European Journal of Neuroscience
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Demonstration of long‐range GABAergic connections distributed throughout the mouse neocortex Abstract γ‐Aminobutyric acid (GABA)ergic neurons in the neocortex have been mainly regarded as interneurons and thought to provide local interactions. Recently, however, glutamate decarboxylase (GAD) immunocytochemistry combined with retrograde labeling experiments revealed the existence of GABAergic projection neurons in the neocortex. We further studied the network of GABAergic projection neurons in the neocortex by using GAD67‐green fluorescent protein (GFP) knock‐in mice for retrograde labeling and a novel neocortical GABAergic neuron labeling method for axon tracing. Many GFP‐positive neurons were retrogradely labeled after Fast Blue injection into the primary somatosensory, motor and visual cortices. These neurons were labeled not only around the injection site, but also at a long distance from the injection site. Of the retrogradely labeled GABAergic neurons remote from the injection sites, the vast majority (91%) exhibited somatostatin immunoreactivity, and were preferentially distributed in layer II, layer VI and in the white matter. In addition, most of GABAergic projection neurons were positive for neuropeptide Y (82%) and neuronal nitric oxide synthase (71%). We confirmed the long‐range projections by tracing GFP‐labeled GABAergic neurons with axon branches traveled rostro‐caudally and medio‐laterally. Axon branches could be traced up to 2 mm. Some (n = 2 of 4) were shown to cross the areal boundaries. The GABAergic projection neurons preferentially received neocortical inputs. From these results, we conclude that GABAergic projection neurons are distributed throughout the neocortex and are part of a corticocortical network.
European Journal of Neuroscience - Tập 21 Số 6 - Trang 1587-1600 - 2005
Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation Abstract Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6/2 transgenic mice for our studies. Unlike denervation atrophy, skeletal muscle atrophy in R6/2 mice occurs uniformly. Paradoxically however, skeletal muscles show age‐dependent denervation‐like abnormalities, including supersensitivity to acetylcholine, decreased sensitivity to µ‐conotoxin, and anode‐break action potentials. Morphological abnormalities of neuromuscular junctions are also present, particularly in older R6/2 mice. Severely affected R6/2 mice show a progressive increase in the number of motor endplates that fail to respond to nerve stimulation. Surprisingly, there was no constitutive sprouting of motor neurons in R6/2 muscles, even in severely atrophic muscles that showed other denervation‐like characteristics. In fact, there was an age‐dependent loss of regenerative capacity of motor neurons in R6/2 mice. Because muscle fibers appear to be released from the activity‐dependent cues that regulate membrane properties and muscle size, and motor axons and nerve terminals become impaired in their capacity to release neurotransmitter and to respond to stimuli that normally evoke sprouting and adaptive reinnervation, we speculate that in these mice there is a progressive dissociation of trophic signalling between motor neurons and skeletal muscle. However, irrespective of the cause, the abnormalities at neuromuscular junctions we report here are likely to contribute to the pathological phenotype in R6/2 mice, particularly in late stages of the disease.
European Journal of Neuroscience - Tập 20 Số 11 - Trang 3092-3114 - 2004
Localization of Neuropeptide Y Y1 mRNA in the Human Brain: Abundant Expression in Cerebral Cortex and Striatum Abstract Many neurobiological functions have been ascribed to the NPY Y1 receptor subtype, but autoradiographic analysis has failed to detect Y1 binding sites in most human brain areas, in contrast to the rat. We examined the regional distribution of Y1 mRNA‐containing cells in the post‐mortem human brain to clarify if there is a major species difference in terms of the existence of Y1 receptors in the human telencephalon, in particular the striatum and cortex. In situ hybridization experiments revealed widespread distribution of Y1 mRNA signals in all layers of most limbic and neocortical regions, predominantly in layer IV (most cortical regions) and layer VI. The striatum showed moderate Y1 receptor mRNA expression levels with intensely expressing cells localized to the nucleus accumbens. The highest Y1 receptor mRNA expression was apparent within the dentate gyrus, and the lowest in the subiculum, parahippocampal gyrus, cerebellum, and thalamus. In vitro autoradiography using [125 I]Leu31 Pro34 ‐PYY and [125 I]PYY with NPY (13–36) or Leu31 Pro34 NPY; confirmed the presence of low Y1–like binding in the human brain despite abundant Y1 mRNA expression. However, using a rat model of the human autopsy process, it was apparent that the inability to reveal high Y1– versus Y2–like receptors in the human brain was related in part to marked reductions of Y1–like, but not Y2–like, receptors within a 4 h post‐mortem delay. Altogether, the results indicate that the Y1 receptor gene is abundant in the human brain and this receptor may have important roles in cognitive, limbic and motor function.
European Journal of Neuroscience - Tập 9 Số 6 - Trang 1212-1225 - 1997
Regional Distribution of Putative NPY Y<sub>1</sub> Receptors and Neurons Expressing Y<sub>1</sub> mRNA in Forebrain Areas of the Rat Central Nervous System Abstract Using monoiodinated radioligands of peptide YY (PYY), and the recently introduced neuropeptide Y (NPY) analogue [Leu31 ,Pro34 ]NPY, receptor binding sites of the Y1 and Y2 type were localized in the rat brain by quantitative in vitro autoradiography. The binding specificity and affinity of both radiolabeled ligands were analysed by ligand binding studies employing rat brain membrane homogenates from cerebral cortex and hippocampus. Using in situ hybridization histochemistry, the regional distribution and cellular localization of mRNA encoding the Y1 receptor were investigated in rat brain sections and compared to the distribution of Y1 ‐specific binding sites. PYY binds to both Y1 and Y2 receptors, while long C‐terminal fragments such as NPY13–36 and NPY16–36 bind preferentially to Y2 receptors. [Leu31 , Pro34 ]NPY is a specific agonist for Y1 receptors. Highest densities of [125 I]PYY binding sites were found in the cerebral cortex, the thalamus, the lateral septum, the hippocampus and the mesencephalic dopaminergic areas. In order to block putative Y2 receptors, a series of [125 I]PYY binding experiments was performed in the presence of NPY13–36 (1 μM), a Y2 preferring C‐terminal fragment. High densities of binding sites remained present in the cerebral cortex, the thalamus and the medial mammillary nucleus when NPY13–36 was present in the incubation medium. Furthermore, these areas were highly enriched with [125 l][Leu31 , Pro34 ]NPY binding sites. In contrast, the hippocampal complex had its binding capacity reduced by ‐50%, while the lateral septum and mesencephalic dopaminergic areas had their binding capacities reduced even further. Linear regression analysis showed a high degree of correspondence between [125 l][Leu31 , Pro34 ]NPY binding and that obtained with [125 I]PYY in the presence of 1 μM NPY13–36 , suggesting that the two independent approaches to visualizing Y1 binding sites are comparable. In situ hybridization histochemistry revealed high levels of Y1 mRNA in the granular cell layer of the hippocampal dentate gyrus, several thalamic nuclei and the hypothalamic arcuate nucleus. Moderate levels of Y1 mRNA were seen in the frontoparietal cortex, several thalamic nuclei, the hippocampal pyramidal layers, the subiculum, the olfactory tubercle, the claustrum and a number of hypothalamic nuclei. The mesencephalon, the amygdala and most basal ganglia showed very low levels of hybridization. The present study further clarifies the anatomical distribution of multiple NPY binding sites within the central nervous system of the rat, and extends earlier suggestions that Y1 and Y2 receptor types are present within the central nervous system.
European Journal of Neuroscience - Tập 5 Số 12 - Trang 1622-1637 - 1993
Bypassing the Saccadic Pulse Generator: Possible Control of Head Movement Trajectory by Rat Superior Colliculus Abstract Saccades produced by electrical stimulation of the superior colliculus in primates are influenced primarily by the location of the stimulating electrode, with the suprathreshold intensity or frequency of the stimulating pulse train having little effect. Any given collicular site produces a characteristic movement of relatively fixed amplitude and velocity. In accordance with this finding, in models of the saccadic eye movement system the superior colliculus specifies the change of eye position: the velocity of movement components are determined by ‘pulse generators’ located between the superior colliculus and the oculomotor neurons. Previous findings in rodents, however, have suggested that eye and head movements induced by stimulation at some collicular sites may be critically dependent on stimulation parameters, implying that in these animals the superior colliculus has access to a non‐saccadic control system. To investigate this possibility, rats with electrodes implanted into the lateral intermediate layers were stimulated with pulse trains of varying frequency and duration, and the resultant head movements analysed from video tape. At seven of the nine sites studied, amplitude of the horizontal component of the head movement was linearly related to stimulating frequency for fixed‐duration trains, in some cases over a ten‐fold range. Subsequent variation of train duration showed that amplitude was affected not by frequency as such, but by the number of pulses in the train; frequency was related to the mean velocity of the movement. By appropriate setting of these parameters, independent control of head movement amplitude and velocity could be achieved. These results suggest that the rodent superior colliculus may be able to control head movement without recourse to a pulse generator, and thus influence the trajectory of the movement directly. If so, it may prove to be a useful preparation for testing theories of trajectory formation.
European Journal of Neuroscience - Tập 3 Số 8 - Trang 790-801 - 1991
Distribution of Glutamatergic Receptors and GAD mRNA‐Containing Neurons in the Vestibular Nuclei of Normal and Hemilabyrinthectomized Rats Abstract Vestibular compensation is an attractive model for investigations of cellular mechanisms underlying post‐lesional plasticity in the adult central nervous system. Immediately after hemilabyrinthectomy, the spontaneous activity in the deafferented second‐order vestibular neurons falls to zero, resulting in a strong asymmetry between the resting discharge of the vestibular complexes on the lesioned and intact sides. This asymmetry most probably causes the static and dynamic vestibular deficits observed in the acute stage. After ∼50 h, the deafferented vestibular neurons recover a quasi‐normal resting activity which is thought to be the key of the compensation of the static vestibular syndromes. However, the molecular mechanisms underlying this recovery are unknown. In this study, we investigate possible changes in the distribution of glutamatergic N ‐methyl‐d‐aspartate (NMDA) and glutamate metabotropic receptors and of glutamate decarboxylase 67k (GAD 67k) mRNAs in the deafferented vestibular neurons induced by the labyrinthine lesion. Specific radioactive oligonucleotides were used to probe sections of rat vestibular nuclei according to in situ hybridization methods. Animals were killed at different times (5 h, 3 days and 3 weeks) following the lesion. Signal was detected by means of film or emulsion autoradiography. In the normal animals, several brainstem regions including the medial, lateral, inferior and superior vestibular nuclei were densely labelled by the antisense oligonucleotide NMDAR1 probe. However, the vestibular nuclei were not labelled by the glutamate metabotropic oligonucleotide antisense probe (mGluR 1). The GAD 67k antisense oligonucleotide probe labelled numerous small‐ to medium‐sized central vestibular neurons but not the larger cell bodies in the lateral vestibular nucleus. This agrees with previous studies. In the hemilabyrinthectomized rats, no asymmetry could be detected, at either the autoradiographic or cellular levels, between the two medial vestibular nuclei whatever the probe used and whatever the delay following the lesion. However, for the NMDAR1 probe, the mean density of silver grains in both the deafferented and intact medial vestibular neurons was 20% lower 5 h after the lesion. Three days and 3 weeks later, the intensity of labelling over all cells was the same as in the control group. Further studies are necessary to confirm the relatively weak modification of the NMDAR1 mRNAs expression and to exclude a change of GAD 65 and of other NMDA subunit mRNAs during the vestibular compensation process.
European Journal of Neuroscience - Tập 6 Số 4 - Trang 565-576 - 1994
β3, a novel auxiliary subunit for the voltage‐gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain Abstract Adult dorsal root ganglia (DRG) have been shown to express a wide range of voltage‐gated sodium channel α‐subunits. However, of the auxiliary subunits, β1 is expressed preferentially in only large‐ and medium‐diameter neurons of the DRG while β2 is absent in all DRG cells. In view of this, we have compared the distribution of β1 in rat DRG and spinal cord with a novel, recently cloned β1‐like subunit, β3. In situ hybridization studies demonstrated high levels of β3 mRNA in small‐diameter c‐fibres, while β1 mRNA was virtually absent in these cell types but was expressed in 100% of large‐diameter neurons. In the spinal cord, β3 transcript was present specifically in layers I/II (substantia gelatinosa) and layer X, while β1 mRNA was expressed in all laminae throughout the grey matter. Since the pattern of β3 expression in DRG appears to correlate with the TTX‐resistant voltage‐gated sodium channel subunit PN3, we co‐expressed the two subunits in Xenopus oocytes. In this system, β3 caused a 5‐mV hyperpolarizing shift in the threshold of activation of PN3, and a threefold increase in the peak current amplitude when compared with PN3 expressed alone. On the basis of these results, we examined the expression of β‐subunits in the chronic constriction injury model of neuropathic pain. Results revealed a significant increase in β3 mRNA expression in small‐diameter sensory neurons of the ipsilateral DRG. These results show that β3 is the dominant auxiliary sodium channel subunit in small‐diameter neurons of the rat DRG and that it is significantly upregulated in a model of neuropathic pain.
European Journal of Neuroscience - Tập 12 Số 11 - Trang 3985-3990 - 2000
Mu‐ and delta‐opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors Abstract Opioids have previously been shown to affect proliferation and differentiation in various neural cell types. In the present study, cultured rat adult hippocampal progenitors (AHPs) were shown to release β‐endorphin. Membrane preparations of AHPs were found to bind [125 I]β‐endorphin, and immunoreactivity for mu‐ and delta‐opioid receptors (MORs and DORs), but not for kappa‐opioid receptors (KORs), was found on cells in culture. Both DNA content and [3 H]thymidine incorporation were reduced after a 48‐h incubation with 100 µm naloxone, 10 µm naltrindole or 10 µm β‐funaltrexamine, but not nor‐binaltorphimine, suggesting proliferative actions of endogenous opioids against MORs and DORs on AHPs. Furthermore, analysis of gene and protein expression after incubation with MOR and DOR antagonists for 48 h using RT‐PCR and Western blotting suggested decreased signalling through the mitogen‐activated protein kinase (MAPK) pathway and lowered levels of genes and proteins that are important in cell cycling. Cultures were incubated with naloxone (10 or 100 µm ) for 10 days to study the effects on differentiation. This resulted in an approximately threefold increase in neurogenesis, a threefold decrease in astrogliogenesis and a 50% decrease in oligodendrogenesis. In conclusion, this study suggests that reduced signalling through MORs and DORs decreases proliferation in rat AHPs, increases the number of in vitro ‐generated neurons and reduces the number of astrocytes and oligodendrocytes in culture.
European Journal of Neuroscience - Tập 17 Số 6 - Trang 1159-1172 - 2003
Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen Abstract Physical activities such as long‐distance running can be habit forming and associated with a sense of well‐being to a degree that justifies comparison with drug‐induced addictive behaviours. To understand molecular similarities and dissimilarities controlling these behaviours in humans we compared the effects of running in running wheels to the effects of chronic cocaine or morphine administration on mRNA levels in brain reward pathways in the inbred Fischer and Lewis rat strains. These strains are both inbred from the Sprague–Dawley strain; Lewis rats display a higher preference towards addictive drugs and running than do Fischer rats. After chronic cocaine or running a similar increase of dynorphin mRNA in medial caudate putamen was found in the Lewis rat, suggesting common neuronal adaptations in this brain region to both cocaine and running. Fischer and Lewis rats both responded to cocaine with increased dynorphin mRNA levels in medial caudate putamen. However, only Lewis rats increased dynorphin mRNA after running, possibly reflecting the much higher degree of running by the Lewis strain as compared to the Fischer strain. Moreover, the running‐induced upregulation of dynorphin mRNA was blocked by the opioid receptor antagonist naloxone. We suggest that running increases dynorphin mRNA by a mechanism that involves endogenous opioids. The voluntary wheel‐running model in rats might be used to study natural reward and compulsive behaviours and possibly also to screen candidate drugs for treatment of compulsive disorders.
European Journal of Neuroscience - Tập 12 Số 8 - Trang 2967-2974 - 2000
Ontogenetic development of the diencephalic MCH neurons: a hypothalamic ‘MCH area’ hypothesis Abstract 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’.
European Journal of Neuroscience - Tập 13 Số 9 - Trang 1733-1744 - 2001
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