Robert Strecker - Academia.edu (original) (raw)

Papers by Robert Strecker

Research paper thumbnail of Fetal Dopamine Neurons Implanted Unilaterally into the Nucleus Accumbens Drive Amphetamine-induced Locomotion and Circling

Annals of the New York Academy of Sciences, 1987

The nucleus accumbens septi (NAS) receives a major innervation from A10 ventral tegmental neurons... more The nucleus accumbens septi (NAS) receives a major innervation from A10 ventral tegmental neurons of the mesolimbic dopaminergic system and is considered to act as an interface between limbic and striatal sensorimotor structures. The NAS has been proposed to act as an "amplifier" in locomotor behaviors because dopamine (DA) injections into the NAS induce locomotion, and because local 6-hydroxydopamine (6-OHDA) lesions of the NAS can block the increases in locomotor or rotational behavior caused by peripheral amphetamine injection. Unilateral lesions of the ascending mesostriatal DA pathway (indicated here as MS lesion) produce rotational asymmetry characterized by ipsilateral rotation (toward side with the lesion) that can be increased by giving amphetamine. Moore and Kelly',* have suggested that in this MS lesion rotational paradigm, depletion of DA in the caudate-putamen is responsible for the postural asymmetry and direction of rotation, whereas levels of DA in the NAS determine the magnitude or speed of rotation. In addition, Moore and Kelly',2 proposed that the NAS complex acts only as an "amplifier" in turning behavior, such that an asymmetry of the NAS system alone will not cause turning.

Research paper thumbnail of Intracerebral Neuronal Grafting in Experimental Animal Models of Age-related Motor Dysfunction

Annals of the New York Academy of Sciences, 1988

Age-related motor decline is not a unitary process and it is important to dissociate motor declin... more Age-related motor decline is not a unitary process and it is important to dissociate motor decline from motivational decline, sensory inattention, and cognitive disorientation. In addition, deficits in balance and coordination of central nervous system origin must be dissociated from motor deficits of peripheral origin such as muscle atrophy. The problem is compounded when looking at the aging organism because all of these changes can be occurring to a small degree simultaneously, thereby giving the picture of a major deficit. Enough is known about the underlying anatomy of these different systems to believe that each system acts with some independence. However, less is known about how each of these systems interacts with each other, especially in relation to age-related decline.

Research paper thumbnail of Intracerebral Grafting of Dopamine Neurons

Annals of the New York Academy of Sciences, 1987

Research paper thumbnail of Human fetal basal forebrain neurons grafted to the denervated rat hippocampus produce an organotypic cholinergic reinnervation pattern

Brain Research, 1988

The septal/diagonal band (SDB) area, obtained from a 9-to 10-week-old aborted human fetus, was gr... more The septal/diagonal band (SDB) area, obtained from a 9-to 10-week-old aborted human fetus, was grafted to the hippocampal formation of adult, immunosuppressed rats subjected to an aspirative lesion of the fimbria-fornix. Nineteen weeks after transplantation, microscopical analysis revealed large, partly acetylcholinesterase (AChE)-positive grafts in the hippocampus in 3 of the 5 recipients. The AChE-positive grafts gave rise to a reinnervation of the host hippocampus and an AChE-positive lamination of the different hippocampal subfields with the same characteristics as the normal septum-derived innervation. Immunological evaluation of host sera revealed that all rats were immunized by the graft. This indicates that grafted human cholinergic SDB neurons can respond to or interact with factors that regulate and guide the innervation of the rat hippocampus.

Research paper thumbnail of Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state

Behavioural Brain Research, 2000

This review describes a series of animal experiments that investigate the role of endogenous aden... more This review describes a series of animal experiments that investigate the role of endogenous adenosine (AD) in sleep. We propose that AD is a modulator of the sleepiness associated with prolonged wakefulness. More specifically, we suggest that, during prolonged wakefulness, extracellular AD accumulates selectively in the basal forebrain (BF) and cortex and promotes the transition from wakefulness to slow wave sleep (SWS) by inhibiting cholinergic and non-cholinergic wakefulness-promoting BF neurons at the AD A1 receptor. New in vitro data are also compatible with the hypothesis that, via presynaptic inhibition of GABAergic inhibitory input, AD may disinhibit neurons in the preoptic/anterior hypothalamus (POAH) that have SWS-selective activity and Fos expression. Our in vitro recordings initially showed that endogenous AD suppressed the discharge activity of neurons in the BF cholinergic zone via the AD A1 receptor. Moreover, in identified mesopontine cholinergic neurons, AD was shown to act post-synaptically by hyperpolarizng the membrane via an inwardly rectifying potassium current and inhibition of the hyperpolarization-activated current, I h . In vivo microdialysis in the cat has shown that AD in the BF cholinergic zone accumulates during prolonged wakefulness, and declines slowly during subsequent sleep, findings confirmed in the rat. Moreover, increasing BF AD concentrations to approximately the level as during sleep deprivation by a nucleoside transport blocker mimicked the effect of sleep deprivation on both the EEG power spectrum and behavioral state distribution: wakefulness was decreased, and there were increases in SWS and REM sleep. As predicted, microdialyis application of the specific A1 receptor antagonist cyclopentyltheophylline (CPT) in the BF produced the opposite effects on behavioral state, increasing wakefulness and decreasing SWS and REM. Combined unit recording and microdialysis studies have shown neurons selectively active in wakefulness, compared with SWS, have discharge activity suppressed by both AD and the A1-specific agonist cyclohexyladenosine (CHA), while discharge activity is increased by the A1 receptor antagonist, CPT. We next addressed the question of whether AD exerts its effects locally or globally. Adenosine accumulation during prolonged wakefulness occurred in the BF and neocortex, although, unlike in the BF, cortical AD levels declined in the 6th h of sleep deprivation and declined further during subsequent recovery sleep. Somewhat to our surprise, AD concentrations did not increase during prolonged wakefulness (6 h) even in regions important in behavioral state control, such as the POAH, dorsal raphe nucleus, and pedunculopontine tegmental nucleus, nor did it increase in the ventrolateral/ventroanterior thalamic nucleii. These data suggest the presence of brain region-specific differences in AD transporters and/or degradation that become evident with prolonged wakefulness, even though AD concentrations are higher in all brain sites sampled during the naturally occurring (and shorter duration) episodes of wakefulness as compared to sleep episodes in the freely moving and behaving cat. Might AD also produce modulation of activity of neurons that have sleep selective transcriptional (Fos) and discharge activity in the preoptic/anterior hypothalamus zone? Whole cell patch clamp recordings in the in vitro horizontal slice showed fast and likely GABAergic inhibitory post-synaptic potentials and currents that were greatly decreased by bath application of AD. Adenosine may thus disinhibit and promote expression of sleep-related neuronal activity in the POAH. In summary, a growing body of evidence supports the role of AD as a mediator of the sleepiness following prolonged wakefulness, a role in which its inhibitory

Research paper thumbnail of Orexin-A levels in the lateral hypothalamus (LH) of rat

Research paper thumbnail of Nocturnal elevation of extracellular adenosine in the rat basal forebrain

Sleep research online: SRO

Research paper thumbnail of Sleep deprivation in rats produces attentional impairments on a 5-choice serial reaction time task

Sleep

To develop a rodent model of the attentional dysfunction caused by sleep loss. The attentional pe... more To develop a rodent model of the attentional dysfunction caused by sleep loss. The attentional performance of rats was assessed after 4, 7, and 10 hours of total sleep deprivation on a 5-choice serial reaction time task, in which rats detect and respond to brief visual stimuli. The rats were housed, sleep deprived, and behaviorally tested in a controlled laboratory setting. Ten male Long-Evans rats were used in the study. Rats were trained to criteria and subsequently tested in daily sessions of 100 trials at approximately 4:00 PM (lights on 8:00 AM-8:00 PM). Attentional performance was measured after 4, 7, 10 hours of total sleep deprivation induced by gentle handling. Sleep deprivation produced a monotonic increase in response latencies across the 4-hour, 7-hour, and 10-hour deprivations. Sleep deprivation also led to increased omission errors, but the overall number of perseverative and premature responses was unchanged. Subgroups of rats were differentially affected in the numbe...

Research paper thumbnail of Regional density of dopamine innervation in the neostriatum of weaver mutant mouse: Effect of ventral mesencephalic grafts

Research paper thumbnail of Another chapter in the adenosine story

Research paper thumbnail of Neuromodulation of the pedunculopontine tegmental nucleus (PPT) in the control of REM sleep as studied by microdialysis

Research paper thumbnail of Sleep allostasis in chronic sleep restriction: The role of the norepinephrine system

Brain research

Sleep responses to chronic sleep restriction may be very different from those observed after acut... more Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the α1- adrenergic receptor in the basal forebrain as well as α2- and β1- adrenergic receptor in the anterior cingulate cortex only on the first sleep...

Research paper thumbnail of Decoupling of sleepiness from sleep time and intensity during chronic sleep restriction: evidence for a role of the adenosine system

Sleep

Sleep responses to chronic sleep restriction (CSR) might be very different from those observed af... more Sleep responses to chronic sleep restriction (CSR) might be very different from those observed after short-term total sleep deprivation. For example, after sleep restriction continues for several consecutive days, animals no longer express compensatory increases in daily sleep time and sleep intensity. However, it is unknown if these allostatic, or adaptive, sleep responses to CSR are paralleled by behavioral and neurochemical measures of sleepiness. This study was designed to investigate CSR-induced changes in (1) sleep time and intensity as a measure of electrophysiological sleepiness, (2) sleep latency as a measure of behavioral sleepiness, and (3) brain adenosine A1 (A1R) and A2a receptor (A2aR) mRNA levels as a putative neurochemical correlate of sleepiness. Male Sprague-Dawley rats A 5-day sleep restriction (SR) protocol consisting of 18-h sleep deprivation and 6-h sleep opportunity each day. Unlike the first SR day, rats did not sleep longer or deeper on days 2 through 5, eve...

Research paper thumbnail of Sleep active cortical neurons expressing neuronal nitric oxide synthase are active after both acute sleep deprivation and chronic sleep restriction

Neuroscience

Non-rapid eye movement (NREM) sleep electroencephalographic (EEG) delta power (∼0.5 to 4 Hz), als... more Non-rapid eye movement (NREM) sleep electroencephalographic (EEG) delta power (∼0.5 to 4 Hz), also known as slow wave activity (SWA), is typically enhanced after acute sleep deprivation (SD) but not after chronic sleep restriction (CSR). Recently, sleep-active cortical neurons expressing neuronal nitric oxide synthase (nNOS) were identified and associated with enhanced SWA after short acute bouts of SD (i.e., 6 h). However, the relationship between cortical nNOS neuronal activity and SWA during CSR is unknown. We compared the activity of cortical neurons expressing nNOS (via c-Fos and nNOS immuno-reactivity, respectively) and sleep in rats in 3 conditions: 1) after 18 h of acute SD; 2) after 5 consecutive days of sleep restriction (SR) (18 h SD per day with 6 h ad libitum sleep opportunity per day); 3) and time-of-day matched ad libitum sleep controls. Cortical nNOS neuronal activity was enhanced during sleep after both 18 h SD and 5 days of SR treatments compared to control treatme...

Research paper thumbnail of Kim Y et al 2012 CSR Adensoine receptor mRNA

Research paper thumbnail of Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain

Journal of sleep research, Jan 21, 2015

Although chronic sleep restriction frequently produces long-lasting behavioural and physiological... more Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep rest...

Research paper thumbnail of Microdialysis elevation of adenosine in the basal forebrain produces vigilance impairments in the rat psychomotor vigilance task

Sleep, 2008

The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts... more The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts potently in the basal forebrain (BF) to increase sleepiness. Here 300 microM of adenosine was dialyzed in the BF of rats, and the effect on vigilance was determined in the rat Psychomotor Vigilance Task (rPVT). Rats experienced all experimental conditions in a repeated-measures, cross-over design. Twelve young adult male Fischer-Norway rats. Sustained attention performance in the rPVT was evaluated following 2 hours of bilateral microdialysis perfusion of vehicle, adenosine (300 microM), or codialysis of 300 microM of adenosine with the A1 receptor antagonist 8-cyclopentyltheophylline. During rPVT performance, response latencies and performance lapses increased significantly after adenosine dialysis when compared with baseline (no dialysis) or vehicle dialysis sessions. The codialysis of 8-cyclopentyltheophylline with adenosine completely blocked the effects produced by adenosine alone,...

Research paper thumbnail of Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species

Neuroscience, 2002

The ventrolateral preoptic nucleus (VLPO) is a group of sleep-active neurons that has been identi... more The ventrolateral preoptic nucleus (VLPO) is a group of sleep-active neurons that has been identified in the hypothalamus of rats and is thought to inhibit the major ascending monoaminergic arousal systems during sleep; lesions of the VLPO cause insomnia. Identification of the VLPO in other species has been complicated by the lack of a marker for this cell population, other than the expression of Fos during sleep. We now report that a high percentage of the sleep-active (Fos-expressing) VLPO neurons express mRNA for the inhibitory neuropeptide, galanin, in nocturnal rodents (mice and rats), diurnal rodents (degus), and cats. A homologous (i.e. galanin mRNA-containing cell group) is clearly distinguishable in the ventrolateral region of the preoptic area in diurnal and nocturnal monkeys, as well as in humans. Galanin expression may serve to identify sleep-active neurons in the ventrolateral preoptic area of the mammalian brain. The VLPO appears to be a critical component of sleep cir...

Research paper thumbnail of Behavioral state control through differential serotonergic inhibition in the mesopontine cholinergic nuclei: a simultaneous unit recording and microdialysis study

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

Cholinergic neurons of the mesopontine nuclei are strongly implicated in behavioral state regulat... more Cholinergic neurons of the mesopontine nuclei are strongly implicated in behavioral state regulation. One population of neurons in the cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as rapid eye movement (REM)-on neurons, shows preferential discharge activity during REM sleep, and extensive data indicate a key role in production of this state. Another neuronal group present in the same cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as Wake/REM-on neurons, shows preferential discharge activity during both wakefulness and REM sleep and is implicated in the production of electroencephalographic activation in both of these states. To test the hypothesis of differential serotonergic inhibition as an explanation of the different state-related discharge activity, we developed a novel methodology that enabled, in freely behaving animals, simultaneous unit recording and local perfusion of neuropharmacol...

Research paper thumbnail of Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations

Proceedings of the National Academy of Sciences of the United States of America, Jan 2, 2015

Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cogniti... more Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ...

Research paper thumbnail of Fetal Dopamine Neurons Implanted Unilaterally into the Nucleus Accumbens Drive Amphetamine-induced Locomotion and Circling

Annals of the New York Academy of Sciences, 1987

The nucleus accumbens septi (NAS) receives a major innervation from A10 ventral tegmental neurons... more The nucleus accumbens septi (NAS) receives a major innervation from A10 ventral tegmental neurons of the mesolimbic dopaminergic system and is considered to act as an interface between limbic and striatal sensorimotor structures. The NAS has been proposed to act as an "amplifier" in locomotor behaviors because dopamine (DA) injections into the NAS induce locomotion, and because local 6-hydroxydopamine (6-OHDA) lesions of the NAS can block the increases in locomotor or rotational behavior caused by peripheral amphetamine injection. Unilateral lesions of the ascending mesostriatal DA pathway (indicated here as MS lesion) produce rotational asymmetry characterized by ipsilateral rotation (toward side with the lesion) that can be increased by giving amphetamine. Moore and Kelly',* have suggested that in this MS lesion rotational paradigm, depletion of DA in the caudate-putamen is responsible for the postural asymmetry and direction of rotation, whereas levels of DA in the NAS determine the magnitude or speed of rotation. In addition, Moore and Kelly',2 proposed that the NAS complex acts only as an "amplifier" in turning behavior, such that an asymmetry of the NAS system alone will not cause turning.

Research paper thumbnail of Intracerebral Neuronal Grafting in Experimental Animal Models of Age-related Motor Dysfunction

Annals of the New York Academy of Sciences, 1988

Age-related motor decline is not a unitary process and it is important to dissociate motor declin... more Age-related motor decline is not a unitary process and it is important to dissociate motor decline from motivational decline, sensory inattention, and cognitive disorientation. In addition, deficits in balance and coordination of central nervous system origin must be dissociated from motor deficits of peripheral origin such as muscle atrophy. The problem is compounded when looking at the aging organism because all of these changes can be occurring to a small degree simultaneously, thereby giving the picture of a major deficit. Enough is known about the underlying anatomy of these different systems to believe that each system acts with some independence. However, less is known about how each of these systems interacts with each other, especially in relation to age-related decline.

Research paper thumbnail of Intracerebral Grafting of Dopamine Neurons

Annals of the New York Academy of Sciences, 1987

Research paper thumbnail of Human fetal basal forebrain neurons grafted to the denervated rat hippocampus produce an organotypic cholinergic reinnervation pattern

Brain Research, 1988

The septal/diagonal band (SDB) area, obtained from a 9-to 10-week-old aborted human fetus, was gr... more The septal/diagonal band (SDB) area, obtained from a 9-to 10-week-old aborted human fetus, was grafted to the hippocampal formation of adult, immunosuppressed rats subjected to an aspirative lesion of the fimbria-fornix. Nineteen weeks after transplantation, microscopical analysis revealed large, partly acetylcholinesterase (AChE)-positive grafts in the hippocampus in 3 of the 5 recipients. The AChE-positive grafts gave rise to a reinnervation of the host hippocampus and an AChE-positive lamination of the different hippocampal subfields with the same characteristics as the normal septum-derived innervation. Immunological evaluation of host sera revealed that all rats were immunized by the graft. This indicates that grafted human cholinergic SDB neurons can respond to or interact with factors that regulate and guide the innervation of the rat hippocampus.

Research paper thumbnail of Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state

Behavioural Brain Research, 2000

This review describes a series of animal experiments that investigate the role of endogenous aden... more This review describes a series of animal experiments that investigate the role of endogenous adenosine (AD) in sleep. We propose that AD is a modulator of the sleepiness associated with prolonged wakefulness. More specifically, we suggest that, during prolonged wakefulness, extracellular AD accumulates selectively in the basal forebrain (BF) and cortex and promotes the transition from wakefulness to slow wave sleep (SWS) by inhibiting cholinergic and non-cholinergic wakefulness-promoting BF neurons at the AD A1 receptor. New in vitro data are also compatible with the hypothesis that, via presynaptic inhibition of GABAergic inhibitory input, AD may disinhibit neurons in the preoptic/anterior hypothalamus (POAH) that have SWS-selective activity and Fos expression. Our in vitro recordings initially showed that endogenous AD suppressed the discharge activity of neurons in the BF cholinergic zone via the AD A1 receptor. Moreover, in identified mesopontine cholinergic neurons, AD was shown to act post-synaptically by hyperpolarizng the membrane via an inwardly rectifying potassium current and inhibition of the hyperpolarization-activated current, I h . In vivo microdialysis in the cat has shown that AD in the BF cholinergic zone accumulates during prolonged wakefulness, and declines slowly during subsequent sleep, findings confirmed in the rat. Moreover, increasing BF AD concentrations to approximately the level as during sleep deprivation by a nucleoside transport blocker mimicked the effect of sleep deprivation on both the EEG power spectrum and behavioral state distribution: wakefulness was decreased, and there were increases in SWS and REM sleep. As predicted, microdialyis application of the specific A1 receptor antagonist cyclopentyltheophylline (CPT) in the BF produced the opposite effects on behavioral state, increasing wakefulness and decreasing SWS and REM. Combined unit recording and microdialysis studies have shown neurons selectively active in wakefulness, compared with SWS, have discharge activity suppressed by both AD and the A1-specific agonist cyclohexyladenosine (CHA), while discharge activity is increased by the A1 receptor antagonist, CPT. We next addressed the question of whether AD exerts its effects locally or globally. Adenosine accumulation during prolonged wakefulness occurred in the BF and neocortex, although, unlike in the BF, cortical AD levels declined in the 6th h of sleep deprivation and declined further during subsequent recovery sleep. Somewhat to our surprise, AD concentrations did not increase during prolonged wakefulness (6 h) even in regions important in behavioral state control, such as the POAH, dorsal raphe nucleus, and pedunculopontine tegmental nucleus, nor did it increase in the ventrolateral/ventroanterior thalamic nucleii. These data suggest the presence of brain region-specific differences in AD transporters and/or degradation that become evident with prolonged wakefulness, even though AD concentrations are higher in all brain sites sampled during the naturally occurring (and shorter duration) episodes of wakefulness as compared to sleep episodes in the freely moving and behaving cat. Might AD also produce modulation of activity of neurons that have sleep selective transcriptional (Fos) and discharge activity in the preoptic/anterior hypothalamus zone? Whole cell patch clamp recordings in the in vitro horizontal slice showed fast and likely GABAergic inhibitory post-synaptic potentials and currents that were greatly decreased by bath application of AD. Adenosine may thus disinhibit and promote expression of sleep-related neuronal activity in the POAH. In summary, a growing body of evidence supports the role of AD as a mediator of the sleepiness following prolonged wakefulness, a role in which its inhibitory

Research paper thumbnail of Orexin-A levels in the lateral hypothalamus (LH) of rat

Research paper thumbnail of Nocturnal elevation of extracellular adenosine in the rat basal forebrain

Sleep research online: SRO

Research paper thumbnail of Sleep deprivation in rats produces attentional impairments on a 5-choice serial reaction time task

Sleep

To develop a rodent model of the attentional dysfunction caused by sleep loss. The attentional pe... more To develop a rodent model of the attentional dysfunction caused by sleep loss. The attentional performance of rats was assessed after 4, 7, and 10 hours of total sleep deprivation on a 5-choice serial reaction time task, in which rats detect and respond to brief visual stimuli. The rats were housed, sleep deprived, and behaviorally tested in a controlled laboratory setting. Ten male Long-Evans rats were used in the study. Rats were trained to criteria and subsequently tested in daily sessions of 100 trials at approximately 4:00 PM (lights on 8:00 AM-8:00 PM). Attentional performance was measured after 4, 7, 10 hours of total sleep deprivation induced by gentle handling. Sleep deprivation produced a monotonic increase in response latencies across the 4-hour, 7-hour, and 10-hour deprivations. Sleep deprivation also led to increased omission errors, but the overall number of perseverative and premature responses was unchanged. Subgroups of rats were differentially affected in the numbe...

Research paper thumbnail of Regional density of dopamine innervation in the neostriatum of weaver mutant mouse: Effect of ventral mesencephalic grafts

Research paper thumbnail of Another chapter in the adenosine story

Research paper thumbnail of Neuromodulation of the pedunculopontine tegmental nucleus (PPT) in the control of REM sleep as studied by microdialysis

Research paper thumbnail of Sleep allostasis in chronic sleep restriction: The role of the norepinephrine system

Brain research

Sleep responses to chronic sleep restriction may be very different from those observed after acut... more Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the α1- adrenergic receptor in the basal forebrain as well as α2- and β1- adrenergic receptor in the anterior cingulate cortex only on the first sleep...

Research paper thumbnail of Decoupling of sleepiness from sleep time and intensity during chronic sleep restriction: evidence for a role of the adenosine system

Sleep

Sleep responses to chronic sleep restriction (CSR) might be very different from those observed af... more Sleep responses to chronic sleep restriction (CSR) might be very different from those observed after short-term total sleep deprivation. For example, after sleep restriction continues for several consecutive days, animals no longer express compensatory increases in daily sleep time and sleep intensity. However, it is unknown if these allostatic, or adaptive, sleep responses to CSR are paralleled by behavioral and neurochemical measures of sleepiness. This study was designed to investigate CSR-induced changes in (1) sleep time and intensity as a measure of electrophysiological sleepiness, (2) sleep latency as a measure of behavioral sleepiness, and (3) brain adenosine A1 (A1R) and A2a receptor (A2aR) mRNA levels as a putative neurochemical correlate of sleepiness. Male Sprague-Dawley rats A 5-day sleep restriction (SR) protocol consisting of 18-h sleep deprivation and 6-h sleep opportunity each day. Unlike the first SR day, rats did not sleep longer or deeper on days 2 through 5, eve...

Research paper thumbnail of Sleep active cortical neurons expressing neuronal nitric oxide synthase are active after both acute sleep deprivation and chronic sleep restriction

Neuroscience

Non-rapid eye movement (NREM) sleep electroencephalographic (EEG) delta power (∼0.5 to 4 Hz), als... more Non-rapid eye movement (NREM) sleep electroencephalographic (EEG) delta power (∼0.5 to 4 Hz), also known as slow wave activity (SWA), is typically enhanced after acute sleep deprivation (SD) but not after chronic sleep restriction (CSR). Recently, sleep-active cortical neurons expressing neuronal nitric oxide synthase (nNOS) were identified and associated with enhanced SWA after short acute bouts of SD (i.e., 6 h). However, the relationship between cortical nNOS neuronal activity and SWA during CSR is unknown. We compared the activity of cortical neurons expressing nNOS (via c-Fos and nNOS immuno-reactivity, respectively) and sleep in rats in 3 conditions: 1) after 18 h of acute SD; 2) after 5 consecutive days of sleep restriction (SR) (18 h SD per day with 6 h ad libitum sleep opportunity per day); 3) and time-of-day matched ad libitum sleep controls. Cortical nNOS neuronal activity was enhanced during sleep after both 18 h SD and 5 days of SR treatments compared to control treatme...

Research paper thumbnail of Kim Y et al 2012 CSR Adensoine receptor mRNA

Research paper thumbnail of Chronic sleep restriction induces long-lasting changes in adenosine and noradrenaline receptor density in the rat brain

Journal of sleep research, Jan 21, 2015

Although chronic sleep restriction frequently produces long-lasting behavioural and physiological... more Although chronic sleep restriction frequently produces long-lasting behavioural and physiological impairments in humans, the underlying neural mechanisms are unknown. Here we used a rat model of chronic sleep restriction to investigate the role of brain adenosine and noradrenaline systems, known to regulate sleep and wakefulness, respectively. The density of adenosine A1 and A2a receptors and β-adrenergic receptors before, during and following 5 days of sleep restriction was assessed with autoradiography. Rats (n = 48) were sleep-deprived for 18 h day(-1) for 5 consecutive days (SR1-SR5), followed by 3 unrestricted recovery sleep days (R1-R3). Brains were collected at the beginning of the light period, which was immediately after the end of sleep deprivation on sleep restriction days. Chronic sleep restriction increased adenosine A1 receptor density significantly in nine of the 13 brain areas analysed with elevations also observed on R3 (+18 to +32%). In contrast, chronic sleep rest...

Research paper thumbnail of Microdialysis elevation of adenosine in the basal forebrain produces vigilance impairments in the rat psychomotor vigilance task

Sleep, 2008

The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts... more The inhibitory neuromodulator adenosine has been proposed as a homeostatic sleep factor that acts potently in the basal forebrain (BF) to increase sleepiness. Here 300 microM of adenosine was dialyzed in the BF of rats, and the effect on vigilance was determined in the rat Psychomotor Vigilance Task (rPVT). Rats experienced all experimental conditions in a repeated-measures, cross-over design. Twelve young adult male Fischer-Norway rats. Sustained attention performance in the rPVT was evaluated following 2 hours of bilateral microdialysis perfusion of vehicle, adenosine (300 microM), or codialysis of 300 microM of adenosine with the A1 receptor antagonist 8-cyclopentyltheophylline. During rPVT performance, response latencies and performance lapses increased significantly after adenosine dialysis when compared with baseline (no dialysis) or vehicle dialysis sessions. The codialysis of 8-cyclopentyltheophylline with adenosine completely blocked the effects produced by adenosine alone,...

Research paper thumbnail of Ventrolateral preoptic nucleus contains sleep-active, galaninergic neurons in multiple mammalian species

Neuroscience, 2002

The ventrolateral preoptic nucleus (VLPO) is a group of sleep-active neurons that has been identi... more The ventrolateral preoptic nucleus (VLPO) is a group of sleep-active neurons that has been identified in the hypothalamus of rats and is thought to inhibit the major ascending monoaminergic arousal systems during sleep; lesions of the VLPO cause insomnia. Identification of the VLPO in other species has been complicated by the lack of a marker for this cell population, other than the expression of Fos during sleep. We now report that a high percentage of the sleep-active (Fos-expressing) VLPO neurons express mRNA for the inhibitory neuropeptide, galanin, in nocturnal rodents (mice and rats), diurnal rodents (degus), and cats. A homologous (i.e. galanin mRNA-containing cell group) is clearly distinguishable in the ventrolateral region of the preoptic area in diurnal and nocturnal monkeys, as well as in humans. Galanin expression may serve to identify sleep-active neurons in the ventrolateral preoptic area of the mammalian brain. The VLPO appears to be a critical component of sleep cir...

Research paper thumbnail of Behavioral state control through differential serotonergic inhibition in the mesopontine cholinergic nuclei: a simultaneous unit recording and microdialysis study

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1998

Cholinergic neurons of the mesopontine nuclei are strongly implicated in behavioral state regulat... more Cholinergic neurons of the mesopontine nuclei are strongly implicated in behavioral state regulation. One population of neurons in the cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as rapid eye movement (REM)-on neurons, shows preferential discharge activity during REM sleep, and extensive data indicate a key role in production of this state. Another neuronal group present in the same cholinergic zone of the laterodorsal tegmentum and the pedunculopontine nuclei, referred to as Wake/REM-on neurons, shows preferential discharge activity during both wakefulness and REM sleep and is implicated in the production of electroencephalographic activation in both of these states. To test the hypothesis of differential serotonergic inhibition as an explanation of the different state-related discharge activity, we developed a novel methodology that enabled, in freely behaving animals, simultaneous unit recording and local perfusion of neuropharmacol...

Research paper thumbnail of Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations

Proceedings of the National Academy of Sciences of the United States of America, Jan 2, 2015

Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cogniti... more Cortical gamma band oscillations (GBO, 30-80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ...