Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are in... more Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.
Several lines of evidence indicate that cholinergic basalis neurons play an important role in cor... more Several lines of evidence indicate that cholinergic basalis neurons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotransmitters were injected into the region of the basalis neurons by remote control in freely moving, naturally sleeping-waking rats during the day when the rats are normally asleep the majority of the time. Effects were observed on behavior and EEG activity, including high-frequency gamma activity (30-60 Hz), which has been demonstrated to reflect behavioral and cortical arousal in the rat. Noradrenaline, which has been shown in previous in vitro studies to depolarize and excite the cholinergic cells, produced a dose-dependent increase in gamma-EEG activity, a decrease in delta activity, and an increase in waking. Serotonin, which has been found in previous in vitro studies to hyperpolarize the cholinergic neurons, produced a dose-dependent decrease in gamma-EEG activity with no significant change in amounts of wake or slow wave sleep. Both chemicals resulted in a dose-dependent decrease in paradoxical sleep. These results demonstrate that noradrenaline and serotonin exert differential modulatory effects on EEG activity through the basal forebrain, the one facilitating gamma activity and eliciting waking and the other diminishing gamma activity and not significantly affecting slow wave sleep. The results also confirm that the cholinergic basalis neurons play an important role in cortical activation and particularly in the high-frequency gamma activity that underlies cortical and behavioral arousal of the wake state.
Several lines of evidence indicate that cholinergic basalis neurons play an important role in cor... more Several lines of evidence indicate that cholinergic basalis neurons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotransmitters were injected into the region of the basalis neurons by remote control in freely moving, naturally sleeping-waking rats during the day when the rats are normally asleep the majority of the time. Effects were observed on behavior and EEG activity, including high-frequency ␥ activity (30-60 Hz), which has been demonstrated to reflect behavioral and cortical arousal in the rat. Noradrenaline, which has been shown in previous in vitro studies to depolarize and excite the cholinergic cells, produced a dose-dependent increase in ␥-EEG activity, a decrease in ␦ activity, and an increase in waking. Serotonin, which has been found in previous in vitro studies to hyperpolarize the cholinergic neurons, produced a dose-dependent decrease in ␥-EEG activity with no significant change in amounts of wake or slow wave sleep. Both chemicals resulted in a dose-dependent decrease in paradoxical sleep. These results demonstrate that noradrenaline and serotonin exert differential modulatory effects on EEG activity through the basal forebrain, the one facilitating ␥ activity and eliciting waking and the other diminishing ␥ activity and not significantly affecting slow wave sleep. The results also confirm that the cholinergic basalis neurons play an important role in cortical activation and particularly in the high-frequency ␥ activity that underlies cortical and behavioral arousal of the wake state.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2000
Cholinergic basal forebrain neurons have long been thought to play an important role in cortical ... more Cholinergic basal forebrain neurons have long been thought to play an important role in cortical activation and behavioral state, yet the precise way in which they influence these processes has yet to be fully understood. Here, we have examined the effects on the electroencephalogram (EEG) and sleep-wake state of basal forebrain administration of neurotensin (NT), a neuropeptide that has been shown in vitro to potently and selectively modulate the cholinergic cells. Microinjection of (0.1-3.0 mm) NT into the basal forebrain of freely moving, naturally waking-sleeping rats produced a dose-dependent decrease in delta ( approximately 1-4 Hz) and increase in both theta ( approximately 4-9 Hz) and high-frequency gamma activity (30-60 Hz) across cortical, areas with no increase in the electromyogram. These EEG changes were accompanied by concomitant decreases in slow wave sleep (SWS) and transitional SWS (tSWS), increases in wake, and most remarkably, increases in paradoxical sleep (PS) a...
Several lines of evidence indicate that cholinergic basalis neu- rons play an important role in c... more Several lines of evidence indicate that cholinergic basalis neu- rons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotrans- mitters were injected into the region of the basalis neurons by remote control in freely moving,
The occurrence of high-frequency g activity (30-60 Hz) and its relationship to other frequency ba... more The occurrence of high-frequency g activity (30-60 Hz) and its relationship to other frequency band activities were examined by spectral analysis of the electroencephalogram in association with sleep-wake states and spontaneous behaviors in the rat. In the electroencephalogram, 7 wave activity was evident in unfiltered and high-frequency filtered recordings, in which it was prominent during attentive or active Wake episodes and during Paradoxical Sleep, when 0-like activity was also apparent. In amplitude spectra from these episodes, multiple peaks were evident within the 7 frequency band, indicating broad-band high-frequency activity, in association with a single low-frequency peak in the 0 band. y peaks were attenuated during quiet Waking, in association with a low-frequency peak between 0 and 8, and during Slow Wave Sleep, in association with a low-frequency peak in the 8 band. In coherence spectra from ipsilateral cortical leads, peaks were also present within the 7 range and were significantly higher in Waking moving and Paradoxical Sleep than in Waking quiet and Slow Wave Sleep. In measures of frequency band amplitude, 7 activity (30.5-58.0 Hz) varied significantly across the sleep waking cycle, being similarly high during Wake and Paradoxical Sleep and lowest during Slow Wave Sleep. Across these states, y was negatively correlated with 8 (1.5~.0 Hz). In contrast, high [3 (19.0-30.0 Hz) was significantly lower in Wake than in Slow Wave Sleep and was positively correlated with 8. ? differed significantly across specific behaviors, being highest in Paradoxical Sleep with twitches and during Waking eating and moving behaviors, slightly lower in Waking attentive, lower in Waking grooming and as low in Waking quiet as during Slow Wave Sleep. These results indicate that the reciprocal variation of high-frequency 7 activity (and not [3) with low-frequency 8 activity reflects the sleel>waking cycle of the rat. Moreover, 7 activity reflects the degree of behavioral arousal, since it is high during active Waking, when the electromyogram is high, and low during quiet Waking, when the electromyogram is low. It also reflects cortical arousal, independent of motor activity, since it attains high levels in association with attentive immobility and maximal levels only during particular active behaviors (eating and moving and not grooming), and it also attains maximal levels during Paradoxical Sleep, when the nuchal electromyogram is minimal, but small twitches evidence dreaming. The co-variation of 7 and a slow oscillation in the 0 band across states and behaviors suggests that a common system may modulate these fast and slow electroencephalogram rhythms, and that such modulation, potentially emanating from the basal forebrain, could predominate during certain states or behaviors, such as Paradoxical Sleep.
Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to th... more Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to the cerebral cortex, basal forebrain neurons, including importantly the cholinergic cells therein, are believed to play a signi®cant role in eliciting and maintaining cortical activation during the states of waking and paradoxical sleep. The present study was undertaken in rats to examine the effects upon electroencephalogram (EEG) activity and sleep±wake state of inactivating basal forebrain neurons with microinjections of procaine versus activating them with microinjections of agonists of glutamate, which is the primary neurotransmitter of the brainstem reticular activating system. Microinjections into the basal forebrain were performed using a remotely controlled device in freely moving, naturally sleeping/waking rats during the day when they are asleep the majority of the time. Procaine produced a decrease in gamma (30±60 Hz) and theta (4±8 Hz) EEG activities, and an increase in delta (1±4 Hz) associated with a loss of paradoxical sleep, despite the persistence of slow wave sleep. a-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) produced an increase in gamma and a decrease in delta, while eliciting waking. In addition, NMDA, which has been shown in vitro to induce rhythmic bursting in the cholinergic cells, signi®cantly increased theta activity. Following the microinjections of NMDA, c-Fos protein, which has been shown to re¯ect neural activity, was found in numerous cholinergic, and also GABAergic (g-aminobutyric acid) and other non-cholinergic neurons, in the substantia innominata and magnocellular preoptic nucleus near the microinjection cannulae. These results substantiate the role of cholinergic, possibly together with other, basal forebrain neurons in cortical activation, including elicitation of gamma and theta activities that underlie cortical arousal during waking and paradoxical sleep.
Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to th... more Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to the cerebral cortex, basal forebrain neurons, including importantly the cholinergic cells therein, are believed to play a signi®cant role in eliciting and maintaining cortical activation during the states of waking and paradoxical sleep. The present study was undertaken in rats to examine the effects upon electroencephalogram (EEG) activity and sleep±wake state of inactivating basal forebrain neurons with microinjections of procaine versus activating them with microinjections of agonists of glutamate, which is the primary neurotransmitter of the brainstem reticular activating system. Microinjections into the basal forebrain were performed using a remotely controlled device in freely moving, naturally sleeping/waking rats during the day when they are asleep the majority of the time. Procaine produced a decrease in gamma (30±60 Hz) and theta (4±8 Hz) EEG activities, and an increase in delta (1±4 Hz) associated with a loss of paradoxical sleep, despite the persistence of slow wave sleep. a-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) produced an increase in gamma and a decrease in delta, while eliciting waking. In addition, NMDA, which has been shown in vitro to induce rhythmic bursting in the cholinergic cells, signi®cantly increased theta activity. Following the microinjections of NMDA, c-Fos protein, which has been shown to re¯ect neural activity, was found in numerous cholinergic, and also GABAergic (g-aminobutyric acid) and other non-cholinergic neurons, in the substantia innominata and magnocellular preoptic nucleus near the microinjection cannulae. These results substantiate the role of cholinergic, possibly together with other, basal forebrain neurons in cortical activation, including elicitation of gamma and theta activities that underlie cortical arousal during waking and paradoxical sleep.
Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are in... more Orexin (hypocretin)-containing neurons of the hypothalamus project to brainstem sites that are involved in the neural control of REM sleep, including the locus coeruleus, the dorsal raphe nucleus, the cholinergic zone of the mesopontine tegmentum, and the pontine reticular formation (PRF). Orexin knockout mice exhibit narcolepsy/cataplexy, and a mutant and defective gene for the orexin type II receptor is present in dogs with an inherited form of narcolepsy/cataplexy. However, the physiological systems mediating these effects have not been described. We reasoned that, since the effector neurons for the majority of REM sleep signs, including muscle atonia, were located in the PRF, this region was likely implicated in the production of these orexin-related abnormalities. To test this possibility, we used microdialysis perfusion of orexin type II receptor antisense in the PRF of rats. Ten to 24 hours after antisense perfusion, REM sleep increased two- to three-fold during both the light period (quiescent phase) and the dark period (active phase), and infrared video showed episodes of behavioral cataplexy. Moreover, preliminary data indicated no REM-related effects following perfusion with nonsense DNA, or when perfusion sites were outside the PRF. More work is needed to provide precise localization of the most effective site of orexin-induced inhibition of REM sleep phenomena.
Several lines of evidence indicate that cholinergic basalis neurons play an important role in cor... more Several lines of evidence indicate that cholinergic basalis neurons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotransmitters were injected into the region of the basalis neurons by remote control in freely moving, naturally sleeping-waking rats during the day when the rats are normally asleep the majority of the time. Effects were observed on behavior and EEG activity, including high-frequency gamma activity (30-60 Hz), which has been demonstrated to reflect behavioral and cortical arousal in the rat. Noradrenaline, which has been shown in previous in vitro studies to depolarize and excite the cholinergic cells, produced a dose-dependent increase in gamma-EEG activity, a decrease in delta activity, and an increase in waking. Serotonin, which has been found in previous in vitro studies to hyperpolarize the cholinergic neurons, produced a dose-dependent decrease in gamma-EEG activity with no significant change in amounts of wake or slow wave sleep. Both chemicals resulted in a dose-dependent decrease in paradoxical sleep. These results demonstrate that noradrenaline and serotonin exert differential modulatory effects on EEG activity through the basal forebrain, the one facilitating gamma activity and eliciting waking and the other diminishing gamma activity and not significantly affecting slow wave sleep. The results also confirm that the cholinergic basalis neurons play an important role in cortical activation and particularly in the high-frequency gamma activity that underlies cortical and behavioral arousal of the wake state.
Several lines of evidence indicate that cholinergic basalis neurons play an important role in cor... more Several lines of evidence indicate that cholinergic basalis neurons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotransmitters were injected into the region of the basalis neurons by remote control in freely moving, naturally sleeping-waking rats during the day when the rats are normally asleep the majority of the time. Effects were observed on behavior and EEG activity, including high-frequency ␥ activity (30-60 Hz), which has been demonstrated to reflect behavioral and cortical arousal in the rat. Noradrenaline, which has been shown in previous in vitro studies to depolarize and excite the cholinergic cells, produced a dose-dependent increase in ␥-EEG activity, a decrease in ␦ activity, and an increase in waking. Serotonin, which has been found in previous in vitro studies to hyperpolarize the cholinergic neurons, produced a dose-dependent decrease in ␥-EEG activity with no significant change in amounts of wake or slow wave sleep. Both chemicals resulted in a dose-dependent decrease in paradoxical sleep. These results demonstrate that noradrenaline and serotonin exert differential modulatory effects on EEG activity through the basal forebrain, the one facilitating ␥ activity and eliciting waking and the other diminishing ␥ activity and not significantly affecting slow wave sleep. The results also confirm that the cholinergic basalis neurons play an important role in cortical activation and particularly in the high-frequency ␥ activity that underlies cortical and behavioral arousal of the wake state.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2000
Cholinergic basal forebrain neurons have long been thought to play an important role in cortical ... more Cholinergic basal forebrain neurons have long been thought to play an important role in cortical activation and behavioral state, yet the precise way in which they influence these processes has yet to be fully understood. Here, we have examined the effects on the electroencephalogram (EEG) and sleep-wake state of basal forebrain administration of neurotensin (NT), a neuropeptide that has been shown in vitro to potently and selectively modulate the cholinergic cells. Microinjection of (0.1-3.0 mm) NT into the basal forebrain of freely moving, naturally waking-sleeping rats produced a dose-dependent decrease in delta ( approximately 1-4 Hz) and increase in both theta ( approximately 4-9 Hz) and high-frequency gamma activity (30-60 Hz) across cortical, areas with no increase in the electromyogram. These EEG changes were accompanied by concomitant decreases in slow wave sleep (SWS) and transitional SWS (tSWS), increases in wake, and most remarkably, increases in paradoxical sleep (PS) a...
Several lines of evidence indicate that cholinergic basalis neu- rons play an important role in c... more Several lines of evidence indicate that cholinergic basalis neu- rons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotrans- mitters were injected into the region of the basalis neurons by remote control in freely moving,
The occurrence of high-frequency g activity (30-60 Hz) and its relationship to other frequency ba... more The occurrence of high-frequency g activity (30-60 Hz) and its relationship to other frequency band activities were examined by spectral analysis of the electroencephalogram in association with sleep-wake states and spontaneous behaviors in the rat. In the electroencephalogram, 7 wave activity was evident in unfiltered and high-frequency filtered recordings, in which it was prominent during attentive or active Wake episodes and during Paradoxical Sleep, when 0-like activity was also apparent. In amplitude spectra from these episodes, multiple peaks were evident within the 7 frequency band, indicating broad-band high-frequency activity, in association with a single low-frequency peak in the 0 band. y peaks were attenuated during quiet Waking, in association with a low-frequency peak between 0 and 8, and during Slow Wave Sleep, in association with a low-frequency peak in the 8 band. In coherence spectra from ipsilateral cortical leads, peaks were also present within the 7 range and were significantly higher in Waking moving and Paradoxical Sleep than in Waking quiet and Slow Wave Sleep. In measures of frequency band amplitude, 7 activity (30.5-58.0 Hz) varied significantly across the sleep waking cycle, being similarly high during Wake and Paradoxical Sleep and lowest during Slow Wave Sleep. Across these states, y was negatively correlated with 8 (1.5~.0 Hz). In contrast, high [3 (19.0-30.0 Hz) was significantly lower in Wake than in Slow Wave Sleep and was positively correlated with 8. ? differed significantly across specific behaviors, being highest in Paradoxical Sleep with twitches and during Waking eating and moving behaviors, slightly lower in Waking attentive, lower in Waking grooming and as low in Waking quiet as during Slow Wave Sleep. These results indicate that the reciprocal variation of high-frequency 7 activity (and not [3) with low-frequency 8 activity reflects the sleel>waking cycle of the rat. Moreover, 7 activity reflects the degree of behavioral arousal, since it is high during active Waking, when the electromyogram is high, and low during quiet Waking, when the electromyogram is low. It also reflects cortical arousal, independent of motor activity, since it attains high levels in association with attentive immobility and maximal levels only during particular active behaviors (eating and moving and not grooming), and it also attains maximal levels during Paradoxical Sleep, when the nuchal electromyogram is minimal, but small twitches evidence dreaming. The co-variation of 7 and a slow oscillation in the 0 band across states and behaviors suggests that a common system may modulate these fast and slow electroencephalogram rhythms, and that such modulation, potentially emanating from the basal forebrain, could predominate during certain states or behaviors, such as Paradoxical Sleep.
Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to th... more Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to the cerebral cortex, basal forebrain neurons, including importantly the cholinergic cells therein, are believed to play a signi®cant role in eliciting and maintaining cortical activation during the states of waking and paradoxical sleep. The present study was undertaken in rats to examine the effects upon electroencephalogram (EEG) activity and sleep±wake state of inactivating basal forebrain neurons with microinjections of procaine versus activating them with microinjections of agonists of glutamate, which is the primary neurotransmitter of the brainstem reticular activating system. Microinjections into the basal forebrain were performed using a remotely controlled device in freely moving, naturally sleeping/waking rats during the day when they are asleep the majority of the time. Procaine produced a decrease in gamma (30±60 Hz) and theta (4±8 Hz) EEG activities, and an increase in delta (1±4 Hz) associated with a loss of paradoxical sleep, despite the persistence of slow wave sleep. a-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) produced an increase in gamma and a decrease in delta, while eliciting waking. In addition, NMDA, which has been shown in vitro to induce rhythmic bursting in the cholinergic cells, signi®cantly increased theta activity. Following the microinjections of NMDA, c-Fos protein, which has been shown to re¯ect neural activity, was found in numerous cholinergic, and also GABAergic (g-aminobutyric acid) and other non-cholinergic neurons, in the substantia innominata and magnocellular preoptic nucleus near the microinjection cannulae. These results substantiate the role of cholinergic, possibly together with other, basal forebrain neurons in cortical activation, including elicitation of gamma and theta activities that underlie cortical arousal during waking and paradoxical sleep.
Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to th... more Serving as the ventral, extra-thalamic relay from the brainstem reticular activating system to the cerebral cortex, basal forebrain neurons, including importantly the cholinergic cells therein, are believed to play a signi®cant role in eliciting and maintaining cortical activation during the states of waking and paradoxical sleep. The present study was undertaken in rats to examine the effects upon electroencephalogram (EEG) activity and sleep±wake state of inactivating basal forebrain neurons with microinjections of procaine versus activating them with microinjections of agonists of glutamate, which is the primary neurotransmitter of the brainstem reticular activating system. Microinjections into the basal forebrain were performed using a remotely controlled device in freely moving, naturally sleeping/waking rats during the day when they are asleep the majority of the time. Procaine produced a decrease in gamma (30±60 Hz) and theta (4±8 Hz) EEG activities, and an increase in delta (1±4 Hz) associated with a loss of paradoxical sleep, despite the persistence of slow wave sleep. a-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) produced an increase in gamma and a decrease in delta, while eliciting waking. In addition, NMDA, which has been shown in vitro to induce rhythmic bursting in the cholinergic cells, signi®cantly increased theta activity. Following the microinjections of NMDA, c-Fos protein, which has been shown to re¯ect neural activity, was found in numerous cholinergic, and also GABAergic (g-aminobutyric acid) and other non-cholinergic neurons, in the substantia innominata and magnocellular preoptic nucleus near the microinjection cannulae. These results substantiate the role of cholinergic, possibly together with other, basal forebrain neurons in cortical activation, including elicitation of gamma and theta activities that underlie cortical arousal during waking and paradoxical sleep.
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Papers by Edmund Cape