European Journal of Neuroscience
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Expression and Coupling to Polyphosphoinositide Hydrolysis of Group I Metabotropic Glutamate Receptors in Early Postnatal and Adult Rat Brain Abstract We investigated the expression and coupling to the phospholipase C signal transduction pathway of metabotropic glutamate receptor (mGluR) subtypes by Western blot analysis and agonist‐stimulated inositol monophosphate formation in several brain regions of postnatal day 9 (P9) and adult rats. In the cerebral cortex, hippocampus, corpus striatum, olfactory bulb, cerebellum and hypothalamus, the expression level of mGluR5 was greater at P9 than in adulthood. The mGluR5 signal was very low or absent in the adult cerebellum and hypothalamus. The expression of mGluR1a was slightly greater at P9 in the hypothalamus, hippocampus and olfactory bulb, whereas it substantially increased with age in the cerebellum, and did not change in the cerebral cortex and corpus striatum. mGluR1b and ‐1c were nearly undetectable by Western blot analysis. The expression level of mGluR5, but not that of mGluR1a, was significantly correlated with the extent of phosphoinositide hydrolysis stimulated by mGluR agonists in slices prepared from these brain regions. The mGluR antagonist cyclopropan[b]chromen‐1a‐carboxylic acid ethylester (CPCCOEt), potently antagonized responses mediated by mGluR1, but much less potently those mediated by mGluR5a in recombinant cells. CPCCOEt, at a concentration which efficently blocks mGluR1 responses, did not substantially affect the polyphosphoinositide response in hippocampal or cerebellar slices from newborn animals, and antagonized only a minor component of the polyphosphoinositide response in adult hippocampal slices. CPCCOEt, however, prevented the small stimulation of polyphosphoinositide hydrolysis by mGluR agonists in adult cerebellar slices. We conclude that (i) the efficient mGluR‐mediated polyphosphoinositide hydrolysis in 9‐day‐old rats is mediated by mGluR5; (ii) the increased expression of mGluR1 in the adult cerebellum does not substitute for the decline of mGluR5 expression in the ability to mediate polyphosphoinositide hydrolysis; and therefore (iii) mGluRla might couple less efficiently than mGluR5 to polyphosphoinositide hydrolysis.
European Journal of Neuroscience - Tập 9 Số 1 - Trang 12-17 - 1997
Mechanisms of neurodegeneration in Huntington’s disease Abstract Huntington’s disease (HD) is caused by an expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss in the striatum and cortex and to the appearance of neuronal intranuclear inclusions of mutant huntingtin. Huntingtin plays a role in protein trafficking, vesicle transport, postsynaptic signaling, transcriptional regulation, and apoptosis. Thus, a loss of function of the normal protein and a toxic gain of function of the mutant huntingtin contribute to the disruption of multiple intracellular pathways. Furthermore, excitotoxicity, dopamine toxicity, metabolic impairment, mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy have been implicated in the progressive degeneration observed in HD. Nevertheless, despite the efforts of a multidisciplinary scientific community, there is no cure for this devastating neurodegenerative disorder. This review presents an overview of the mechanisms that may contribute for HD pathogenesis. Ultimately, a better understanding of these mechanisms will lead to the development of more effective therapeutic targets.
European Journal of Neuroscience - Tập 27 Số 11 - Trang 2803-2820 - 2008
Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor‐deficient mice Abstract Ghrelin, a hormone produced by the stomach, is generally associated with feeding responses and the regulation of food intake. Recent evidence, however, suggests that ghrelin is also a stress hormone, given that it is released following acute and chronic stressors. The present study examined the role of ghrelin in producing normal metabolic and neurochemical responses to chronic stress. This was achieved by examining these responses in mice with targeted deletions of the ghrelin receptor gene (GHSR KO mice), and comparing them with the same responses in their wild‐type (WT) littermates. As expected, WT stressed mice decreased their caloric intake, body weight gain and caloric efficiency while maintaining adiposity. GHSR KO mice, however, did not show these alterations despite having normal glucocorticoid responses to stress. In parallel with these changes, chronic unpredictable stress caused changes in norepinephrine, dopamine and serotonin in a number of brain regions. Of these, norepinephrine neurotransmission in the arcuate nucleus and prefrontal cortex was differentially altered in GHSR KO mice. Within the nucleus acumbens, dopamine utilization was increased in WT mice but not in GHSR KO mice. Finally, there were strain differences in serotonin neurotransmission that may explain interstrain body weight and adiposity differences. These results suggest that the metabolic changes necessary to deal with the energetic challenge presented by repeated exposure to stressors do not occur in GHSR KO mice, and they are discussed within the context of the potential vulnerability to stress‐induced pathology.
European Journal of Neuroscience - Tập 32 Số 4 - Trang 632-639 - 2010
Neuroendocrine responses to an emotional stressor: evidence for involvement of the medial but not the central amygdala Abstract The amygdala plays a pivotal role in the generation of appropriate responses to emotional stimuli. In the case of emotional stressors, these responses include activation of the hypothalamic–pituitary–adrenal (HPA) axis. This effect is generally held to depend upon the central nucleus of the amygdala, but recent evidence suggests a role for the medial nucleus. In the present study, c‐fos expression, amygdala lesion and retrograde tracing experiments were performed on adult rats in order to re‐evaluate the role of the central as opposed to the medial amygdala in generating neuroendocrine responses to an emotional stressor. Brief restraint (15 min) was used as a representative emotional stressor and was found to elicit c‐fos expression much more strongly in the medial than central nucleus of the amygdala; relatively few Fos‐positive cells were seen in other amygdala nuclei. Subsequent experiments showed that ibotenic acid lesions of the medial amygdala, but not the central amygdala, greatly reduced restraint‐induced activation of cells of the medial paraventricular nucleus, the site of the tuberoinfundibular corticotropin‐releasing factor cells that constitute the apex of the HPA axis. Medial amygdala lesions also reduced the activation of supraoptic and paraventricular nucleus oxytocinergic neurosecretory cells that commonly accompanies stress‐induced HPA axis activation in rodents. To assess whether the role of the medial amygdala in the control of neuroendocrine cell responses to emotional stress might involve a direct projection to such cells, retrograde tracing of amygdala projections to the paraventricular nucleus was performed in combination with Fos immunolabelling. This showed that although some medial amygdala cells activated by exposure to an emotional stressor project directly to the paraventricular nucleus, the number is very small. These findings provide the first direct evidence that it is the medial rather than the central amygdala that is critical to hypothalamic neuroendocrine cell responses during an emotional response, and also provide the first evidence that the amygdala governs oxytocin as well as HPA axis responses to an emotional stressor.
European Journal of Neuroscience - Tập 11 Số 7 - Trang 2312-2322 - 1999
Substance induced plasticity in noradrenergic innervation of the paraventricular hypothalamic nucleus Abstract Single administration of the cytokine interleukin‐1α (IL‐1), or the psychostimulant amphetamine, enhanced adrenocorticotropin hormone and corticosterone responses to a stress challenge weeks later. This long‐lasting hypothalamic‐pituitary‐adrenal (HPA)‐sensitization is paralleled by an increase in electrically evoked release of noradrenaline in the paraventricular hypothalamic nucleus (PVN). We hypothesized that these functional changes may be associated with morphological plasticity of noradrenergic projections to the PVN, a parameter that shows high reproducibility. Specific alterations in relative (nor)adrenergic innervation density were studied by using dopamine‐α‐hydroxylase (DBH) as a marker. An image analysis system was used to detect changes in the relative DBH innervation density of the PVN. Groups of adult male rats were given IL‐1 (10 µg/kg i.p.), amphetamine (5 mg/kg i.p.), or saline. Three weeks later, IL‐1 and amphetamine primed rats showed enhanced adrenocorticotropin hormone and corticosterone responses to an amphetamine challenge. In another set of experiments, the relative DBH innervation density was measured in different PVN subnuclei at four rostro‐caudal levels. Single administration of either IL‐1 or amphetamine causes three weeks later a selective decrease in relative DBH innervation density in those subnuclei of the PVN that contain high numbers of corticotrophin‐releasing hormone (CRH) producing neurons: the dorsal parvocellular and medial parvocellular PVN. We conclude that (1) long‐lasting sensitization induced by single exposure to IL‐1 and amphetamine induces specific pattern of neuroplastic changes in (nor)adrenergic innervation in the PVN and (2) reduction of relative DBH innervation density in CRH‐rich areas is associated with paradoxical increase of electrically evoked release of (nor)adrenaline.
European Journal of Neuroscience - Tập 17 Số 2 - Trang 298-306 - 2003
Disgust sensitivity predicts the insula and pallidal response to pictures of disgusting foods Abstract The anterior insula has been implicated in coding disgust from facial, pictorial and olfactory cues, and in the experience of this emotion. Personality research has shown considerable variation in individuals' trait propensity to experience disgust (‘disgust sensitivity’). Our study explored the neural expression of this trait, and demonstrates that individual variation in disgust sensitivity is significantly correlated with participants' ventroanterior insular response to viewing pictures of disgusting, but not appetizing or bland, foods. Similar correlations were also seen in the pallidum and orofacial regions of motor and somatosensory cortices. Our results also accord with comparative research showing an anterior to posterior gradient in the rat pallidum reflecting increased ‘liking’ of foods [Smith, K. S. and Berridge, K. C. (2005) J. Neurosci. , 25 , 849–8637].
European Journal of Neuroscience - Tập 25 Số 11 - Trang 3422-3428 - 2007
Dentate granule cell GABA<sub>A</sub> receptors in epileptic hippocampus: enhanced synaptic efficacy and altered pharmacology Abstract The dentate gyrus (DG) normally functions as a filter, preventing propagation of synchronized activity into the seizure‐prone hippocampus. This filter or ‘gatekeeper’ attribute of the DG is compromised in various pathological states, including temporal lobe epilepsy (TLE). This study examines the role that altered inhibition may play in the deterioration of this crucial DG function. Using the pilocarpine animal model of TLE, we demonstrate that inhibitory synaptic function is altered in principal cells of the DG. Spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in dentate granule cells (DGCs) from epileptic animals were larger, more sensitive to blockade by zinc and less sensitive to augmentation by the benzodiazepine type site 1 modulator zolpidem. Furthermore, mIPSCs examined during a quiescent period following injury but preceding onset of epilepsy were significantly smaller than those present either in control or in TLE DGCs, and had already acquired sensitivity to blockade by zinc prior to the onset of spontaneous seizures. Rapid agonist application experiments demonstrated that prolonged (>35 ms) exposure to zinc is required to block GABAA receptors (GABAA Rs) in patches pulled from epileptic DGCs. Therefore, zinc must be tonically present to block DGC GABAA Rs and alter DG function. This would occur only during repetitive activation of mossy fibres. Thus, in the pilocarpine animal model of TLE, an early, de novo , expression of zinc‐sensitive GABAA Rs is coupled with delayed, epilepsy‐induced development of a zinc delivery system provided by aberrant sprouting of zinc‐containing mossy fibre recurrent collaterals. The temporal and spatial juxtaposition of these pathophysiological alterations may compromise normal ‘gatekeeper’ function of the DG through dynamic zinc‐induced failure of inhibition, predisposing the hippocampal circuit to generate seizures.
European Journal of Neuroscience - Tập 17 Số 8 - Trang 1607-1616 - 2003
Systematic review of the effects of acute stress in binge eating disorder Abstract Binge eating disorder (BED ) is characterized by recurrent episodes of eating an excessive amount of food over a discrete time period, while feeling a loss of control over one's eating. Although stress is one of the most commonly reported triggers of binge eating in individuals with BED , there has been little work examining the stress response specifically in individuals with the disorder. In this review, we examine what is known about how individuals with BED respond to acute stressors. A systematic literature search identified 14 relevant articles that report on the effects of experimentally induced stress on objective measures. Dependent measures that have been examined include changes in the levels of hormones such as cortisol and ghrelin, cardiovascular function, ad libitum food intake and eating rate. In this review, we describe the published findings and discuss their implications in the context of the wider literature. Overall, we found partial evidence that BED is associated with a heightened response to stress. Given the inconsistencies between studies, we suggest that reported differences between individuals with and without BED might be driven by factors that are correlated with, but not specific to, BED . We suggest that two priorities for this research area are to identify factors that modulate the stress response in individuals with BED , and to address the underrepresentation of males in this literature.
European Journal of Neuroscience - Tập 50 Số 3 - Trang 2415-2429 - 2019
Contrast‐dependent Dissociation of Visual Recognition and Detection Fields Abstract Seeing an object‘as something’is different from simply seeing it (see Watanabe, S., 1985, Pattern Recognition: Human and Mechanical , John Wiley). This distinction between recognition and detection often goes unnoticed in physiology and clinical practice, where visual performance is characterized in terms of acuity, visual field and contrast sensitivity. The corresponding functions of stimulus detection are consistent with the neural projection properties from the retina to the striate cortex, i.e. the‘cortical magnification theory’. Yet recognition performance for characters (Strasburger, H. et al. , 1994, Eur. J. Neurosci. , 6, 1583‐1588) and grey‐level patterns (Jüttner, M. and Reutschler, I., 1996, Vision Res. , 36, 1007–1022) does not fit into this scheme. Here we show that this discrepancy results in the dissociation of visual recognition and detection fields, which is dramatic at low pattern contrast. Form proper can be appreciated exclusively within the much narrower field of recognition, the window of visual intelligence. Its function is, at low contrast, probably mediated by the magnocellular pathway and at all contrasts is determined by the processing characteristics of higher stages of the ventral visual pathway.
European Journal of Neuroscience - Tập 8 Số 8 - Trang 1787-1791 - 1996
Cortical Magnification Theory Fails to Predict Visual Recognition Abstract The sense of form is poor in indirect view. Yet the cortical magnification theory asserts that the disadvantage can be made up by scaling the image size according to the spatial variation in the mapping of the retina onto the cortex. It is thus assumed that all visual information passes through a functionally homogeneous neural circuitry, with the spatial sampling of input signals varying across the visual field. We challenge this notion by showing that character recognition in the visual field cannot be accommodated by any concept of sole size scaling but requires increasing both size and contrast of the target being viewed. This finding is formalized into a hyperbolic law which states that target size multiplied by log contrast is constant across the visual field. We conclude that the scalar cortical magnification theory fails for character recognition since the latter depends on multidimensional pattern representations in higher, i.e. striate and prestriate, cortical areas.
European Journal of Neuroscience - Tập 6 Số 10 - Trang 1583-1588 - 1994
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