[Show abstract][Hide abstract] ABSTRACT: This study provides the first systematic analysis of the nuclear organization of the neural systems related to sleep and wake in the basal forebrain, diencephalon, midbrain and pons of the river hippopotamus, one of the closest extant terrestrial relatives of the cetaceans. All nuclei involved in sleep regulation and control found in other mammals, including cetaceans, were present in the river hippopotamus, with no specific nuclei being absent, but novel features of the cholinergic system, including novel nuclei, were present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic and orexinergic systems and is extended to the GABAergic elements of these nuclei. Quantitative analysis reveals that the numbers of pontine cholinergic (259 578) and noradrenergic (127 752) neurons, and hypothalamic orexinergic neurons (68 398) are markedly higher than other large-brained mammals. These features, along with novel cholinergic nuclei in the intralaminar nuclei of the dorsal thalamus and the ventral tegmental area of the midbrain, as well as a major expansion of the hypothalamic cholinergic nuclei and a large laterodorsal tegmental nucleus of the pons that has both parvocellular and magnocellular cholinergic neurons, indicates an unusual sleep phenomenology for the hippopotamus. Our observations indicate that the hippopotamus is likely to be a bihemispheric sleeper that expresses REM sleep. The novel features of the cholinergic system suggest the presence of an undescribed sleep state in the hippopotamus, as well as the possibility that this animal could, more rapidly than other mammals, switch cortical EEG activity from one state to another. This article is protected by copyright. All rights reserved.
The Journal of Comparative Neurology 12/2015; DOI:10.1002/cne.23930 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current study provides the first systematic immunohistochemical neuroanatomical investigation of the systems involved in the control and regulation of sleep in an odontocete cetacean, the harbour porpoise (Phocoena phocoena). The odontocete cetaceans show an unusual form of mammalian sleep, with unihemispheric slow waves, suppressed REM sleep and continuous bodily movement. All the neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals were present in the harbour porpoise, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity of nuclear organization relates to the cholinergic, noradrenergic, serotonergic and orexinergic systems and is extended to the GABAergic elements involved with these nuclei. Quantitative analysis of the cholinergic and noradrenergic nuclei of the pontine region revealed that in comparison to other mammals, the numbers of pontine cholinergic (126 776) and noradrenergic (122 878) neurons are markedly higher than in other large-brained bihemispheric sleeping mammals. The diminutive telencephalic commissures (anterior commissure, corpus callosum and hippocampal commissure) along with an enlarged posterior commissure and supernumerary pontine cholinergic and noradrenergic neurons indicate that the control of unihemispheric slow wave sleep is likely to be a function of interpontine competition, facilitated through the posterior commissure, in response to unilateral telencephalic input related to the drive for sleep. In addition, an expanded peripheral division of the dorsal raphe nuclear complex appears likely to play a role in the suppression of REM sleep in odontocete cetaceans. Thus, the current study provides several clues to the understanding of the neural control of the unusual sleep phenomenology present in odontocete cetaceans. This article is protected by copyright. All rights reserved.
The Journal of Comparative Neurology 12/2015; DOI:10.1002/cne.23929 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current study analyses the nuclear organization of the neural systems related to the control and regulation of sleep and wake in the basal forebrain, diencephalon, midbrain and pons of the minke whale, a mysticete cetacean. While odontocete cetaceans sleep in an unusual manner, with unihemispheric slow wave sleep (USWS) and suppressed REM sleep, it is unclear whether the mysticete whales show a similar sleep pattern. Previously, we detailed a range of features in the odontocete brain that appear to be related to odontocete-type sleep, and here present our analysis of these features in the minke whale brain. All neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals and the harbour porpoise were present in the minke whale, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic and orexinergic systems and the GABAergic elements of these nuclei. Quantitative analysis revealed that the numbers of pontine cholinergic (274 242) and noradrenergic (203 686) neurons, and hypothalamic orexinergic neurons (277 604), are markedly higher than other large-brained bihemispheric sleeping mammals. Small telencephalic commissures (anterior, corpus callosum and hippocampal), an enlarged posterior commissure, supernumerary pontine cholinergic and noradrenergic cells, and an enlarged peripheral division of the dorsal raphe nuclear complex of the minke whale, all indicate that the suite of neural characteristics thought to be involved in the control of USWS and the suppression of REM in the odontocete cetaceans are present in the minke whale. This article is protected by copyright. All rights reserved.
The Journal of Comparative Neurology 12/2015; DOI:10.1002/cne.23931 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: How did humans sleep before the modern era?
Because the tools to measure sleep under natural
conditions were developed long after the invention
of the electric devices suspected of delaying and
reducing sleep, we investigated sleep in three preindustrial
societies [1–3]. We find that all three show
similar sleep organization, suggesting that they
express core human sleep patterns, most likely characteristic
of pre-modern era Homo sapiens. Sleep
periods, the times from onset to offset, averaged
6.9–8.5 hr, with sleep durations of 5.7–7.1 hr,
amounts near the low end of those industrial societies
[4–7]. There was a difference of nearly 1 hr between
summer and winter sleep. Daily variation in
sleep duration was strongly linked to time of onset,
rather than offset. None of these groups began sleep
near sunset, onset occurring, on average, 3.3 hr after
sunset. Awakening was usually before sunrise. The
sleep period consistently occurred during the nighttime
period of falling environmental temperature,
was not interrupted by extended periods of waking,
and terminated, with vasoconstriction, near the nadir
of daily ambient temperature. The daily cycle of temperature
change, largely eliminated from modern
sleep environments, may be a potent natural regulator
of sleep. Light exposure was maximal in the
morning and greatly decreased at noon, indicating
that all three groups seek shade at midday and that
light activation of the suprachiasmatic nucleus
is maximal in the morning. Napping occurred
on <7% of days in winter and <22% of days in summer.
Mimicking aspects of the natural environment
might be effective in treating certain modern sleep
Current Biology 10/2015; 25:1-7. DOI:10.1016/j.cub.2015.09.046 · 9.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.
[Show abstract][Hide abstract] ABSTRACT: Histamine neurons are active during waking and largely inactive during sleep, with minimal activity during rapid-eye movement (REM) sleep. Caffeine, the most widely used stimulant, causes a significant increase of sleep onset latency in rats and humans. We hypothesized that caffeine increases glutamate release in the posterior hypothalamus (PH) and produces increased activity of wake-active histamine neurons. Using in vivo microdialysis, we collected samples from the PH after caffeine administration in freely behaving rats. HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 minutes. Gamma-amino butyric acid (GABA) levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 minutes. Immunostaining showed a significantly elevated number of c-Fos labeled histamine neurons in caffeine treated rats compared to saline treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness.
[Show abstract][Hide abstract] ABSTRACT: Female hypocretin knockout (Hcrt KO) mice have increased body weight despite decreased food intake compared to wild type (WT) mice. In order to understand the nature of the increased body weight, we carried out a detailed study of Hcrt KO and WT, male and female mice. Female KO mice showed consistently higher body weight than WT mice, from 4-20 months (20%-60%). Fat, muscle and free fluid levels were all significantly higher in adult (7-9 months) as well as old (18-20 months) female KO mice compared to age-matched WT mice. Old male KO mice showed significantly higher fat content (150%) compared to age-matched WT mice, but no significant change in body weight. Respiratory quotient (-19%) and metabolic rates (-14%) were significantly lower in KO mice compared to WT mice, regardless of gender or age. Female KO mice had significantly higher serum leptin levels (191%) than WT mice at 18-20 months, but no difference between male mice were observed. Conversely, insulin resistance was significantly higher in both male (73%) and female (93%) KO mice compared to age- and sex-matched WT mice. We conclude that absence of the Hcrt peptide has gender-specific effects. In contrast, Hcrt-ataxin mice and human narcoleptics, with loss of the whole Hcrt cell, show weight gain in both sexes.This article is protected by copyright. All rights reserved.
Journal of Neurochemistry 07/2014; 131(5). DOI:10.1111/jnc.12840 · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hypocretins (HCRTs) are two hypothalamic peptides predominantly localized to neurons in the perifornical, dorsomedial, and lateral hypothalamic area (PF-LHA). Evidence suggests that HCRT signaling is critical for the promotion and stabilization of active-arousal and its loss or malfunction leads to symptoms of narcolepsy. In the PF-LHA, HCRT neurons are intermingled with glutamate-expressing neurons and also co-express glutamate. Evidence suggests that HCRT-glutamate interactions within the PF-LHA may play a critical role in maintaining behavioral arousal. However, the relative contributions of the glutamate and HCRT in sleep-wake regulation are not known.
We determined whether a lack of HCRT signaling in the prepro-orexin-knockout (HCRT-KO) mouse attenuates/compromises the wake-promoting ability of glutamatergic activation of the PF-LHA region. We used reverse microdialysis to deliver N-methyl-D-aspartate (NMDA) into the HCRT zone of the PF-LHA in HCRT-KO and wild-type (WT) mice to evaluate the contributions of glutamatergic vs. HCRT signaling in sleep-wake regulation.
As compared to respective controls, local perfusion of NMDA into the PF-LHA, dose-dependently increased active-waking with concomitant reductions in nonREM and REM sleep in spontaneously sleeping WT as well as HCRT-KO mice. However, compared to WT, the NMDA-induced behavioral changes in HCRT-KO mice were significantly attenuated, as evidenced by the higher dose of NMDA needed and lower magnitude of changes induced in sleep-wake parameters. Although not observed in WT mice, the number of cataplectic events increased significantly during NMDA-induced behavioral arousal in HCRT-KO mice.
The findings of this study are consistent with a hypothesis that synergistic interactions between hypocretin and glutamatergic mechanisms within the perifornical, dorsomedial, and lateral hypothalamic area are critical for maintaining behavioral arousal, especially arousal involving elevated muscle tone.
Kostin A, Siegel JM, Alam MN. Lack of hypocretin attenuates behavioral changes produced by glutamatergic activation of the perifornical-lateral hypothalamic area. SLEEP 2014;37(5):1011-1020.
[Show abstract][Hide abstract] ABSTRACT: The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.
[Show abstract][Hide abstract] ABSTRACT: On land, fur seals predominately display bilaterally synchronized electroencephalogram (EEG) activity during slow-wave sleep (SWS), similar to that observed in all terrestrial mammals. In water, however, fur seals exhibit asymmetric slow-wave sleep (ASWS), resembling the unihemispheric slow-wave sleep of odontocetes (toothed whales). The unique sleeping pattern of fur seals allows us to distinguish neuronal mechanisms mediating EEG changes from those mediating behavioral quiescence. In a prior study we found that cortical acetylcholine release is lateralized during ASWS in the northern fur seal, with greater release in the hemisphere displaying low-voltage (waking) EEG activity, linking acetylcholine release to hemispheric EEG activation (Lapierre et al. 2007). In contrast to acetylcholine, we now report that cortical serotonin release is not lateralized during ASWS. Our data demonstrate that bilaterally symmetric levels of serotonin are compatible with interhemispheric EEG asymmetry in the fur seal. We also find greatly elevated levels during eating and hosing the animals with water, suggesting that serotonin is more closely linked to bilateral variables, such as axial motor and autonomic control, than to the lateralized cortical activation manifested in asymmetrical sleep.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2013; 33(6):2555-2561. DOI:10.1523/JNEUROSCI.2603-12.2013 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
An abnormality in auditory evoked responses localised to the inferior colliculus (IC) has been reported in rapid eye movement (REM) sleep behaviour disorder (RBD) patients. The external cortex of the inferior colliculus (ICX) has been demonstrated not only to be involved in auditory processing, but also to participate in the modulation of motor activity.
Rats were surgically implanted with electrodes for electroencephalography (EEG) and electromyography (EMG) recording and guide cannulae aimed at the ICX for drug infusions. Drug infusions were conducted after the animals recovered from surgery. Polysomnographic recordings with video were analysed to detect normal and abnormal sleep states.
Baclofen, a gamma-aminobutyric acid B (GABAB) receptor agonist, infused into the ICX increased phasic motor activity in slow-wave sleep (SWS) and REM sleep and tonic muscle activity in REM sleep; it also elicited RBD-like activity during the infusion and post-infusion period. In contrast, saclofen, a GABAB receptor antagonist, did not produce significant changes in motor activities in sleep. Baclofen infusions in ICX also significantly increased REM sleep during the post-infusion period, while saclofen infusions did not change the amount of any sleep-waking states.
This study suggests that GABAB receptor mechanisms in the ICX may be implicated in the pathology of RBD.
Sleep Medicine 10/2012; 14(8). DOI:10.1016/j.sleep.2012.08.008 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Slow wave sleep (SWS) in the northern fur seal (Callorhinus ursinus) is characterized by a highly expressed interhemispheric electroencephalogram (EEG) asymmetry, called 'unihemispheric' or 'asymmetrical' SWS. The aim of this study was to examine the regional differences in slow wave activity (SWA; power in the range of 1.2-4.0 Hz) within one hemisphere and differences in the degree of interhemispheric EEG asymmetry within this species. Three seals were implanted with 10 EEG electrodes, positioned bilaterally (five in each hemisphere) over the frontal, occipital and parietal cortex. The expression of interhemispheric SWA asymmetry between symmetrical monopolar recordings was estimated based on the asymmetry index [AI = (L-R)/(L+R), where L and R are the power in the left and right hemispheres, respectively]. Our findings indicate an anterior-posterior gradient in SWA during asymmetrical SWS in fur seals, which is opposite to that described for other mammals, including humans, with a larger SWA recorded in the parietal and occipital cortex. Interhemispheric EEG asymmetry in fur seals was recorded across the entire dorsal cerebral cortex, including sensory (visual and somatosensory), motor and associative (parietal or suprasylvian) cortical areas. The expression of asymmetry was greatest in occipital-lateral and parietal derivations and smallest in frontal-medial derivations. Regardless of regional differences in SWA, the majority (90%) of SWS episodes with interhemispheric EEG asymmetry meet the criteria for 'unihemispheric SWS' (one hemisphere is asleep while the other is awake). The remaining episodes can be described as episodes of bilateral SWS with a local activation in one cerebral hemisphere.
Journal of Sleep Research 06/2012; 21(6). DOI:10.1111/j.1365-2869.2012.01023.x · 3.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study describes the organization of the orexinergic (hypocretinergic) neurons in the hypothalamus of the giraffe and harbour porpoise--two members of the mammalian Order Cetartiodactyla which is comprised of the even-toed ungulates and the cetaceans as they share a monophyletic ancestry. Diencephalons from two sub-adult male giraffes and two adult male harbour porpoises were coronally sectioned and immunohistochemically stained for orexin-A. The staining revealed that the orexinergic neurons could be readily divided into two distinct neuronal types based on somal volume, area and length, these being the parvocellular and magnocellular orexin-A immunopositive (OxA+) groups. The magnocellular group could be further subdivided, on topological grounds, into three distinct clusters--a main cluster in the perifornical and lateral hypothalamus, a cluster associated with the zona incerta and a cluster associated with the optic tract. The parvocellular neurons were found in the medial hypothalamus, but could not be subdivided, rather they form a topologically amorphous cluster. The parvocellular cluster appears to be unique to the Cetartiodactyla as these neurons have not been described in other mammals to date, while the magnocellular nuclei appear to be homologous to similar nuclei described in other mammals. The overall size of both the parvocellular and magnocellular neurons (based on somal volume, area and length) were larger in the giraffe than the harbour porpoise, but the harbour porpoise had a higher number of both parvocellular and magnocellular orexinergic neurons than the giraffe despite both having a similar brain mass. The higher number of both parvocellular and magnocellular orexinergic neurons in the harbour porpoise may relate to the unusual sleep mechanisms in the cetaceans.
Journal of chemical neuroanatomy 06/2012; 44(2):98-109. DOI:10.1016/j.jchemneu.2012.06.001 · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several behavioral and physiological adaptations have been developed in evolution of Pinnipeds allowing them to sleep both on land and in water. To date sleep has been examined in detail in eared and true seals (the families of Otariidae and Phocidae). The aim of this study was to examine sleep in another semiaquatic mammal - the walrus, which is the only extant representative of the family Odobenidae. Slow wave and paradoxical sleep (SWS and PS) in the examined walrus (2 year old female, weight 130 kg) averaged 19.4 ± 2.0 and 6.9 ± 1.1% of 24-h when on land, and 20.5 ± 0.8% of 24-h and 1.1 ± 0.6% when in water, respectively. The average duration of PS episode was 6.4 ± 0.6 min (maximum 23 min) when on land and 1.8 ± 0.1 min (maximum 3.3 min) when in water. In water, sleep occurred predominantly while the walrus submerged and lay on the bottom of the pool (89% of total sleep time). The walrus usually woke up while emerging to the surface for breathing. Most often EEG slow waves developed synchronously in both cortical hemispheres (90% of SWS time when on land and 97% when in water). Short episodes of interhemispheric EEG asymmetry usually coincided with brief opening of one eye. The pattern of sleep in the walrus was similar to the pattern of sleep in the Otariidae seals while on land (predominantly bilateral SWS, accompanied by regular breathing) and to the pattern of sleep in the Phocidae while in water (sleep during apneas both in depth and at the surface, interrupted by brief arousal when emerging for breathing).