Neuropathology and Applied Neurobiology, Dec 1, 1999
Systemic administration of the mitochondrial toxin 3‐nitropropionic acid (3‐NP) to rats results i... more Systemic administration of the mitochondrial toxin 3‐nitropropionic acid (3‐NP) to rats results in selective striatal lesions and serves as an experimental model of Huntington’s disease (HD). However, the effects of the 3‐NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the striatal lesions induced by systemic administration of 3‐NP using osmotic pumps. Hematoxylin–eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse the neurotoxic effects of 3‐NP. In general, chronic systemic administration of 3‐NP resulted in obvious bilateral striatal lesions, which ranged from mild to severe, together with a subtle, but detectable behavioural lesion. Severe type lesions showed marked neuronal loss and an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesion area, whereas in the core of the lesion GFAP‐immunoreactivity was absent. The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP‐positive astrocytes throughout the lesion. In a number of 3‐NP‐treated animals, neither type of lesion was observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3‐NP‐treated animals, compromised rk’ neurones were detected, suggestive of subtle and early 3‐NP‐induced neuronal injury. Similar dark neurones were also detected in mild and severe lesions and were immunocytochemically characterized as γ‐aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3‐NP to rats may result in a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.
Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks mea... more Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA re...
In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallid... more In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallidus (GP) of the basal ganglia where nerve cell death is seen most dramatically. The distribution of five gap junction proteins (connexins 26, 32, 40, 43 and 50) has been examined in these areas in normal and Huntington's diseased human brain using immunohistochemical techniques. There was no Cx50 expression observed and Cx40 was localized in the endothelial cells of blood vessels, with the Huntington's diseased brains having more numerous and smaller blood vessels than normal tissue. Cx26 and Cx32 revealed a similar distribution pattern to each other in both normal and diseased brains with little labelling in the CN but clear labelling in the GP. Cx43, expressed by astrocytes, was the most abundant connexin type of those studied. In both normal and diseased brains Cx43 in the GP was homogeneously distributed in the neuropil. In the CN, however, Cx43 density was both increased with Huntington's disease and became located in patches. Glial fibrillary acidic protein(GFAP) staining of astrocytes was also highly increased in the CN compared with normal brains. These labelling patterns indicate a reactive astrocytosis around degenerating neurons with an increased expression of astrocytic gap junctions. The enhanced coupling state between astrocytes, assuming the junctions are functional, could provide an increased spatial buffering capacity by the astrocytes in an attempt to maintain a proper environment for the neurons, helping promote neuronal survival in this neurodegenerative disorder.
Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia ar... more Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia are largely unknown, yet disturbances in brain indexes of arousal seem to accompany the disorder. We here investigate whether insomnia patients and control participants differ with respect to brain responses to direct stimulation, i.e., cortical excitability. Transcranial magnetic stimulation (TMS) offers a method to directly investigate the excitability level of the human cerebral cortex in psychiatric and neurological disease. We investigated cortical excitability in 16 insomnia patients and 14 carefully matched control participants using absolute and relative amplitudes of motor evoked potentials in response to single- and paired-pulse stimulation using TMS. Nonmedicated insomnia patients showed, first, an exaggerated absolute response to both suprathreshold single- and paired-pulse stimulation compared with control participants and second, a reduced relative response to paired-pulse stimulation at long interpulse intervals (i.e., a reduced intracortical facilitation). The abnormal excitability persisted despite sleep therapy that effectively improved sleep quality as well as behavioral and neuroimaging indexes of brain function. The results suggest that a subtly disturbed intracortical excitability characterizes patients with chronic insomnia: a relatively reduced intracortical facilitation in the context of a globally increased absolute excitability. The findings do not resemble TMS findings after sleep deprivation or in sleep apnea and thus seem specific to insomnia. They may offer diagnostic value and implications for assessment of risk to develop this common and disabling disorder.
In murine corticostriatal slice cultures, we studied the protective effects of the bioenergetic c... more In murine corticostriatal slice cultures, we studied the protective effects of the bioenergetic compound creatine on neuronal cell death induced by the mitochondrial toxin 3-nitropropionic acid (3-NP). 3-NP caused a dose-dependent neuronal degeneration accompanied by an increased lactate dehydrogenase (LDH) activity in the cell culture medium. An increased ratio of lactate to pyruvate concentration in the medium suggested that metabolic activity shifted to anaerobic energy metabolism. These effects were predominantly observed in the 24-h recovery period after 3-NP exposure. Creatine protected against 3-NP neurotoxicity: LDH activity was reduced and aerobic respiration of pyruvate was stimulated, which resulted in lower lactate levels and less cell death. In both striatum and cortex, apoptosis in 3-NP-exposed slices was demonstrated by increased activation of the pro-apoptotic protein caspase-3 and by numerous cells exhibiting DNA fragmentation detected by the terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL) technique. Creatine administration to the 3-NP-exposed corticostriatal slices resulted in a reduced number of TUNEL-positive cells in the recovery period. However, in the striatum, an unexpected increase of both TUNEL-positive cells and caspase-3-immunostained cells was observed in the exposure phase in the presence of creatine. In the recovery phase, caspase-3-immunostaining decreased to basal levels in both striatum and cortex. These findings suggest that 3-NP-induced neuronal degeneration in corticostriatal slices results from apoptosis that in the cortex can be prevented by creatine, while in the more vulnerable striatal cells it may lead to an accelerated and increased execution of apoptotic cell death, preventing further necrosis-related damage in this region.
are two examples of diseases affecting both sleep and heart rate activity. Often an electrocardio... more are two examples of diseases affecting both sleep and heart rate activity. Often an electrocardiogram is used in clinical polysomnography. It is therefore important to understand the relation between sleep and heart rate. In 1973 Aldredge and Welch studied this relation. They found a decreasing mean and variability of heart rate with deeper night-time sleep
The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats an... more The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats and serves as an experimental model for the neurodegenerative disorder Huntington's disease (HD). Apoptotic cell death has been implicated for the neuronal degeneration that occurs in HD brains. The present study was designed to investigate whether the 3-NP-induced cell death in rats involves apoptosis and an altered expression of Bcl-2 family proteins. Systemic administration of 3-NP via subcutaneous Alzet pumps resulted in lesions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase-mediated biotinylated-UTP nick end-labelling (TUNEL) of DNA, TUNEL-positive cells exhibiting typical apoptotic morphology were detected only in the striatum of rats with a severe lesion. Furthermore, the neuronal expression of the pro-apoptotic protein Bax was strongly increased in the core of the severe lesion. Expression of the anti-apoptotic marker Bcl-2 was unchanged in this location, but was enhanced in the margins of the lesions. A moderately increased expression of both Bax and Bcl-2 was observed in dark neurones in the mild lesion and in the subtle lesion. The presence of nuclear DNA fragmentation, strong granular Bax expression and an increased Bax/Bcl-2 ratio in the centre of severe lesions suggests the occurrence of apoptotic cell death following 3-NP administration. In contrast, the dark compromised neurones observed in 3-NP-treated animals revealed an equally enhanced expression of both Bax and Bcl-2, but lacked TUNEL-labelling, and are therefore not apoptotic.
Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks mea... more Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA re...
Neuropathology and Applied Neurobiology, Dec 1, 1999
Systemic administration of the mitochondrial toxin 3‐nitropropionic acid (3‐NP) to rats results i... more Systemic administration of the mitochondrial toxin 3‐nitropropionic acid (3‐NP) to rats results in selective striatal lesions and serves as an experimental model of Huntington’s disease (HD). However, the effects of the 3‐NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the striatal lesions induced by systemic administration of 3‐NP using osmotic pumps. Hematoxylin–eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse the neurotoxic effects of 3‐NP. In general, chronic systemic administration of 3‐NP resulted in obvious bilateral striatal lesions, which ranged from mild to severe, together with a subtle, but detectable behavioural lesion. Severe type lesions showed marked neuronal loss and an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesion area, whereas in the core of the lesion GFAP‐immunoreactivity was absent. The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP‐positive astrocytes throughout the lesion. In a number of 3‐NP‐treated animals, neither type of lesion was observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3‐NP‐treated animals, compromised rk’ neurones were detected, suggestive of subtle and early 3‐NP‐induced neuronal injury. Similar dark neurones were also detected in mild and severe lesions and were immunocytochemically characterized as γ‐aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3‐NP to rats may result in a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.
Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks mea... more Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA re...
In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallid... more In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallidus (GP) of the basal ganglia where nerve cell death is seen most dramatically. The distribution of five gap junction proteins (connexins 26, 32, 40, 43 and 50) has been examined in these areas in normal and Huntington's diseased human brain using immunohistochemical techniques. There was no Cx50 expression observed and Cx40 was localized in the endothelial cells of blood vessels, with the Huntington's diseased brains having more numerous and smaller blood vessels than normal tissue. Cx26 and Cx32 revealed a similar distribution pattern to each other in both normal and diseased brains with little labelling in the CN but clear labelling in the GP. Cx43, expressed by astrocytes, was the most abundant connexin type of those studied. In both normal and diseased brains Cx43 in the GP was homogeneously distributed in the neuropil. In the CN, however, Cx43 density was both increased with Huntington's disease and became located in patches. Glial fibrillary acidic protein(GFAP) staining of astrocytes was also highly increased in the CN compared with normal brains. These labelling patterns indicate a reactive astrocytosis around degenerating neurons with an increased expression of astrocytic gap junctions. The enhanced coupling state between astrocytes, assuming the junctions are functional, could provide an increased spatial buffering capacity by the astrocytes in an attempt to maintain a proper environment for the neurons, helping promote neuronal survival in this neurodegenerative disorder.
Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia ar... more Chronic insomnia is a poorly understood disorder. Risk factors for developing chronic insomnia are largely unknown, yet disturbances in brain indexes of arousal seem to accompany the disorder. We here investigate whether insomnia patients and control participants differ with respect to brain responses to direct stimulation, i.e., cortical excitability. Transcranial magnetic stimulation (TMS) offers a method to directly investigate the excitability level of the human cerebral cortex in psychiatric and neurological disease. We investigated cortical excitability in 16 insomnia patients and 14 carefully matched control participants using absolute and relative amplitudes of motor evoked potentials in response to single- and paired-pulse stimulation using TMS. Nonmedicated insomnia patients showed, first, an exaggerated absolute response to both suprathreshold single- and paired-pulse stimulation compared with control participants and second, a reduced relative response to paired-pulse stimulation at long interpulse intervals (i.e., a reduced intracortical facilitation). The abnormal excitability persisted despite sleep therapy that effectively improved sleep quality as well as behavioral and neuroimaging indexes of brain function. The results suggest that a subtly disturbed intracortical excitability characterizes patients with chronic insomnia: a relatively reduced intracortical facilitation in the context of a globally increased absolute excitability. The findings do not resemble TMS findings after sleep deprivation or in sleep apnea and thus seem specific to insomnia. They may offer diagnostic value and implications for assessment of risk to develop this common and disabling disorder.
In murine corticostriatal slice cultures, we studied the protective effects of the bioenergetic c... more In murine corticostriatal slice cultures, we studied the protective effects of the bioenergetic compound creatine on neuronal cell death induced by the mitochondrial toxin 3-nitropropionic acid (3-NP). 3-NP caused a dose-dependent neuronal degeneration accompanied by an increased lactate dehydrogenase (LDH) activity in the cell culture medium. An increased ratio of lactate to pyruvate concentration in the medium suggested that metabolic activity shifted to anaerobic energy metabolism. These effects were predominantly observed in the 24-h recovery period after 3-NP exposure. Creatine protected against 3-NP neurotoxicity: LDH activity was reduced and aerobic respiration of pyruvate was stimulated, which resulted in lower lactate levels and less cell death. In both striatum and cortex, apoptosis in 3-NP-exposed slices was demonstrated by increased activation of the pro-apoptotic protein caspase-3 and by numerous cells exhibiting DNA fragmentation detected by the terminal transferase-mediated biotinylated-UTP nick end-labeling (TUNEL) technique. Creatine administration to the 3-NP-exposed corticostriatal slices resulted in a reduced number of TUNEL-positive cells in the recovery period. However, in the striatum, an unexpected increase of both TUNEL-positive cells and caspase-3-immunostained cells was observed in the exposure phase in the presence of creatine. In the recovery phase, caspase-3-immunostaining decreased to basal levels in both striatum and cortex. These findings suggest that 3-NP-induced neuronal degeneration in corticostriatal slices results from apoptosis that in the cortex can be prevented by creatine, while in the more vulnerable striatal cells it may lead to an accelerated and increased execution of apoptotic cell death, preventing further necrosis-related damage in this region.
are two examples of diseases affecting both sleep and heart rate activity. Often an electrocardio... more are two examples of diseases affecting both sleep and heart rate activity. Often an electrocardiogram is used in clinical polysomnography. It is therefore important to understand the relation between sleep and heart rate. In 1973 Aldredge and Welch studied this relation. They found a decreasing mean and variability of heart rate with deeper night-time sleep
The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats an... more The mitochondrial toxin 3-nitropropionic acid (3-NP) causes selective striatal lesions in rats and serves as an experimental model for the neurodegenerative disorder Huntington's disease (HD). Apoptotic cell death has been implicated for the neuronal degeneration that occurs in HD brains. The present study was designed to investigate whether the 3-NP-induced cell death in rats involves apoptosis and an altered expression of Bcl-2 family proteins. Systemic administration of 3-NP via subcutaneous Alzet pumps resulted in lesions of variable severity with neuronal loss and gliosis in the striatum. Using the terminal transferase-mediated biotinylated-UTP nick end-labelling (TUNEL) of DNA, TUNEL-positive cells exhibiting typical apoptotic morphology were detected only in the striatum of rats with a severe lesion. Furthermore, the neuronal expression of the pro-apoptotic protein Bax was strongly increased in the core of the severe lesion. Expression of the anti-apoptotic marker Bcl-2 was unchanged in this location, but was enhanced in the margins of the lesions. A moderately increased expression of both Bax and Bcl-2 was observed in dark neurones in the mild lesion and in the subtle lesion. The presence of nuclear DNA fragmentation, strong granular Bax expression and an increased Bax/Bcl-2 ratio in the centre of severe lesions suggests the occurrence of apoptotic cell death following 3-NP administration. In contrast, the dark compromised neurones observed in 3-NP-treated animals revealed an equally enhanced expression of both Bax and Bcl-2, but lacked TUNEL-labelling, and are therefore not apoptotic.
Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks mea... more Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA re...
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