaptic junctions during ischemia and reperfusion which could be due to a persistent change in the intracellular calcium ion homeostasis. The expression of the messenger RNA of the α-subunit of Ca2+/calmodulin-dependent protein kinase II decreased in the entire hippocampus during reperfusion, and was most marked in the dentate gyrus at 12 h of reperfusion. This decrease could be a feedback downregulation of the mRNA due to increased Ca2+/calmodulin-dependent protein kinase II activation. Intraischemic hypothermia protected against ischemic neuronal damage and attenuated the ischemia-induced decrease of Ca2+/calmodulin-dependent protein kinase II immunostaining in all hippocampal regions. Hypothermia also reduced the translocation of Ca2+/calmodulin-dependent protein kinase II and restored Ca2+/calmodulin-dependent protein kinase II α messenger RNA after ischemia. The data suggest that ischemia leads to an aberrant Ca2+/calmodulin-dependent protein kinase II mediated signal transduction in the CA1 region, which is important for the delopment of delayed neuronal damage. Hypothermia enhances the restoration of the Ca2+/calmodulin-dependent protein kinase II mediated cell signalling.
15.	Kokaia, Merab, et al. (author) Immunolesioning of basal forebrain cholinergic neurons facilitates hippocampal kindling and perturbs neurotrophin messenger RNA regulation 1996 In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 70:2, s. 313-327 Journal article (peer-reviewed)abstract The immunotoxin 192 IgG-saporin induces an efficient and specific lesion of low-affinity nerve growth factor receptor-bearing cholinergic neurons in the basal forebrain. Intraventricular injection of 192 IgG-saporin, which caused a complete loss of cholinergic afferents to the hippocampus and neocortex and a partial denervation of amygdala and piriform cortex, was found to markedly facilitate the initial stages of seizure development in hippocampal kindling. In contrast, the progression of kindling process from focal to generalized seizures was not affected. In situ hybridization demonstrated that basal levels of brain-derived neutrotrophic factor messenger RNA in the hippocampal formation and piriform cortex were significantly decreased by the lesion, which also attenuated the seizure-induced increase of brain-derived neurotrophic factor messenger RNA expression in the hippocampus and frontal cortex. In the dentate gyrus, the 192 IgG-saporin lesion selectively reduced the upregulation of messenger RNAs for brain-derived neurotrophic factor exons I and III after a generalized seizure, whereas the increase of exon II messenger RNA was unchanged. The lesion abolished the seizure-evoked increase of nerve growth factor and TrkC messenger RNA levels and decrease of neutrophin-3 messenger RNA expression in dentate granule cells, while TrkB messenger RNA levels were not affected. We conclude that the basal forebrain cholinergic system (1) suppresses kindling epileptogenesis in the hippocampus, and (2) enhances both basal and seizure-evoked brain-derived neurotrophic factor synthesis in the hippocampal formation and some cortical areas through a specific pattern of activation of promoters within the brain-derived neurotrophic factor gene.
16.	Kokaia, Zaal, et al. (author) Seizure-induced differential expression of messenger RNAs for neurotrophins and their receptors in genetically fast and slow kindling rats 1996 In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 75:1, s. 197-207 Journal article (peer-reviewed)abstract Levels of messenger RNAs for brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3, and their high-affinity receptors, TrkB and TrkC, were analysed in the brains of genetically fast and slow kindling rats using in situ hybridization. Basal expression of neurotrophins and Trk messenger RNAs in the hippocampal formation, amygdala, frontoparietal and piriform cortices did not differ between the two strains. At 2 h after the third generalized grade 5 seizure, induced by kindling stimulations in the amygdala, increased expression of brain-derived neurotrophic factor messenger RNA was detected in the dentate gyrus granule cell layer, amygdala, frontoparietal and piriform cortices of the fast kindlers. Similar seizure-evoked increases of brain-derived neurotrophic factor messenger RNA levels were also observed in the amygdala and piriform cortex of slow kindlers. However, in these animals, brain-derived neurotrophic factor messenger RNA expression was not significantly altered by the seizures in the dentate gyrus granule cell layer and frontoparietal cortex. Furthermore, the seizure-induced increase of nerve growth factor, TrkB and TrkC messenger RNAs and decrease of neurotrophin-3 messenger RNA levels in the dentate gyrus granule cell layer was only observed in fast, but not in slow, kindlers. The neurotrophins are believed to regulate synaptic plasticity and efficacy and to facilitate long-term potentiation and kindling epileptogenesis. The present data suggest that the slow and fast kindling rates in the two strains studied here might partly be due to differences in seizure-evoked neurotrophin and Trk synthesis.
17.	Leanza, G, et al. (author) Effects of neonatal lesions of the basal forebrain cholinergic system by 192 immunoglobulin G-saporin : biochemical, behavioural and morphological characterization 1996 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 74:1, s. 41-119 Journal article (peer-reviewed)abstract Selective removal of the basal forebrain cholinergic neurons by the immunotoxin 192 immunoglobulin G-saporin has offered a new powerful tool for the study of the relationships between cholinergic dysfunction and cognitive impairments. In the present study the morphological and functional consequences of selective lesions of the basal forebrain cholinergic system during early postnatal development have been investigated following bilateral intraventricular injections of 192 immunoglobulin G-saporin to immature (four-day-old) rats. Administration of increasing doses (0.2-0.8 microgram) of the immunotoxin produced dose-dependent loss of cholinergic neurons in the septal/diagonal band area (up to 72-86%) and in the nucleus basalis magnocellularis (up to 91-93%), paralleled by marked reductions in choline acetyltransferase activity in the hippocampus and several cortical regions (73-84%). The parvalbumin-positive neurons in the septal/diagonal band area and the calbindin-positive Purkinje cells in the cerebellum were unaffected at all dose levels. Brain dopamine or noradrenaline levels were unaffected or increased by the immunotoxin treatment. At the optimal dose, 0.4 microgram, the toxin conjugate produced maximal cholinergic depletion without significant mortality. Higher doses (0.8, 1.2 and 1.6 micrograms) of toxin, on the other hand, proved to be lethal for most or all of the injected animals. When tested at three and eight months after the optimal dose, in spite of persisting cholinergic depletion, the noenatally lesioned animals showed no impairment in the water maze task or in locomotor activity and exploration as compared to normal controls, probably reflecting partial sparing of the cholinergic neurons by the neonatal immunotoxic lesion (above all in the vertical and horizontal limbs of the diagonal band area), and/or a greater degree of plasticity in the developing as compared to the mature cholinergic system. The place navigational performance of the neonatally lesioned animals in the water maze task was abolished by central muscarinic cholinergic receptor blockade (by atropine) or by a second immunotoxic lesion, which eliminated virtually all residual cholinergic neurons in the septal/diagonal band area and the nucleus basalis. Administration of 192 immunoglobulin G-saporin to similarly trained, but previously normal adult rats, produced similar cholinergic depletions but much less severe place navigation deficits, suggesting that preoperative training on the task may reduce the functional consequences of a subsequent cholinergic lesion. The results thus support the view that the basal forebrain cholinergic system may be implicated in the acquisition rather than retention of spatial memory in the water maze task.
18.	Leclere, P., et al. (author) Effects of glial cell line-derived neurotrophic factor on axonal growth and apoptosis in adult mammalian sensory neurons in vitro 1997 In: Neuroscience. - 0306-4522. ; 82:2, s. 545-558 Journal article (peer-reviewed)abstract The effects of glial cell line-derived neurotrophic factor on axonal outgrowth and apoptosis were studied in vitro using explanted dorsal root ganglia-peripheral nerve preparations of adult mice. In gels of matrigel or collagen type 1, glial cell line-derived neurotrophic factor increased both the numbers and lengths of axons growing out of explanted preparations, although less effectively than nerve growth factor. Stimulation of axonal outgrowth by glial cell line-derived neurotrophic factor was unaffected by K252a, a protein kinase inhibitor which blocks the effects of nerve growth factor and other neurotrophins acting through trk receptors. To determine the phenotype of the axons responding to glial cell line-derived neurotrophic factor, preparations were stained using antibodies to trkA, calcitonin gene- related peptide, 200,000 mol. wt phosphorylated neurofilaments (monoclonal antibody RT97) and the lectin Bandeiraea simplicifolia 1B4. RT97 recognizes large diameter neurons whilst 1B4 labels small diameter neurons which broadly do not express neurotrophin receptors. In preparations cultured with glial cell line-derived neurotrophic factor, significant increases in the numbers of outgrowing axons labelled with RT97 and 1B4 were observed but the numbers of calcitonin gene-related peptide-positive axons were not significantly increased and their staining intensity was generally faint. In separate preparations it was found that in the presence of glial cell line-derived neurotrophic factor, the majority of the 1B4 labelled axons were trkA negative, indicating that this factor can stimulate axonal growth in this population of neurons which do not respond to the neurotrophins. Spontaneous apoptosis in neurons and satellite cells occurs in explanted preparations of the type used in the present investigations, but in cryostat sections of preparations cultured in the presence of glial cell line-derived neurotrophic factor, the incidence of apoptosis was lower than in control preparations which had been cultured in the absence of this factor. This suggests that glial cell line-derived neurotrophic factor may promote survival of some adult sensory neurons in vitro.
19.	Meissl, H., et al. (author) Photoreceptor responses to light in the isolated pineal organ of the trout, Salmo gairdneri 1988 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 25:3, s. 1071-1076 Journal article (peer-reviewed)abstract Photoreceptor potentials were recorded intracellularly from the isolated pineal organ of the teleost, Salmo gairdneri, maintained in tissue culture medium for 2-20 h. After electrophysiological characterization the photoreceptor cells were iontophoretically injected with Lucifer Yellow or with horseradish peroxidase for subsequent morphological identification. A brief flash of light elicited a hyperpolarization which was graded with light intensity in the dark-adapted photoreceptor. For dim flashes, the responses were purely monophasic. At higher intensities responses either remained purely monophasic or displayed an initial transient wave which became prominent for supersaturating intensities. The latency of the responses and their rise time decreased with increasing light intensity. Threshold responses showed latencies of about 600 ms, reached a maximum in about 1100 ms and returned to the dark potential in about 5 s. Saturating flashes considerably diminished the latency to 55 ms, the rise time to about 250 ms, but increased the time of recovery from peak to dark potential up to 60 s. Intracellular responses to background illumination exhibited two different response types. One type repolarized immediately, when the background light was extinguished, whereas the other type was characterized by a slow recovery of the dark potential. The spectral sensitivity of all intracellular recorded photoreceptors peaked at λmax = 520-530 nm.
20.	Nakao, Naoyuki, et al. (author) Antioxidant treatment protects striatal neurons against excitotoxic insults 1996 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 73:1, s. 185-200 Journal article (peer-reviewed)abstract It has been suggested that oxidative stress plays an important role in mediating excitotoxic neuronal death. We have therefore investigated the protective effects of antioxidants against excitotoxic injury in the rat on striatal neurons both in vitro and in vivo. In the first part of the study, we determined whether two different types of antioxidants, the spin trapping agent, alpha-phenyl-tert-butyl nitrone and an inhibitor of lipid peroxidation, U-83836E, could protect cultured striatal neurons against either hypoglycemic injury or N-methyl-D-aspartate-induced excitotoxicity. Dopamine- and cyclic AMP-regulated phosphoprotein, which is enriched in medium-sized spiny neurons, was chosen as a marker for striatal neurons. alpha-Phenyl-t-butyl nitrone and U-83836E both significantly reduced cell death induced by these insults as indicated by an increased number of surviving dopamine- and cyclic AMP-regulated phospho-protein-positive neurons. The two antioxidants also promoted the survival of cultured striatal neurons grown at low cell density under serum-free culture conditions. In an in vivo experiment systemically administered alpha-phenyl-t-butyl nitrone exerted neuroprotective effects in the rat striatum following injection of the excitotoxin quinolinic acid. Apomorphine-induced rotation tests revealed that alpha-phenyl-t-butyl nitrone-treated animals were significantly less asymmetric in their motor behavior than control rats. Treatment with alpha-phenyl-t-butyl nitrone significantly reduced the size of the quinolinic acid-induced striatal lesions, as assessed by the degree of sparing of dopamine- and cyclic AMP-regulated phospho-protein-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons, and of microtubule-associated protein-2-immunorective areas. Furthermore, lesion-induced morphological changes in the substantia nigra pars reticulate, i.e. loss of dopamine- and cyclic AMP-regulated phosphoprotein-positive afferent fibers and atrophic changes due to transsynaptic degeneration, were also less extensive in the alpha-phenyl-t-butyl nitrone-treated animals. The results support the hypothesis that oxygen-free radicals contribute to excitotoxic neuronal injury. The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity.
21.	Nakao, Naoyuki, et al. (author) DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw reaching in an animal model of Huntington's disease 1996 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 74:4, s. 70-959 Journal article (peer-reviewed)abstract Grafts of striatal tissue comprise two different types of tissue: regions with (P-zones) and without (NP-zones) neurons that express markers characteristic of the striatum, such as dopamine- and cyclic AMP-regulated phosphoprotein with a mol. wt of 32,000 (DARPP-32). It remains unclear whether P-zones alone play a crucial role in functional effects of striatal grafts in an animal model of Huntington's disease. The present study has been performed to determine: (i) the yield of DARPP-32-positive neurons in grafts of lateral ganglionic eminence; (ii) whether treatment of graft tissue with the spin-trapping agent alpha-phenyl-tert-butyl nitrone enhances the survival of implanted DARPP-32-positive neurons; and (iii) the relationship between the number of DARPP-32-positive neurons in the grafts and functional effects of the grafts on paw-reaching ability in rats with unilateral quinolinic acid lesions of the striatum. Dissociated tissue derived from the lateral ganglionic eminence of rat embryos (embryonic day 14), with or without addition of alpha-phenyl-tert-butyl nitrone (3 mM), was implanted into the quinolinic acid-lesioned striatum. Compared to unlesioned normal animals, rats with striatal lesions showed substantial impairment in paw-reaching ability, particularly on the side contralateral to the lesion, as judged from the number of pellets retrieved by each paw. Intrastriatal grafts gave rise to a significant improvement in paw-reaching ability. The mean total number of surviving DARPP-32-positive cells in grafts without alpha-phenyl-tert-butyl nitrone treatment was estimated at 115 x 10(3), which did not significantly differ from that in alpha-phenyl-tert-butyl nitrone-treated grafts. The paw-reaching scores were significantly correlated with the volumes of P-zones and the number of DARPP-32-positive neurons, but with neither the volumes of NP-zones nor the total graft volume. The results suggest that P-zones in striatal grafts mediate graft-derived functional recovery in a complex task such as skilled forelimb use. Although the antioxidant treatment with alpha-phenyl-tert-butyl nitrone failed to promote graft survival, the positive correlation between the yield of DARPP-32-positive cells in the graft and the extent of the functional recovery highly warrants further attempts to increase the yield of the striatal component in the graft.
22.	Nikkhah, G, et al. (author) A microtransplantation approach for cell suspension grafting in the rat Parkinson model : a detailed account of the methodology 1994 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 63:1, s. 57-72 Journal article (peer-reviewed)abstract Shortcomings of current techniques used for the intracerebral transplantation of ventral mesencephalic dopamine neurons include low graft survival, high variability, considerable implantation trauma and suboptimal graft integration. In order to overcome these limitations, we have adopted a microtransplantation approach which allows precise and reproducible implantation of ventral mesencephalon cell suspensions at single or multiple sites with minimal trauma and improved survival and integration of the grafted neurons [Nikkhah et al. (1994) Brain Res. 633, 133-143]. The present study was undertaken to determine the influence of different grafting parameters as well as the time-course of development of micrografted dopaminergic neurons and to devise an optimal microtransplantation procedure in the rat Parkinson model, Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway received four graft deposits of either 0.25, 0.5, 1.0 or 2.0 microliters along four injection tracts (150,000 cells/microliters) using either a glass capillary (o.d. 50-70 microns) or a regular cannula (o.d. 0.50 mm, metal cannula grafts). At one, two and 12 weeks postgrafting (capillary grafts) and at 12 weeks postgrafting (metal cannula grafts) dopamine neuron survival and graft volumes were measured and the implantation trauma assessed by glial fibrillary acidic protein expression. The results demonstrate that single deposits of 50,000-75,000 cells in 0.5 microliter, implanted with a glass capillary, provide the best environment both for dopaminergic and non-dopaminergic neuron survival. Grafts implanted with the glass capillary showed much weaker long-term glial fibrillary acidic protein expression along the injection tract and around the implants than was the case in grafts implanted with the thicker metal cannula. Optimal graft integration and minimal disturbances of host brain structures can reliably be achieved by small-sized implants (20,000-35,000 cells/deposit). Tyrosine hydroxylase-positive fiber outgrowth from micrografted dopaminergic neurons was seen not only in the surrounding caudate-putamen, but also along white matter tracts into the nucleus accumbens and the overlying cerebral cortex. Spreading of dopaminergic micrografts over multiple small deposits rather than increasing the volume of single grafts gave more extensive reinnervation of the entire host striatum. The micrografting technique provides a useful tool to improve graft-host interactions in the rat Parkinson model, and it allows more precise and reproducible quantitative studies on dopamine neuron survival and growth in intrastriatal ventral mesencephalon transplants. This technique should also be highly useful for the intracerebral implantation of cells derived from primary cultures or cell lines [Gage and Fisher (1991) Neuron 6, 1-12].
23.	Nilsson, O G, et al. (author) Acetylcholine release in the rat hippocampus as studied by microdialysis is dependent on axonal impulse flow and increases during behavioural activation 1990 In: Neuroscience. - : Elsevier BV. - 0306-4522. ; 36:2, s. 325-338 Journal article (peer-reviewed)abstract Changes in extracellular levels of acetylcholine and choline in the hippocampal formation were measured using intracerebral microdialysis coupled to high performance liquid chromatography with post-column enzyme reaction and electrochemical detection. Various pharmacological and physiological manipulations were applied to awake unrestrained normal rats and rats subjected to a cholinergic denervation of the hippocampus by a complete fimbria-fornix lesion (1-2 weeks previously). Low baseline levels of acetylcholine (about 0.3 pmol/15 min sample) could be detected in the absence of acetylcholinesterase inhibition in all animals. However, in order to obtain stable and more readily detectable levels, the acetylcholinesterase inhibitor neostigmine was added to the perfusion medium at a concentration of 5 or 10 microM and was used during all subsequent manipulations. Addition of neostigmine increased acetylcholine levels approximately 10-fold (to 3.7 pmol 15 min) in the normal rats, which was about 4-fold higher than the levels recovered from the denervated hippocampi. Depolarization by adding KCl (100 mM) to the perfusion fluid produced a 3-fold increase in the extracellular acetylcholine levels, and the muscarinic antagonist atropine (3 microM) resulted in a 4-fold increase in the normal rats, whereas these drugs induced only small responses in the denervated rats. Neuronal impulse blockade by tetrodotoxin (1 microM) resulted, in normal rats, in a 70% reduction in extracellular acetylcholine levels. Sensory stimulation by handling increased acetylcholine levels by 94% in the normal rats, whereas this response was almost totally abolished in the denervated hippocampi. Behavioural activation by electrical stimulation of the lateral habenula resulted in a 4-fold increase in acetylcholine release in normal animals, and this response was totally blocked by a transection of the lateral habenular efferents running in the fasciculus retroflexus. The levels obtained by lateral habenula stimulation were reduced by about 95% in the rats with fimbria-fornix lesions. Following an acute knife transection of the fimbria-fornix performed during ongoing dialysis, acetylcholine levels dropped instantaneously by 70%, indicating that the extracellular acetylcholine levels in the hippocampus are maintained by a tonic impulse flow in the septohippocampal pathway. The extracellular levels of choline were reduced by about 30% after the addition of neostigmine in the normal rats, and increased by about 50% in both normal and denervated rats after addition of KCl to the perfusion fluid. No changes could be detected after atropine, handling, lateral habenula stimulation, or acute fimbria-fornix or fasciculus retroflexus transection.(ABSTRACT TRUNCATED AT 400 WORDS)
24.	Nilsson, O G, et al. (author) Behaviour-dependent changes in acetylcholine release in normal and graft-reinnervated hippocampus : evidence for host regulation of grafted cholinergic neurons 1992 In: Neuroscience. - 0306-4522. ; 49:1, s. 33-44 Journal article (peer-reviewed)abstract Grafted neurons obtained from the fetal basal forebrain can provide a functional cholinergic reinnervation of the hippocampal formation in rats with a lesion of the intrinsic septal cholinergic afferents. In the present experiments graft-derived acetylcholine release in the hippocampus was studied by microdialysis in awake rats during different types of behaviours which are known to activate the innate septohippocampal cholinergic system and during different activity periods of the day-night cycle. Two types of basal forebrain grafts were studied: cell suspensions implanted into the hippocampus in rats with an aspirative lesion of the fimbria-fornix, and grafts of solid tissue implanted as a tissue bridge into the fimbria-fornix lesion cavity. Increased acetylcholine overflow was seen in both groups with grafts during sensory stimulation (by handling). The strongest response (50% increase in acetylcholine release) was seen in rats with solid basal forebrain grafts (equivalent to two-thirds of that seen in intact rats). Immobilization stress and motor activity (swimming) also resulted in increased, but more variable, acetylcholine release (+ 30%; about one-third of the normal response). None of these effects was seen in the control rats with fimbria-fornix lesion only. The two-fold difference in hippocampal acetylcholine release in normal animals between day and night was absent in both types of grafted rats. An acute knife-cut, transecting the connections between the solid basal forebrain graft and the host hippocampus, caused an immediate 75% reduction in acetylcholine release (similar to the effect of an acute fimbria-fornix transection in the normal rats) and the response to swimming was no longer evident. The results show that grafted cholinergic neurons can be functionally integrated into the host brain, allowing the grafted neurons to be activated in the correct behavioural contexts, although the changes in acetylcholine overflow were overall smaller and more variable than normal. The ability of the host to influence cholinergic graft activity, most probably mediated via activation of afferent host-graft connections, may contribute to the efficacy of basal forebrain grafts in the amelioration of behavioural impairments in animals with lesions of the forebrain cholinergic system.
25.	Pratt, G D, et al. (author) Differential regulation of N-methyl-D-aspartate receptor subunit messenger RNAs in kindling-induced epileptogenesis 1993 In: Neuroscience. - 0306-4522. ; 57:2, s. 18-307 Journal article (peer-reviewed)abstract N-methyl-D-aspartate-receptors are implicated in several neuropathological conditions including epilepsy. As a model of complex partial seizures, rapid hippocampal kindling was chosen to investigate changes in the expression of messenger RNAs encoding the N-methyl-D-aspartate-receptor subunits NR1, NR2A and NR2B both during and in the period immediately following the induction of the kindled state. The study demonstrates a cell-specific, time-dependent modulation of the N-methyl-D-aspartate-receptor subunit messenger RNAs almost entirely restricted to the granule cells of the dentate gyrus. In partially kindled animals (10 stimulations), while the NR1 subunit messenger RNA remained unaltered after a period of 2 h, the NR2A and NR2B subunit messenger RNAs were bilaterally reduced in dentate gyrus granule cells by around 50% below control values. In fully kindled animals (40 stimulations), a progressive reduction in NR1 subunit messenger RNA levels in the dentate gyrus was observed, being maximal after 4 h (-67%). At the same time point, NR2A and NR2B transcript levels were transiently increased by 102% and 46% above control values, respectively. These data point to a differential regulation of N-methyl-D-aspartate-receptor subunit messenger RNAs. No alterations were detected in pyramidal cells. Long-term maintenance of the kindled state was not associated with alterations in N-methyl-D-aspartate-receptor subunit messenger RNAs since control levels of messenger RNA were attained by 12 h and persisted for at least five days. The early changes in messenger RNAs described in this study indicate that the expression of N-methyl-D-aspartate-receptor subunits is under independent regulatory control. This phenomenon may contribute to epileptogenesis and to kindling-associated plasticity by mediating a structural reorganization of N-methyl-D-aspartate-receptors, leading to an altered excitability of dentate gyrus granule cells.

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