Coupled Flip-Flop Model for REM Sleep Regulation in the Rat

Recent experimental studies investigating the neuronal regulation of rapid eye movement (REM) sleep have identified mutually inhibitory synaptic projections among REM sleep-promoting (REM-on) and REM sleep-inhibiting (REM-off) neuronal populations that act to maintain the REM sleep state and control its onset and offset. The control mechanism of mutually inhibitory synaptic interactions mirrors the proposed flip-flop switch for sleep-wake regulation consisting of mutually inhibitory synaptic projections between wake- and sleep-promoting neuronal populations. While a number of synaptic projections have been identified between these REM-on/REM-off populations and wake/sleep-promoting populations, the specific interactions that govern behavioral state transitions have not been completely determined. Using a minimal mathematical model, we investigated behavioral state transition dynamics dictated by a system of coupled flip-flops, one to control transitions between wake and sleep states, and another to control transitions into and out of REM sleep. The model describes the neurotransmitter-mediated inhibitory interactions between a wake- and sleep-promoting population, and between a REM-on and REM-off population. We proposed interactions between the wake/sleep and REM-on/REM-off flip-flops to replicate the behavioral state statistics and probabilities of behavioral state transitions measured from experimental recordings of rat sleep under ad libitum conditions and after 24 h of REM sleep deprivation. Reliable transitions from REM sleep to wake, as dictated by the data, indicated the necessity of an excitatory projection from the REM-on population to the wake-promoting population. To replicate the increase in REM-wake-REM transitions observed after 24 h REM sleep deprivation required that this excitatory projection promote transient activation of the wake-promoting population. Obtaining the reliable wake-nonREM sleep transitions observed in the data required that activity of the wake-promoting population modulated the interaction between the REM-on and REM-off populations. This analysis suggests neuronal processes to be targeted in further experimental studies of the regulatory mechanisms of REM sleep.     

Sleep-promoting functions of the hypothalamic median preoptic nucleus: inhibition of arousal systems

Recent work supports the hypotheses developed by von Economo and Nauta and elaborated by Sallanon et al. that the POA contains a sleep-promoting output that opposes wake-promoting neuronal groups in the PH. The POA gives rise to descending pathways that terminate within wake-promoting populations in pLH, PH and midbrain. Current evidence suggests that this output originates in POA sleep-active GABAergic neurons. This output also seems to convey the signals of homeostatic drive. Disynaptic projections from the SCN to both MnPN and VLPO were recently identified. These may regulate the circadian control of sleep propensity. The hypothesis that the descending projections from POA sleep-active neurons to sites of arousal-related neurons originates in GABAergic neurons must be confirmed. Also to be further clarified is the anatomical distribution of putative sleep-active GABAergic neurons within the POA. Segregated groups have been found in the MnPN and VLPO, but unit recording studies of sleep-active neurons, lesion studies and local neurochemical application studies all indicate that sleep-active neurons may be found diffusely in the POA and adjacent areas. The MnPN has been shown previously to be involved in water balance and blood pressure regulation and to be responsive to hyperthermia. Our studies suggest that this nucleus also contains sleep-active, putative sleep-promoting neurons. However, interactions between sleep control and physiological variables must be considered. In particular, the details of neuronal basis of the coupling of warm-sensitive neurons in MnPN to the POA hypnogenic output has not been explored. It is also worth noting that both the VLPO and MnPN lie close to the ventricular and subarachnoid surface and are punctuated by radial arterioles. The possibility that the sleep-regulatory functions of these sites is coupled to physiological signals conveyed through epithelial cells has been suggested for the actions of PGD2 but has yet to be explored in detail for other putative hypnogens.     

Hypothalamic releasing hormones mediating the effects of interleukin-1 on sleep

There is a substantial literature describing the interactions between the endocrine and immune systems. Although such interactions are less well known within the brain, one major brain function altered during inflammation and infection and by several endocrine hormones is sleep. Pathological disturbances, be they inflammation, infectious disease, and/or sleep deprivation, result in altered hypothalamus-pituitary function and cytokine metabolism. In respect to hormone secretion from the pituitary, cytokines are now recognized to play an important role in modulating the neuroendocrine system. Changes in sleep provide a useful illustration of the interactions between cytokines and the hypothalamus-pituitary axis. Evidence linking interleukin-1 (IL-1) to growth hormone releasing hormone and to corticotropin releasing hormone in regard to their effects on sleep is reviewed.     

Restraint increases prolactin and REM sleep in C57BL/6J mice but not in BALB/cJ mice

Sleep is generally considered to be a recovery from prior wakefulness. The architecture of sleep not only depends on the duration of wakefulness but also on its quality in terms of specific experiences. In the present experiment, we studied the effects of restraint stress on sleep architecture and sleep electroencephalography (EEG) in different strains of mice (C57BL/6J and BALB/cJ). One objective was to determine if the rapid eye movement (REM) sleep-promoting effects of restraint stress previously reported for rats would also occur in mice. In addition, we examined whether the effects of restraint stress on sleep are different from effects of social defeat stress, which was found to have a non-REM (NREM) sleep-promoting effect. We further measured corticosterone and prolactin levels as possible mediators of restraint stress-induced changes in sleep. Adult male C57BL/6J and BALB/cJ mice were subjected to 1 h of restraint stress in the middle of the light phase. To control for possible effects of sleep loss per se, the animals were also kept awake for 1 h by gentle handling. Restraint stress resulted in a mild increase in NREM sleep compared with baseline, but, overall, this effect was not significantly different from sleep deprivation by gentle handling. In contrast, restraint stress caused a significant increase in REM sleep compared with handling in the C57BL/6J mice but not in BALB/cJ mice. Corticosterone levels were significantly and similarly elevated after restraint in both strains, but prolactin was increased only in the C57BL/6J mice. In conclusion, this study shows that the restraint stress-induced increase in REM sleep in mice is strongly strain dependent. The concomitant increases in prolactin and REM sleep in the C57BL/6J mice, but not in BALB/cJ mice, suggest prolactin may be involved in the mechanism underlying restraint stress-induced REM sleep. Furthermore, this study confirms that different stressors differentially affect NREM and REM sleep. Whereas restraint stress promotes REM sleep in C57BL/6J mice, we previously found that in the same strain, social defeat stress promotes NREM sleep. As such, studying the consequences of specific stressful stimuli may be an important tool to unravel both the mechanism and function of different sleep stages.     

Organizational and activational effects of sex steroids on brain and behavior: A reanalysis

The actions of sex steroids on brain and behavior traditionally have been divided into organizational and activational effects. Organizational effects are permanent and occur early in development; activational effects are transient and occur throughout life. Over the past decade, experimental results have accumulated which do not fit such a simple two-process theory. Specifically, the characteristics said to distinguish organizational and activational effects on behavior are sometimes mixed, as when permanent effects occur in adulthood. Attempts to determine whether specific cellular processes are uniquely associated with either organizational or activational effects are unsuccessful. These considerations blur the organizational-activational distinction sufficiently to suggest that a rigid dichotomy is no longer tenable.     

Effects of a sleep education program with self-help treatment on sleeping patterns and daytime sleepiness in Japanese adolescents: A cluster randomized trial

Subjective insufficient sleep and delayed sleep–wake patterns have been reported as the primary causes for daytime sleepiness, a reasonably significant and prevalent problem for adolescents worldwide. Systematic reviews have indicated that the success of sleep education programs has thus far been inconsistent, due to the lack of a tailored approach that allows for evaluation of individual differences in behavior patterns. One way to resolve this problem is to assess the individual sleep behaviors of adolescents by using a checklist containing the recommended behaviors for promoting sleep health. Such self-help education programs have already been implemented for elementary school children, school nurses and the elderly. The present study aimed to verify the effects of a sleep education program with supplementary self-help treatment, based on a checklist of sleep-promoting behaviors, in addition to evaluation of changes in sleeping patterns, sleep-promoting behaviors and daytime sleepiness in adolescents. A cluster randomized controlled trial involving 5 Japanese junior high schools was conducted, and 243 students (sleep education: n = 122; waiting list: n = 121; 50.6% female; 7th grade) were included in the final analysis. The sleep education group was provided with information on proper sleep health and sleep-promoting behaviors. The students in this group were asked to practice one sleep-promoting behavior as a goal for 2 weeks and to monitor their practice using sleep diaries. Both pre- and post-treatment questionnaires were administered to students in order to assess knowledge of sleep-promoting behaviors, sleeping patterns and daytime functioning. Students in the sleep education group showed significant improvement in their knowledge of sleep health (F_1,121 = 648.05, p < 0.001) and in their sleep-promoting behaviors (F_1,121 = 55.66, p < 0.001). Bedtime on both school nights (F_1,121 = 50.86, p < 0.001) and weekends (F_1,121 = 15.03, p < 0.001), sleep-onset latency (F_1,121 = 10.26, p = 0.002), total sleep time on school nights (F_1,121 = 12.45, p = 0.001), subjective experience of insufficient sleep (McNemar χ²(1) = 4.03, p = 0.045) and daytime sleepiness (McNemar χ²(1) = 4.23, p = 0.040) were also improved in the sleep education group. In contrast, no significant improvement in these variables was observed for students in the waiting-list group. In conclusion, the sleep education program with self-help treatment was effective not only in increasing sleep knowledge but also in improving sleep-promoting behavior and sleeping patterns/reducing daytime sleepiness for students in the sleep education group, in comparison with the waiting-list group.     

Molecular determinants and regulation of Leishmania virulence

A Leishmania model to explain microbial virulence in chronic infectious diseases is proposed. All these diseases progress from infection to symptomatic phase to host death or recovery. The outcome of each phase is depicted to result from the interactions of a distinct group of parasite molecules with a specific host immune compartment. The first group consists of invasive/evasive determinants, which are largely parasite cell surface and secreted molecules. Their activities help parasites establish infection by overcoming host immunologic and non-immunologic barriers. These determinants do not cause disease per se, but are indispensable for infection necessary for the development of a disease-state. The second group of parasite molecules consists of "pathoantigenic" determinants – unique parasite epitopes present often within otherwise highly conserved cytoplasmic molecules. Immune response against these determinants is thought to result in immunopathology manifested as clinical signs or symptoms, namely the virulent phenotype. The third group of parasite molecules is hypothetically perceived as vaccine determinants. Their interactions with the host immune system lead to the elimination or reduction of parasites to effect a clinical cure. Differential expression of these determinants alone by parasites may alter their interactions with the hosts. Virulent phenotype is consequently presented as a spectrum of manifestations from asymptomatic infection to fatality. A secondary level of regulation lies in host genetic and environmental factors. The model suggests that different parasite determinants may be targeted by different strategies to achieve more effective control of leishmaniasis and other similar diseases.     

Effects on sleep of microdialysis of adenosine A1 and A2a receptor analogs into the lateral preoptic area of rats

Evidence suggests that adenosine (AD) is an endogenous sleep factor. The hypnogenic action of AD is mediated through its inhibitory A1 and excitatory A2A receptors. Although AD is thought to be predominantly active in the wake-active region of the basal forebrain (BF), a hypnogenic action of AD has been demonstrated in several other brain areas, including the preoptic area. We hypothesized that in lateral preoptic area (LPOA), a region with an abundance of sleep-active neurons, AD acting via A1 receptors would induce waking by inhibition of sleep-active neurons and that AD acting via A2A receptors would promote sleep by stimulating the sleep-active neurons. To this end, we studied the effects on sleep of an AD transport inhibitor, nitrobenzyl-thio-inosine (NBTI) and A1 and A2A receptor agonists/antagonists by microdialyzing them into the LPOA. The results showed that, in the sleep-promoting area of LPOA: 1) A1 receptor stimulation or inhibition of AD transport by NBTI induced waking and 2) A2A receptor stimulation induced sleep. We also confirmed that NBTI administration in the wake promoting area of the BF increased sleep. The effects of AD could be mediated either directly or indirectly via interaction with other neurotransmitter systems. These observations support a hypothesis that AD mediated effects on sleep-wake cycles are site and receptor dependent.     

Effects of Pair-Bond and Social Context on Male–Female Interactions in Captive Titi Monkeys (Callicebus moloch, Primates: Cebidae)

In monogamous species, an abiding relationship between a specific adult male and a specific adult female is a defining feature of the social system. The interactions between these individuals are influenced by many factors, including not only the history of their relationship (for example, development of a mutual bond), but also the immediate effects of the prevailing social context (for example, presence and sex of extra‐pair conspecifics). In this study we examined the effects of an existing bond and of social context on interactions between adult heterosexual pairs of the monogamous titi monkeys (Callicebus moloch). Twelve adult males and 12 adult females were tested with their cagemates and with an unfamiliar partner of the opposite sex in five social contexts: (1) mated male–female pair; (2) unfamiliar pair; (3) single female; (4) single male; and (5) empty stimulus cage. Results show that mated pairs were more affiliative than unfamiliar pairs and differentiated social contexts more sharply. Males were more responsive to context than females. Distance between mates was less and physical contact was more frequent in the presence of male–female pairs or a single male, than in the presence of a single female or an empty cage. These findings suggest that the presence and sex of strangers have a stronger influence on male–female interactions when the pair has an existing relationship.     

Sleep mechanisms in health and disease

Excess sleepiness, abnormal sleep patterns, non-restorative sleep, and fatigue are becoming increasingly pervasive in modern society. Identifying substances and mechanisms that modulate sleep and vigilance during health and disease is a critical prelude to eventual development of interventions to prevent or alleviate these disabling problems. A unified interdisciplinary approach that includes neurophysiology, neuroanatomy, neurochemistry, and molecular biology will promote elucidation of the complex biology of sleep. Integration of basic sleep physiology with modern genetic techniques will eventually lead to identification of specific genes and substances involved in regulation of various facets of sleep. The review presented here highlights recent progress in defining the anatomy and physiology of sleep-wake regulatory systems, delineating the role of homeostatic and circadian process in regulating sleep and wakefulness, and establishing the relationship of sleep and sleep disorders to other medical conditions. Particular emphasis is placed on reviewing the interactions between sleep, infectious challenge, and host defense response, and on identifying mechanisms that contribute to variation in sleep patterns among various strains of inbred mice.     

Infectious animal disease and its control

The control of infectious diseases in the main food-producing animals is considered and the main factors involved in the epizootiology of disease are presented. The properties of infectious agents and their natural history together with factors that influence the spread and development of disease are summarized. The factors in intensive animal husbandry that affect the occurrence of infectious disease and its control are considered. These include population density, population movement, management, hygiene and genetic constitution of the host. They encourage the appearance of new diseases, changes in the character of established diseases and the development of pathogenicity in infectious agents that were previously of no importance. Intensive animal husbandry has also increased the importance of multifactorial disease, which includes diseases that require more than one infectious agent or one or more infectious agents plus other factors for their cause. The methods of control of infectious disease currently available are described and the success and difficulties of their control on a global, national and local (farm or enterprise) basis are considered. Examples of diseases of global importance where national and world programmes of control and eradication have been of varying success are described. Examples of diseases that are enzootic throughout the world and the procedures used for their control are also described. The technological opportunities for the improvement of the control of infectious disease in the future are discussed. It is considered that developments in molecular biology and immunology will provide improvements in diagnostic tools and will revolutionize the development of animal resistance to disease and the production and use of vaccines.     

Re-patterning sleep architecture in Drosophila through gustatory perception and nutritional quality

Organisms perceive changes in their dietary environment and enact a suite of behavioral and metabolic adaptations that can impact motivational behavior, disease resistance, and longevity. However, the precise nature and mechanism of these dietary responses is not known. We have uncovered a novel link between dietary factors and sleep behavior in Drosophila melanogaster. Dietary sugar rapidly altered sleep behavior by modulating the number of sleep episodes during both the light and dark phase of the circadian period, independent of an intact circadian rhythm and without affecting total sleep, latency to sleep, or waking activity. The effect of sugar on sleep episode number was consistent with a change in arousal threshold for waking. Dietary protein had no significant effect on sleep or wakefulness. Gustatory perception of sugar was necessary and sufficient to increase the number of sleep episodes, and this effect was blocked by activation of bitter-sensing neurons. Further addition of sugar to the diet blocked the effects of sweet gustatory perception through a gustatory-independent mechanism. However, gustatory perception was not required for diet-induced fat accumulation, indicating that sleep and energy storage are mechanistically separable. We propose a two-component model where gustatory and metabolic cues interact to regulate sleep architecture in response to the quantity of sugar available from dietary sources. Reduced arousal threshold in response to low dietary availability may have evolved to provide increased responsiveness to cues associated with alternative nutrient-dense feeding sites. These results provide evidence that gustatory perception can alter arousal thresholds for sleep behavior in response to dietary cues and provide a mechanism by which organisms tune their behavior and physiology to environmental cues.     

Carbachol models of REM sleep: recent developments and new directions

Since the early '60s, injections of a broad-spectrum muscarinic cholinergic agonist, carbachol, into the medial pontine reticular formation (mPRF) of cats have been extensively used as a tool with which to study the neural mechanisms of rapid eye movement (REM) sleep. During the last decade, new carbachol models of REM sleep were introduced, including chronically instrumented/behaving rats and "reduced" preparations such as decerebrate or anesthetized cats and rats. The combined results from these distinct models show interspecies similarities and differences. The dual nature, both REM sleep-promoting and wakefulness (or arousal)-promoting, of the cholinergic effects exerted within the mPRF is more strongly expressed in rats than in cats. This strengthens the possibility suggested by earlier central neuronal recordings that active wakefulness and REM sleep have extensive common neuronal substrates, and may have evolved from a common behavioral state. Carbachol studies using different intact and reduced models also suggest that powerful REM sleep episode-terminating effects originate in suprapontine structures. In contrast, the timing of REM sleep-like episodes in decerebrate models is determined by a pontomedullary neuronal network responsible for the generation of an ultradian cycle similar to the basic rest-activity cycle of N. Kleitman. Other presumed species differences, such as the more widespread distribution of carbachol-sensitive sites or the relative failure of carbachol to increase the duration of REM sleep episodes in rats when compared to cats, may be of a quantitative or technical nature. While carbachol and many other neurotransmitters and peptides microinjected into the mPRF evoke, enhance or suppress REM sleep, the most sensitive site(s) of their actions have not been fully mapped, and the nature of the cellular and neurochemical interactions taking place at the sites where carbachol triggers the REM sleep-like state remain largely unknown. Similarly, little is known about the pathways between the mPRF and medial medullary reticular formation, but the existing evidence suggests that they are reciprocal and essential for the generation of both natural and carbachol-induced REM sleep. Studies of the mesopontine cholinergic neurons, which are hypothesized to be the main source of endogenous acetylcholine for the mPRF, need to be extended to neurons of the mPRF and cells located functionally downstream from this important site for REM sleep, or both REM sleep and active wakefulness.     

Gene–environment interactions at the FKBP5 locus: sensitive periods,mechanisms and pleiotropism

Psychiatric phenotypes are multifactorial and polygenic, resulting from the complex interplay of genes and environmental factors that act cumulatively throughout an organism's lifetime. Adverse life events are strong predictors of risk for a number of psychiatric disorders and a number of studies have focused on gene–environment interactions (GxEs) occurring at genetic loci involved in the stress response. Such a locus that has received increasing attention is the gene encoding FK506 binding protein 51 (FKBP5), a heat shock protein 90 cochaperone of the steroid receptor complex that among other functions regulates sensitivity of the glucocorticoid receptor. Interactions between FKBP5 gene variants and life stressors alter the risk not only for mood and anxiety disorders, but also for a number of other disease phenotypes. In this review, we will focus on molecular and system‐wide mechanisms of this GxE with the aim of establishing a framework that explains GxE interactions. We will also discuss how an understanding of the biological effects of this GxE may lead to novel therapeutic approaches .     

Ecophysiology meets conservation: understanding the role of disease in amphibian population declines

Infectious diseases are intimately associated with the dynamics of biodiversity. However, the role that infectious disease plays within ecological communities is complex. The complex effects of infectious disease at the scale of communities and ecosystems are driven by the interaction between host and pathogen. Whether or not a given host-pathogen interaction results in progression from infection to disease is largely dependent on the physiological characteristics of the host within the context of the external environment. Here, we highlight the importance of understanding the outcome of infection and disease in the context of host ecophysiology using amphibians as a model system. Amphibians are ideal for such a discussion because many of their populations are experiencing declines and extinctions, with disease as an important factor implicated in many declines and extinctions. Exposure to pathogens and the host's responses to infection can be influenced by many factors related to physiology such as host life history, immunology, endocrinology, resource acquisition, behaviour and changing climates. In our review, we discuss the relationship between disease and biodiversity. We highlight the dynamics of three amphibian host-pathogen systems that induce different effects on hosts and life stages and illustrate the complexity of amphibian-host-parasite systems. We then review links between environmental stress, endocrine-immune interactions, disease and climate change.     

Role of androgens in fetal and pubertal development

During fetal development, androgens exert long-term effects which are either organizational on specific organs during a critical phase of morphogenesis (e.g. sexual differentiation of external genitalia), or programming neural functions or enzyme activities expressed later in life. At all stages of development, which extends from fetal and neonatal stages to pubertal accomplishment, androgens also have activational effects that are immediate, multiple, reversible and dose dependent. Both types of actions are intricate during human development. This review will focus (1) on the intricate morphological and activational roles of androgens on sexual differentiation and pubertal development of the genital tract, external genitalia and mammary glands, and (2) on the organizational effects of androgens on four central nervous system functions: pituitary regulation of liver metabolism, gonadotropin secretions, sex dimorphic behavioral patterns, and 'sexualization of the brain'. If the molecular basis of the immediate androgenic action is known, depending of androgen receptor's availability and affinity, little is known of the way androgens exert their influence on either so various morphological processes or neuroendocrine imprinting.     

Ghrelin promotes slow-wave sleep in humans

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor, stimulates GH release, appetite, and weight gain in humans and rodents. Synthetic GHSs modulate sleep electroencephalogram (EEG) and nocturnal hormone secretion. We studied the effect of 4 x 50 microg of ghrelin administered hourly as intravenous boluses between 2200 and 0100 on sleep EEG and the secretion of plasma GH, ACTH, cortisol, prolactin, and leptin in humans (n = 7). After ghrelin administration, slow-wave sleep was increased during the total night and accumulated delta-wave activity was enhanced during the second half of the night. Rapid-eye-movement (REM) sleep was reduced during the second third of the night, whereas all other sleep EEG variables remained unchanged. Furthermore, GH and prolactin plasma levels were enhanced throughout the night, and cortisol levels increased during the first part of the night (2200-0300). The response of GH to ghrelin was most distinct after the first injection and lowest after the fourth injection. In contrast, cortisol showed an inverse pattern of response. Leptin levels did not differ between groups. Our data show a distinct action of exogenous ghrelin on sleep EEG and nocturnal hormone secretion. We suggest that ghrelin is an endogenous sleep-promoting factor. This role appears to be complementary to the already described effects of the peptide in the regulation of energy balance. Furthermore, ghrelin appears to be a common stimulus of the somatotropic and hypothalamo-pituitary-adrenocortical systems. It appears that ghrelin is a sleep-promoting factor in humans.     

With Allee effects,life for the social carnivore is complicated

Anthropogenic modification of the landscape, resultant habitat loss, and decades of persecution have resulted in severe decline and fragmentation of large carnivore populations worldwide. Infectious disease is also identified as a primary threat to many carnivores. In wildlife species, population demography and group persistence are strongly influenced by group or population size. This is referred to as the Allee effect, in which a population or group is at an increased risk of extinction when the number or density of individuals falls below some threshold due to ecological and/or genetic factors. However, in social mammalian species, the relationship between the number of individuals and the risk of extinction is complicated because aggregation may enhance pathogen exposure and transmission. Although theoretical studies of the interaction between infectious disease transmission and Allee effects reveal important implications for carnivore management and population extinction risk, information about the interaction has yet to be synthesized. In this paper, we assess life history strategies of medium to large carnivore species (≥2.4 kg) and their influence on population dynamics, with a special focus on infectious disease. While declining population trends are observed in 73 % of all carnivores (both social and solitary species), infectious disease is identified as a significant cause of population decline in 45 % of social carnivores and 3 % of solitary carnivores. Furthermore, where carnivores suffer a combination of rapid population decline and infectious disease, Allee effects may be more likely to impact social as compared to solitary carnivore populations. These potentially additive interactions may strongly influence disease transmission dynamics and population persistence potential. Understanding the mechanisms that can result in Allee effects in endangered carnivore populations and the manner in which infectious disease interfaces at this nexus may define the outcome of developed conservation strategies.