Jidong Fang - Academia.edu (original) (raw)
Papers by Jidong Fang
Experimental Biology and Medicine, 1995
Sleepiness is a common perception during viral infection. Nevertheless, very little is known abou... more Sleepiness is a common perception during viral infection. Nevertheless, very little is known about the effects of viral infection on sleep. The aim of the present study was to test whether sleep was altered by influenza viral infection in mice. After 2-3 days of baseline sleep recordings, Swiss-Webster mice were infected intranasally with a lethal (H1N1) or a nonlethal (H3N2) strain of influenza virus. Sleep was recorded again for an additional 3 days. Non-rapid eye movement sleep (NREMS) was dramatically increased after inoculation of the H1N1 virus with a latency about 16 hr. Rapid eye movement sleep (REMS) was significantly suppressed after a long latency. Both changes lasted until the end of the recording and occurred in both young (35-day-old) and adult (90- to 100-day-old) animals. Control animals did not show changes in sleep after sham infection with allantoic fluid. The H1N1 virus also caused dramatic decreases in body temperature and locomotor activities with a latency about 4-5 hr after viral inoculation. The H3N2 virus induced very similar changes in sleep, although the effects were much smaller in magnitude than those induced by the H1N1 virus, even though a much higher dose (10-fold) of the H3N2 virus was used. The present study shows that influenza viral infection induces profound and long-lasting increase of NREMS and suppression of REMS. These viral-induced changes in sleep likely represent a host-defense response.
Neurology, 2016
OBJECTIVE: Assess a behavior-based criteria for determining rat wake-sleep stages in an animal mo... more OBJECTIVE: Assess a behavior-based criteria for determining rat wake-sleep stages in an animal model of REM sleep disorder (RBD) and its correlation with clinical phenomenology. BACKGROUND: RBD is a non-motor symptom associated with Parkinson’s disease (PD), characterized by motor phenomenology and absence of atonia during REM sleep. The pathophysiology of RBD is not fully elucidated and preclinical models of RBD have not been behaviorally adequately characterized to correlate with the phenomenology seen in patients with RBD. DESIGN/METHODS: We recently demonstrated that the hemiparkinsonian (HP) rat model of PD exhibited RBD-like features (Vo et. al., 2014). Here we characterize the RBD associated motor phenomenology using 1-hour recordings of 10 normal and 5 HP rats using 6 behavioral hallmarks seen on video sleep recordings scored by blinded raters with excellent inter-rater reliability. Scores were correlated to time-locked polysomnography (PSG) that was rated independently. RES...
Sleep
Study Objectives Psychiatric/learning disorders are associated with sleep disturbances, including... more Study Objectives Psychiatric/learning disorders are associated with sleep disturbances, including those arising from abnormal cortical activity. The odds ratio product (ORP) is a standardized electroencephalogram metric of sleep depth/intensity validated in adults, while ORP data in youth are lacking. We tested ORP as a measure of sleep depth/intensity in adolescents with and without psychiatric/learning disorders. Methods 418 adolescents (median 16y) underwent a 9-hour, in-lab polysomnography. Of them, 263 were typically developing (TD), 89 were unmedicated and 66 were medicated for disorders including attention-deficit/hyperactivity (ADHD), learning (LD) and internalizing (ID). Central ORP during non-rapid eye movement (NREM) sleep was the primary outcome. Secondary/exploratory outcomes included central and frontal ORP during NREM stages, in the 9-seconds following arousals (ORP-9), in first and second halves of the night, during REM sleep and wakefulness. Results Unmedicated yout...
Sleep
Introduction Sleep spindles occur as bursts of EEG activity in the sigma (11-16 Hz) frequency ran... more Introduction Sleep spindles occur as bursts of EEG activity in the sigma (11-16 Hz) frequency range and are purported biomarkers of cortical development. However, the few studies examining maturational changes in sleep spindles are limited by small samples and/or short follow-up periods. Thus, large longitudinal population-based studies are needed to determine their developmental trajectories as the child transitions to adolescence. Methods We analyzed the sleep EEG of 572 un-medicated subjects aged 6-21 (47.6% female, 25.9% racial/ethnic minority), of whom 332 were 5-12 years at baseline and followed-up at ages 12-22. Multivariable-adjusted models tested the cross-sectional and longitudinal trajectories of sleep spindle density, frequency, and power. Results From age 6 to 21, the trajectory of sleep spindle density was best fit by a quadratic model (p=0.02), particularly in males (p-quadratic=0.05). Females maintained more stable levels of sleep spindle density (p-linear=0.26), as ...
Molecular Psychiatry
Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic dr... more Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague–Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
npj Parkinson's Disease
Rapid-eye-movement (REM) sleep without atonia (RSWA), a marker of REM sleep behavior disorder (RB... more Rapid-eye-movement (REM) sleep without atonia (RSWA), a marker of REM sleep behavior disorder (RBD), is frequently comorbid with Parkinson’s disease (PD). Although rodent models are commonly used for studying PD, the neurobiological and behavioral correlates of RBD remain poorly understood. Therefore, we developed a behavior-based criteria to identify RSWA in the hemiparkinsonian rat model of PD. Video recordings of rats were analyzed, to develop a criteria consisting of behavioral signs that occurred during polysomnographically confirmed epochs of sleep-wake stages. The sleep-slouch, a postural shift of the body or head caused only by gravity, was identified as a unique behavioral sign of REM sleep onset and was altered in hemiparkinsonian rats during RSWA. There was a significant correlation between the behavior-based criteria and polysomnograms for all sleep-wake stages in control but not hemiparkinsonian rats indicating a deterioration of sleep-wake architecture in parkinsonism....
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Much evidence indicates that growth hormone-releasing hormone (GHRH) is involved in sleep regulat... more Much evidence indicates that growth hormone-releasing hormone (GHRH) is involved in sleep regulation. We hypothesized that GHRH mRNA would increase and somatostatin (SRIH) mRNA would decrease during sleep deprivation. With the use of RT-PCR and truncated internal standards, rat hypothalamic GHRH mRNA and SRIH mRNA levels were evaluated after sleep deprivation. After 8 or 12 h of sleep deprivation there was a significant increase in rat hypothalamic GHRH mRNA expression compared with time-matched control samples. Hypothalamic GHRH mRNA levels were not significantly different from control values after 1 or 2 h of recovery after 8 h of sleep deprivation or after 2 h of recovery after 12 h of sleep deprivation. In control animals, variations in hypothalamic GHRH mRNA levels were observed. GHRH mRNA expression was significantly higher in the afternoon than at dark onset or during the dark period. SRIH mRNA levels were significantly suppressed at the termination of an 8-h sleep deprivatio...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found... more Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found in the brain, and it influences the production of several sleep-promoting substances. We determined, therefore, whether administration of exogenous EGF affected spontaneous sleep in rabbits. Twenty-five rabbits were implanted with electroencephalographic electrodes, a brain thermistor, and an intracerebroventricular guide cannula. Three doses of EGF (0.5, 5, and 25 μg) were used. The animals were injected intracerebroventricularly with saline as control and one dose of EGF on 2 separate days. Five and twenty-five micrograms of EGF enhanced non-rapid eye movement sleep and increased brain temperature. The 25-μg dose of EGF also inhibited rapid eye movement sleep across the 23-h postinjection recording period. Results are consistent with the hypothesis that EGF, like other growth factors, could be involved in sleep regulation.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Several well-defined sleep regulatory substances, e.g., interleukin-1β, activate the heterodimeri... more Several well-defined sleep regulatory substances, e.g., interleukin-1β, activate the heterodimeric transcription factor nuclear factor-κB (NF-κB). Several substances that inhibit sleep, e.g., interleukin-4, inhibit NF-κB activation. NF-κB activation promotes production of several additional substances thought to be involved in sleep regulation, e.g., nitric oxide. We investigated, therefore, whether there are diurnal rhythms of NF-κB activation in brain and changes in the activation after sleep deprivation. Mice were kept on a 12:12-h light-dark cycle. In one experiment, groups of mice were killed every 3 h across the 24-h cycle. In another experiment, mice were killed at 1500 after 6 h of sleep deprivation, and a group of control mice were killed at the same time. Nuclear proteins were extracted from each brain tissue sample, and NF-κB-like activity was determined with an electrophoretic mobility shift assay. In cerebral cortex, but not other areas of brain, there was a diurnal rhy...
Physiology
Cytokines and hormones, including interleukin-1, tumor necrosis factor, growth hormone-releasing ... more Cytokines and hormones, including interleukin-1, tumor necrosis factor, growth hormone-releasing hormone, vasoactive intestinal polypeptide and prolactin, are involved in sleep regulation. These substances enhance sleep, inhibition of them inhibits sleep, and their brain levels vary with sleep. This knowledge helps our understanding of the humoral regulation of sleep.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF)... more Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family; it and its receptors are found in normal brain. Furthermore, cerebral cortical levels of BDNF mRNA have a diurnal variation and increase after sleep deprivation. Therefore, we investigated whether BDNF would promote sleep. Twenty-four male Sprague-Dawley rats (320–380 g) and 25 male New Zealand White rabbits (4.5–5.5 kg) were surgically implanted with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and, on a separate day, one of the following doses of BDNF: 25 or 250 ng in rabbits; 10, 50, or 250 ng in rats. The EEG, brain temperature, and motor activity were recorded for 23 h after the intracerebroventricular injections. BDNF increased time spent in non-rapid eye movement sleep (NREMS) in rats and rabbits and REMS ...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Both tumor necrosis factor (TNF) and interleukin (IL)-1 are somnogenic cytokines. They also induc... more Both tumor necrosis factor (TNF) and interleukin (IL)-1 are somnogenic cytokines. They also induce each other’s production and both induce nuclear factor kappa B activation, which in turn enhances IL-1 and TNF transcription. We hypothesized that TNF and IL-1 could influence each other’s somnogenic actions. To test this hypothesis, we determined the effects of blocking both endogenous TNF and IL-1 on spontaneous sleep and on sleep rebound after sleep deprivation in rabbits. Furthermore, the effects of inhibition of TNF on IL-1-induced sleep and the effects of blocking IL-1 on TNF-induced sleep were determined. A TNF receptor fragment (TNFRF), as a TNF inhibitor, and an IL-1 receptor fragment (IL-1RF), as an IL-1 inhibitor, were used. Intracerebroventricular injection of a combination of the TNFRF plus the IL-1RF significantly reduced spontaneous non-rapid eye movement sleep by 87 min over a 22-h recording period. Pretreatment of rabbits with the combination of TNFRF and IL-1RF also s...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin-1β (IL-1β) is a well characterized sleep regulatory substance. To study receptor mech... more Interleukin-1β (IL-1β) is a well characterized sleep regulatory substance. To study receptor mechanisms for the sleep-promoting effects of IL-1β, sleep patterns were determined in control and IL-1 type I receptor knockout (IL-1RI KO) mice with a B6x129 background after intraperitoneal injections of saline or murine recombinant IL-1β. The IL-1RI KO mice had slightly but significantly less sleep during the dark period compared with the controls. IL-1β dose dependently increased non-rapid eye movement sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the controls. The IL-1RI KO mice did not respond to IL-1β. In contrast, the IL-1RI KO mice increased NREMS and decreased REMS after administration of tumor necrosis factor-α (TNF-α), another well characterized sleep-promoting substance. These results 1) provide further evidence that IL-1β is involved in sleep regulation, 2) indicate that the effects of IL-1β on sleep are mediated by the type I receptor, and 3) suggest that TN...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Feeding rats a cafeteria diet results in increased food intake and excess sleep. Furthermore, vag... more Feeding rats a cafeteria diet results in increased food intake and excess sleep. Furthermore, vagal afferent activity is altered by a variety of gastrointestinal factors, and vagal stimulation can induce sleep. We investigated, therefore, the hypothesis that the vagal nerve plays a critical role in mediating the sleep-inducing effects of cafeteria feeding. We examined the effects of a cafeteria diet on sleep, electroencephalographic (EEG) slow-wave activity (SWA), and brain temperature (Tbr) in control and vagotomized rats. EEG, electromyogram, and Tbr were recorded for 7 consecutive days. Day 1 was considered a baseline day; normal rat chow was available ad libitum. On days 2- 4, the animals were fed, in addition to normal chow, a mixed, energy-rich diet (cafeteria diet). On days 5- 7, the rats were again fed only normal rat chow. In control rats, the cafeteria diet resulted in an increase in non-rapid eye movement sleep (NREMS), which was the result of a significant lengthening of...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α, are invo... more Proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Much evidence suggests that tumor necrosis factor-α (TNF-α) is involved in the regulation of phys... more Much evidence suggests that tumor necrosis factor-α (TNF-α) is involved in the regulation of physiological sleep. However, it remains unclear whether peripheral administration of TNF-α induces sleep in rats. Furthermore, the role of the vagus nerve in the somnogenic actions of TNF-α had not heretofore been studied. Four doses of TNF-α were administered intraperitoneally just before the onset of the dark period. The three higher doses of TNF-α (50, 100, and 200 μg/kg) dose dependently increased nonrapid eye movement sleep (NREMS), accompanied by increases in electroencephalogram (EEG) slow-wave activity. TNF-α increased EEG δ-power and decreased EEG α- and β-power during the initial 3 h after injection. In vagotomized rats, the NREMS responses to 50 or 100 μg/kg of TNF-α were attenuated, while significant TNF-α-induced increases in NREMS were observed in a sham-operated group. Moreover, the vagotomized rats failed to exhibit the increase in EEG δ-power induced by TNF-α intraperitonea...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) com... more Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalog...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin (IL)-1β is involved in physiological sleep regulation. IL-18 is a member of the IL-1 ... more Interleukin (IL)-1β is involved in physiological sleep regulation. IL-18 is a member of the IL-1 family, and its signal-transduction mechanism is similar to that of IL-1. Therefore, we hypothesized that IL-18 might also be involved in sleep regulation. Three doses of IL-18 (10, 100, and 500 ng) were injected intracerebroventricularly (icv) into rabbits at the onset of the dark period. The two higher doses of IL-18 markedly increased non-rapid eye movement sleep (NREMS), accompanied by increases in brain temperature (Tbr). These effects were lost after the heat inactivation of IL-18. The 500 ng of IL-18 injection during the light period also increased NREMS and Tbr. Similar results were obtained after icv injection of 100 ng of IL-18 into rats. Furthermore, intraperitoneal injection of 30 μg/kg of IL-18 slightly, but significantly, increased NREMS, whereas it significantly decreased electroencephalogram slow-wave activity in rats. Intraperitoneal IL-18 failed to induce fever. An anti...
Experimental Biology and Medicine, 1995
Sleepiness is a common perception during viral infection. Nevertheless, very little is known abou... more Sleepiness is a common perception during viral infection. Nevertheless, very little is known about the effects of viral infection on sleep. The aim of the present study was to test whether sleep was altered by influenza viral infection in mice. After 2-3 days of baseline sleep recordings, Swiss-Webster mice were infected intranasally with a lethal (H1N1) or a nonlethal (H3N2) strain of influenza virus. Sleep was recorded again for an additional 3 days. Non-rapid eye movement sleep (NREMS) was dramatically increased after inoculation of the H1N1 virus with a latency about 16 hr. Rapid eye movement sleep (REMS) was significantly suppressed after a long latency. Both changes lasted until the end of the recording and occurred in both young (35-day-old) and adult (90- to 100-day-old) animals. Control animals did not show changes in sleep after sham infection with allantoic fluid. The H1N1 virus also caused dramatic decreases in body temperature and locomotor activities with a latency about 4-5 hr after viral inoculation. The H3N2 virus induced very similar changes in sleep, although the effects were much smaller in magnitude than those induced by the H1N1 virus, even though a much higher dose (10-fold) of the H3N2 virus was used. The present study shows that influenza viral infection induces profound and long-lasting increase of NREMS and suppression of REMS. These viral-induced changes in sleep likely represent a host-defense response.
Neurology, 2016
OBJECTIVE: Assess a behavior-based criteria for determining rat wake-sleep stages in an animal mo... more OBJECTIVE: Assess a behavior-based criteria for determining rat wake-sleep stages in an animal model of REM sleep disorder (RBD) and its correlation with clinical phenomenology. BACKGROUND: RBD is a non-motor symptom associated with Parkinson’s disease (PD), characterized by motor phenomenology and absence of atonia during REM sleep. The pathophysiology of RBD is not fully elucidated and preclinical models of RBD have not been behaviorally adequately characterized to correlate with the phenomenology seen in patients with RBD. DESIGN/METHODS: We recently demonstrated that the hemiparkinsonian (HP) rat model of PD exhibited RBD-like features (Vo et. al., 2014). Here we characterize the RBD associated motor phenomenology using 1-hour recordings of 10 normal and 5 HP rats using 6 behavioral hallmarks seen on video sleep recordings scored by blinded raters with excellent inter-rater reliability. Scores were correlated to time-locked polysomnography (PSG) that was rated independently. RES...
Sleep
Study Objectives Psychiatric/learning disorders are associated with sleep disturbances, including... more Study Objectives Psychiatric/learning disorders are associated with sleep disturbances, including those arising from abnormal cortical activity. The odds ratio product (ORP) is a standardized electroencephalogram metric of sleep depth/intensity validated in adults, while ORP data in youth are lacking. We tested ORP as a measure of sleep depth/intensity in adolescents with and without psychiatric/learning disorders. Methods 418 adolescents (median 16y) underwent a 9-hour, in-lab polysomnography. Of them, 263 were typically developing (TD), 89 were unmedicated and 66 were medicated for disorders including attention-deficit/hyperactivity (ADHD), learning (LD) and internalizing (ID). Central ORP during non-rapid eye movement (NREM) sleep was the primary outcome. Secondary/exploratory outcomes included central and frontal ORP during NREM stages, in the 9-seconds following arousals (ORP-9), in first and second halves of the night, during REM sleep and wakefulness. Results Unmedicated yout...
Sleep
Introduction Sleep spindles occur as bursts of EEG activity in the sigma (11-16 Hz) frequency ran... more Introduction Sleep spindles occur as bursts of EEG activity in the sigma (11-16 Hz) frequency range and are purported biomarkers of cortical development. However, the few studies examining maturational changes in sleep spindles are limited by small samples and/or short follow-up periods. Thus, large longitudinal population-based studies are needed to determine their developmental trajectories as the child transitions to adolescence. Methods We analyzed the sleep EEG of 572 un-medicated subjects aged 6-21 (47.6% female, 25.9% racial/ethnic minority), of whom 332 were 5-12 years at baseline and followed-up at ages 12-22. Multivariable-adjusted models tested the cross-sectional and longitudinal trajectories of sleep spindle density, frequency, and power. Results From age 6 to 21, the trajectory of sleep spindle density was best fit by a quadratic model (p=0.02), particularly in males (p-quadratic=0.05). Females maintained more stable levels of sleep spindle density (p-linear=0.26), as ...
Molecular Psychiatry
Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic dr... more Sleep abnormalities are often a prominent contributor to withdrawal symptoms following chronic drug use. Notably, rapid eye movement (REM) sleep regulates emotional memory, and persistent REM sleep impairment after cocaine withdrawal negatively impacts relapse-like behaviors in rats. However, it is not understood how cocaine experience may alter REM sleep regulatory machinery, and what may serve to improve REM sleep after withdrawal. Here, we focus on the melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH), which regulate REM sleep initiation and maintenance. Using adult male Sprague–Dawley rats trained to self-administer intravenous cocaine, we did transcriptome profiling of LH MCH neurons after long-term withdrawal using RNA-sequencing, and performed functional assessment using slice electrophysiology. We found that 3 weeks after withdrawal from cocaine, LH MCH neurons exhibit a wide range of gene expression changes tapping into cell membrane signaling, intracellular signaling, and transcriptional regulations. Functionally, they show reduced membrane excitability and decreased glutamatergic receptor activity, consistent with increased expression of voltage-gated potassium channel gene Kcna1 and decreased expression of metabotropic glutamate receptor gene Grm5. Finally, chemogenetic or optogenetic stimulations of LH MCH neural activity increase REM sleep after long-term withdrawal with important differences. Whereas chemogenetic stimulation promotes both wakefulness and REM sleep, optogenetic stimulation of these neurons in sleep selectively promotes REM sleep. In summary, cocaine exposure persistently alters gene expression profiles and electrophysiological properties of LH MCH neurons. Counteracting cocaine-induced hypoactivity of these neurons selectively in sleep enhances REM sleep quality and quantity after long-term withdrawal.
npj Parkinson's Disease
Rapid-eye-movement (REM) sleep without atonia (RSWA), a marker of REM sleep behavior disorder (RB... more Rapid-eye-movement (REM) sleep without atonia (RSWA), a marker of REM sleep behavior disorder (RBD), is frequently comorbid with Parkinson’s disease (PD). Although rodent models are commonly used for studying PD, the neurobiological and behavioral correlates of RBD remain poorly understood. Therefore, we developed a behavior-based criteria to identify RSWA in the hemiparkinsonian rat model of PD. Video recordings of rats were analyzed, to develop a criteria consisting of behavioral signs that occurred during polysomnographically confirmed epochs of sleep-wake stages. The sleep-slouch, a postural shift of the body or head caused only by gravity, was identified as a unique behavioral sign of REM sleep onset and was altered in hemiparkinsonian rats during RSWA. There was a significant correlation between the behavior-based criteria and polysomnograms for all sleep-wake stages in control but not hemiparkinsonian rats indicating a deterioration of sleep-wake architecture in parkinsonism....
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Much evidence indicates that growth hormone-releasing hormone (GHRH) is involved in sleep regulat... more Much evidence indicates that growth hormone-releasing hormone (GHRH) is involved in sleep regulation. We hypothesized that GHRH mRNA would increase and somatostatin (SRIH) mRNA would decrease during sleep deprivation. With the use of RT-PCR and truncated internal standards, rat hypothalamic GHRH mRNA and SRIH mRNA levels were evaluated after sleep deprivation. After 8 or 12 h of sleep deprivation there was a significant increase in rat hypothalamic GHRH mRNA expression compared with time-matched control samples. Hypothalamic GHRH mRNA levels were not significantly different from control values after 1 or 2 h of recovery after 8 h of sleep deprivation or after 2 h of recovery after 12 h of sleep deprivation. In control animals, variations in hypothalamic GHRH mRNA levels were observed. GHRH mRNA expression was significantly higher in the afternoon than at dark onset or during the dark period. SRIH mRNA levels were significantly suppressed at the termination of an 8-h sleep deprivatio...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found... more Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found in the brain, and it influences the production of several sleep-promoting substances. We determined, therefore, whether administration of exogenous EGF affected spontaneous sleep in rabbits. Twenty-five rabbits were implanted with electroencephalographic electrodes, a brain thermistor, and an intracerebroventricular guide cannula. Three doses of EGF (0.5, 5, and 25 μg) were used. The animals were injected intracerebroventricularly with saline as control and one dose of EGF on 2 separate days. Five and twenty-five micrograms of EGF enhanced non-rapid eye movement sleep and increased brain temperature. The 25-μg dose of EGF also inhibited rapid eye movement sleep across the 23-h postinjection recording period. Results are consistent with the hypothesis that EGF, like other growth factors, could be involved in sleep regulation.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Several well-defined sleep regulatory substances, e.g., interleukin-1β, activate the heterodimeri... more Several well-defined sleep regulatory substances, e.g., interleukin-1β, activate the heterodimeric transcription factor nuclear factor-κB (NF-κB). Several substances that inhibit sleep, e.g., interleukin-4, inhibit NF-κB activation. NF-κB activation promotes production of several additional substances thought to be involved in sleep regulation, e.g., nitric oxide. We investigated, therefore, whether there are diurnal rhythms of NF-κB activation in brain and changes in the activation after sleep deprivation. Mice were kept on a 12:12-h light-dark cycle. In one experiment, groups of mice were killed every 3 h across the 24-h cycle. In another experiment, mice were killed at 1500 after 6 h of sleep deprivation, and a group of control mice were killed at the same time. Nuclear proteins were extracted from each brain tissue sample, and NF-κB-like activity was determined with an electrophoretic mobility shift assay. In cerebral cortex, but not other areas of brain, there was a diurnal rhy...
Physiology
Cytokines and hormones, including interleukin-1, tumor necrosis factor, growth hormone-releasing ... more Cytokines and hormones, including interleukin-1, tumor necrosis factor, growth hormone-releasing hormone, vasoactive intestinal polypeptide and prolactin, are involved in sleep regulation. These substances enhance sleep, inhibition of them inhibits sleep, and their brain levels vary with sleep. This knowledge helps our understanding of the humoral regulation of sleep.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF)... more Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family; it and its receptors are found in normal brain. Furthermore, cerebral cortical levels of BDNF mRNA have a diurnal variation and increase after sleep deprivation. Therefore, we investigated whether BDNF would promote sleep. Twenty-four male Sprague-Dawley rats (320–380 g) and 25 male New Zealand White rabbits (4.5–5.5 kg) were surgically implanted with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and, on a separate day, one of the following doses of BDNF: 25 or 250 ng in rabbits; 10, 50, or 250 ng in rats. The EEG, brain temperature, and motor activity were recorded for 23 h after the intracerebroventricular injections. BDNF increased time spent in non-rapid eye movement sleep (NREMS) in rats and rabbits and REMS ...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Both tumor necrosis factor (TNF) and interleukin (IL)-1 are somnogenic cytokines. They also induc... more Both tumor necrosis factor (TNF) and interleukin (IL)-1 are somnogenic cytokines. They also induce each other’s production and both induce nuclear factor kappa B activation, which in turn enhances IL-1 and TNF transcription. We hypothesized that TNF and IL-1 could influence each other’s somnogenic actions. To test this hypothesis, we determined the effects of blocking both endogenous TNF and IL-1 on spontaneous sleep and on sleep rebound after sleep deprivation in rabbits. Furthermore, the effects of inhibition of TNF on IL-1-induced sleep and the effects of blocking IL-1 on TNF-induced sleep were determined. A TNF receptor fragment (TNFRF), as a TNF inhibitor, and an IL-1 receptor fragment (IL-1RF), as an IL-1 inhibitor, were used. Intracerebroventricular injection of a combination of the TNFRF plus the IL-1RF significantly reduced spontaneous non-rapid eye movement sleep by 87 min over a 22-h recording period. Pretreatment of rabbits with the combination of TNFRF and IL-1RF also s...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin-1β (IL-1β) is a well characterized sleep regulatory substance. To study receptor mech... more Interleukin-1β (IL-1β) is a well characterized sleep regulatory substance. To study receptor mechanisms for the sleep-promoting effects of IL-1β, sleep patterns were determined in control and IL-1 type I receptor knockout (IL-1RI KO) mice with a B6x129 background after intraperitoneal injections of saline or murine recombinant IL-1β. The IL-1RI KO mice had slightly but significantly less sleep during the dark period compared with the controls. IL-1β dose dependently increased non-rapid eye movement sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the controls. The IL-1RI KO mice did not respond to IL-1β. In contrast, the IL-1RI KO mice increased NREMS and decreased REMS after administration of tumor necrosis factor-α (TNF-α), another well characterized sleep-promoting substance. These results 1) provide further evidence that IL-1β is involved in sleep regulation, 2) indicate that the effects of IL-1β on sleep are mediated by the type I receptor, and 3) suggest that TN...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Feeding rats a cafeteria diet results in increased food intake and excess sleep. Furthermore, vag... more Feeding rats a cafeteria diet results in increased food intake and excess sleep. Furthermore, vagal afferent activity is altered by a variety of gastrointestinal factors, and vagal stimulation can induce sleep. We investigated, therefore, the hypothesis that the vagal nerve plays a critical role in mediating the sleep-inducing effects of cafeteria feeding. We examined the effects of a cafeteria diet on sleep, electroencephalographic (EEG) slow-wave activity (SWA), and brain temperature (Tbr) in control and vagotomized rats. EEG, electromyogram, and Tbr were recorded for 7 consecutive days. Day 1 was considered a baseline day; normal rat chow was available ad libitum. On days 2- 4, the animals were fed, in addition to normal chow, a mixed, energy-rich diet (cafeteria diet). On days 5- 7, the rats were again fed only normal rat chow. In control rats, the cafeteria diet resulted in an increase in non-rapid eye movement sleep (NREMS), which was the result of a significant lengthening of...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α, are invo... more Proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Much evidence suggests that tumor necrosis factor-α (TNF-α) is involved in the regulation of phys... more Much evidence suggests that tumor necrosis factor-α (TNF-α) is involved in the regulation of physiological sleep. However, it remains unclear whether peripheral administration of TNF-α induces sleep in rats. Furthermore, the role of the vagus nerve in the somnogenic actions of TNF-α had not heretofore been studied. Four doses of TNF-α were administered intraperitoneally just before the onset of the dark period. The three higher doses of TNF-α (50, 100, and 200 μg/kg) dose dependently increased nonrapid eye movement sleep (NREMS), accompanied by increases in electroencephalogram (EEG) slow-wave activity. TNF-α increased EEG δ-power and decreased EEG α- and β-power during the initial 3 h after injection. In vagotomized rats, the NREMS responses to 50 or 100 μg/kg of TNF-α were attenuated, while significant TNF-α-induced increases in NREMS were observed in a sham-operated group. Moreover, the vagotomized rats failed to exhibit the increase in EEG δ-power induced by TNF-α intraperitonea...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) com... more Interleukin (IL)-15 and -2 share receptor- and signal-transduction pathway (Jak-STAT pathway) components. IL-2 is somnogenic in rats but has not been tested in other species. Furthermore, the effects of IL-15 on sleep have not heretofore been described. We investigated the somnogenic actions of IL-15 in rabbits and compared them with those of IL-2. Three doses of IL-15 or -2 (10, 100, and 500 ng) were injected intracerebroventriculary at the onset of the dark period. In addition, 500 ng of IL-15 and -2 were injected 3 h after the beginning of the light period. IL-15 dose dependently increased non-rapid eye movement sleep (NREMS) and induced fever. IL-15 inhibited rapid eye movement sleep (REMS) after its administration during the light period; however, all doses of IL-15 failed to affect REMS if given at dark onset. IL-2 also dose dependently increased NREMS and fever. IL-2 inhibited REMS, and this effect was observed only in the light period. IL-15 and -2 enhanced electroencephalog...
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Interleukin (IL)-1β is involved in physiological sleep regulation. IL-18 is a member of the IL-1 ... more Interleukin (IL)-1β is involved in physiological sleep regulation. IL-18 is a member of the IL-1 family, and its signal-transduction mechanism is similar to that of IL-1. Therefore, we hypothesized that IL-18 might also be involved in sleep regulation. Three doses of IL-18 (10, 100, and 500 ng) were injected intracerebroventricularly (icv) into rabbits at the onset of the dark period. The two higher doses of IL-18 markedly increased non-rapid eye movement sleep (NREMS), accompanied by increases in brain temperature (Tbr). These effects were lost after the heat inactivation of IL-18. The 500 ng of IL-18 injection during the light period also increased NREMS and Tbr. Similar results were obtained after icv injection of 100 ng of IL-18 into rats. Furthermore, intraperitoneal injection of 30 μg/kg of IL-18 slightly, but significantly, increased NREMS, whereas it significantly decreased electroencephalogram slow-wave activity in rats. Intraperitoneal IL-18 failed to induce fever. An anti...