Article

Mirmiran M, Scholtens J, van de Poll NE, Uylings HB, van der Gugten J, Boer GJ. Effects of experimental suppression of active (REM) sleep during early development upon adult brain and behavior in the rat. Brain Res 283: 277-286

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  • University ofIsfahan
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Abstract

In order to test the hypothesis that active sleep (AS) is important for the normal development of the central nervous system, 3 different deprivation methods were applied to male Wistar rat pups during the first month of life. Daily injection of clomipramine from 8 to 21 days of age reduced the high level of AS to less than the adult value throughout most of the experimental period. Administration of clonidine from 8 to 21 days of life induced an almost total suppression of AS. Instrumental deprivation, using the 'pendulum' method, led to a significant (but less severe) AS reduction during 2-4 weeks of postnatal age. Open-field behavior testing in adulthood revealed a higher than normal level of ambulation in all 3 experimental groups. Masculine sexual responses were deficient, due to a low level of both mounts and ejaculations, in both clomipramine- and clonidine-treated animals. Neither passive avoidance learning nor dark preference tests revealed any differences between the experimental and control rats. Sleep observations showed that there was an abnormally high incidence of large myoclonic jerks during AS in both clomipramine- and clonidine-treated rats. Subsequent measurement of regional brain weights showed a significant reduction in the cerebral cortex and medulla oblongata, as compared with the respective control groups, in both the clomipramine- and the clonidine-treated rats. In addition, DNA and protein determination in the affected brain areas showed a proportional reduction in the cortex and in the medulla. These results demonstrate that interference with normal functioning either of AS per se or of specific monoaminergic transmitter systems during early development can produce long-lasting behavioral as well as brain morphological and biochemical abnormalities in later life.

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... The objective of these manipulations is to alter the viability of monoaminergic neurotransmission systems during a sensitive stage of development to modify their long-term balance and behavioral disturbances. One early study (1980s) in this field was conducted by Mirmiran et al. (1983) to analyze the importance of active or rapid eye movement sleep (REM) for neurodevelopment, since a greater amount of REM sleep occurs in early stages of development than in adulthood. Those authors deprived rats of REM sleep in the second and third weeks of life by administering clomipramine, a REM sleep inhibitor, tricyclic and SSRIs antidepressant. ...
... Those authors deprived rats of REM sleep in the second and third weeks of life by administering clomipramine, a REM sleep inhibitor, tricyclic and SSRIs antidepressant. As adults, those animals presented behavioral and physiological disturbances (Corner et al., 1980;Mirmiran et al., 1983). Later, was observed that adult animals treated neonatally with clomipramine had decreased male sexual behavior and intracranial stimulation, with abnormalities in REM sleep and greater motor activity in stressful situations; alterations that resemble symptoms in patients with MDD Vogel and Vogel, 1982). ...
... Also, reports indicate that neonatal exposure to SSRIs produces behavioral changes that resemble secondary symptoms of human depression, including altered motor activity (hyperactivity or hypoactivity) on open-field tests (Mirmiran et al., 1983;Lee and Lee, 2012;Ansorge, 2004), sleep abnormalities (Mirmiran et al., 1981;Popa et al., 2008), greater food intake and weight gain (Kummet et al., 2012;Harris et al., 2012), reduced conspecific interaction and juvenile play , and cognitive alterations in spatial learning (Bairy et al., 2007;Bhagya et al., 2008). Greater HPA hyperactivity may occur in rats treated with clomipramine during the neonatal period (Prathiba, Kumar and Karanth, 1998), though these manifestations could depend on the type of antidepressant administered. ...
Chapter
Depression is a common, complex, life-threatening mental disorder that imposes a serious social and economic burden worldwide as a debilitating mental illness with significant morbidity and mortality. Despite a recent increase in research, the precise mechanisms that underlie depression are not fully understood. Numerous animal models have been established to elucidate the pathophysiology of depression and test new treatment strategies but, despite these substantial efforts, the animal models currently available have only limited utility for these purposes, likely because none can completely mimic this complex disorder. Animal models must fulfill three basic requirements: face validity (i.e., a phenotype similar to humans with the illness); construct validity (i.e., they replicate the processes that generate this pathology in humans); and predictive validity (i.e., sensitivity to pharmacological and non-pharmacological interventions that effectively treat the disease or condition in humans). This article reviews the most widely-used animal models of depression, discusses their advantages and limitations, and delineates the salient features of each one in terms of its behavioral and neurobiological outcomes
... Thus, in adulthood, animals subjected to neonatal antidepressant treatment procedure have been shown to exhibit a number of behavioural impairments, including anxietyand depression-like behaviour [7]. However, the most consistent phenotype shown is long-lasting sleep abnormalities, reported in numerous previous studies using neonatal antidepressant administration e.g., [5,6,[9][10][11]. ...
... The present study extends these findings by demonstrating that the response to melatonin may depend on individual characteristics of animal with melatonin treatment being more effective in animals with disrupted function of the serotonergic system. As mentioned above, this procedure is known to cause long-lasting sleep alterations and other behavioural changes in animals e.g., [5,6,[9][10][11]. These findings are in line with previous studies showing that individual differences may have a considerable impact on the treatment outcome. ...
Article
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The reason for the limited treatment success of substance-use-related problems may be a causal heterogeneity of this disorder that, at least partly, is manifested as differences in substance-use motives between individuals. The aim of the present study was to assess if rats with pharmacologically induced differences in the function of the serotonergic system would respond differently to melatonin treatment compared to control rats with respect to voluntary alcohol consumption. To achieve this goal, we treated rats neonatally with the selective serotonin transporter (SERT) inhibitor escitalopram. This procedure has been reported to cause long-lasting sleep abnormalities in rodents. The study demonstrated that during adulthood, rats that had been treated with escitalopram tended to drink higher amounts of alcohol compared to control rats. Further, administration of melatonin significantly decreased the alcohol intake in escitalopram-treated animals but caused only a slight, nonsignificant reduction in the alcohol consumption by control rats. In conclusion, our data support the therapeutic potential of melatonin as a treatment for alcohol use disorder. However, interindividual differences between alcohol users may considerably modify the outcome of the melatonin treatment, whereby patients that manifest lower sleep quality due to disruption of serotonergic activity are more likely to benefit from this treatment.
... Other studies have shown that there is a long-term effect on behavior following neonatal REM sleep deprivation. In particular, REM sleep deprivation in neonatal rats leads to depressive-like behaviors in adult-hood (Mirmiran et al., 1983;Feng et al., 2001;Feng and Ma, 2003). Rather than total REM sleep deprivation, we focus on the long-term effects of chronic sleep restriction (regardless of sleep stage). ...
... results are consistent with our previous results (Sare et al., 2015), they contrast other studies that found hyperactivity in rats following REM sleep deprivation (Mirmiran et al., 1983). The differences between our results and those finding hyperactivity might be a species difference or a difference in the response to either total or REM sleep deprivation. ...
Article
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Sleep abnormalities are prevalent in autism spectrum disorders (ASD). Moreover, the severity of ASD symptoms are correlated with the degree of disturbed sleep. We asked if disturbed sleep during brain development itself could lead to ASD-like symptoms, particularly behavioral manifestations. We reasoned that sleep is known to be important for normal brain development and plasticity, so disrupted sleep during development might result in changes that contribute to behavioral impairments associated with ASD. We sleep-restricted C57BL/6J male mice [beginning at postnatal day 5 (P5) and continuing through P52] 3 h per day by means of gentle handling and compared the data with a stress group (handled every 15 min during the 3-h period) and a control group (no additional handling). From P42–P52, we assessed the behavioral effects of sleep-restriction in this pre-recovery phase. Then, we allowed the mice to recover for 4 weeks and tested behavior once again. Compared to the control group, we found that sleep restricted-mice had long-lasting hypoactivity, and impaired social behavior; repetitive behavior was unaffected. These behavior changes were accompanied by an increase in the downstream signaling products of the mammalian target of rapamycin pathway. These data affirm the importance of undisturbed sleep during development and show that, at least in this model, sleep-restriction can play a causative role in the development of behavioral abnormalities. Assessing and treating sleep abnormalities in ASD may be important in alleviating some of the symptoms.
... Additionally, following surgery, upper airway collapse in REM sleep decreases in frequency but does not normalize completely [5,12]. REM sleep is important for brain and cognitive development [13,14]. A lower proportion of REM sleep has been reported in children with attention deficit hyperactivity https://doi.org/10.1016/j.ijporl.2019.01.013 ...
... Additionally, when the total O-AHI value worsens postoperatively, the postoperative condition may still be improved versus preoperatively. REM sleep is important for brain and cognitive development [13,14]; however, apnea events occur more frequently during REM versus NREM sleep [9][10][11]. Use of the supine position also increases postoperatively, and may be more comfortable and/or favorable for breathing [2]; however, AHI values during sleep in the supine position are similar to or worse than those during sleep in other positions [24][25][26][27]. ...
Article
Objectives: In pediatric obstructive sleep apnea (OSA), the relationship between rapid eye movement sleep and upper airway collapse, and between sleep position and airway dimensions are well known. However, the interrelations between these factors and the obstructive apnea hypopnea index (O-AHI) have not been thoroughly investigated. Methods: A retrospective study including 100 children who underwent adenotonsillectomy between March 2010 and July 2017. Total O-AHI was divided into four subcategories by sleep stage and position. Results: Preoperatively 14 of 47 mild cases of OSA (1 ≤ total O-AHI) and 17 of 18 moderate (5 ≤ total O-AHI) had time showing severe apnea (10 ≤ subcategorized O-AHI). Twenty-two of 24 severe cases (10 ≤ total O-AHI) exhibited very severe apnea (30 ≤ subcategorized O-AHI). All 11 very severe cases (30 ≤ total O-AHI) experienced more than 50 apnea events per hour in at least one of the O-AHI subcategories. After surgery, 23 of 70 cases classified as completely resolved (total O-AHI < 1) still had mild apnea in the O-AHI subcategories, and six of 13 cases who continued to experience apnea events had moderate-to-severe apnea. Seventeen cases worsened in the O-AHI subcategories, and total O-AHI deteriorated in two cases of the 17. The amount of REM sleep and use of the supine position increased significantly postoperatively in the quartile groups with the lowest baseline values (p < 0.0001). Conclusions: When an unexpected AHI value is encountered, the O-AHI subcategories may be informative regarding the indications for surgery and evaluating the efficacy thereof.
... For example, research indicates that sleep, especially REMS sleep, is necessary for proper neural development in neonate, termed the ontogenetic REM sleep hypothesis [51]. Sleep loss during development can reduce brain mass, induce neuronal cell death, and increase risk of eventual behavioral problems [52]. One hypothesis of sleep and memory suggests that NREMS and REMS contribute to different types of memory [53]. ...
... The basal forebrain receives input from brainstem glutamatergic, GABAergic, noradrenergic, serotonergic, and histaminergic neurons, and may in turn influence the thalamo-cortical circuit that promotes arousal [68][69][70][71][72]. GABAergic, glutamatergic, and cholinergic neurons in the basal forebrain directly and indirectly activate cortical pyramidal cells and enhance cortical activation, producing the EEG desynchronization indicative of arousal [50,73,74]. Additionally, the basal forebrain inhibits cortical GABAergic interneurons and deep layer pyramidal cells, thus promoting wakefulness [52,75,76]. The posterior region of the lateral hypothalamus contains neurons that produce hypocretin (orexin) [65]. ...
Article
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Sleep is a complex physiological process that is regulated globally, regionally, and locally by both cellular and molecular mechanisms. It occurs to some extent in all animals, although sleep expression in lower animals may be co-extensive with rest. Sleep regulation plays an intrinsic part in many behavioral and physiological functions. Currently, all researchers agree there is no single physiological role sleep serves. Nevertheless, it is quite evident that sleep is essential for many vital functions including development, energy conservation, brain waste clearance, modulation of immune responses, cognition, performance, vigilance, disease, and psychological state. This review details the physiological processes involved in sleep regulation and the possible functions that sleep may serve. This description of the brain circuitry, cell types, and molecules involved in sleep regulation is intended to further the reader’s understanding of the functions of sleep.
... It is a physiologically complex state that is essential for wellbeing, health, and even survival, as can be demonstrated by the ultimately lethal effects of sleep deprivation (Everson et al., 1989). Although yet to be fully clarified, sleep is known to be involved in childhood development (Roffwarg et al., 1966;Mirmiran et al., 1983;Zielinski et al., 2016), energy conservation (Benington and Heller, 1995;Scharf et al., 2008;Zielinski et al., 2016), immune modulation (Krueger, 2008;Zielinski and Krueger, 2011;Zielinski et al., 2016), cognitive and physical performance (Walker, 2008;Killgore, 2010;Zielinski et al., 2016;Watson, 2017;Cunha et al., 2023), psychological wellbeing (Scott et al., 2021), and clearance of brain waste (Xie et al., 2013;Zielinski et al., 2016). ...
Method
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Adequate sleep duration has recently been recognized as a major determinant of cardiovascular health by the American Heart Association. This is a significant step toward recognizing sleep as a major lifestyle factor and pillar of health, along with physical activity and nutrition. However, healthy sleep is not only a matter of duration. Other dimensions, such as timing, regularity, efficiency, satisfaction with sleep, and daytime alertness are also deemed important to consider. We have designed a systematic review protocol according to the PRISMA-P guidelines with the objective of determining which sleep dimensions are predictors of all-cause mortality and major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina requiring hospitalization), and whether or not the use of multiple dimensions of sleep yields superior predictive value to the use of sleep duration alone in predicting the above-mentioned outcomes. We will implement a systematic search strategy in 10 databases with independent manual screening by two reviewers. The aim is to comprehensively identify longitudinal studies which have examined the relationship between sleep duration and at least one other dimension of sleep and mortality or MACE. Meta-analysis will be performed after data extraction to address these objectives quantitatively. We anticipate that several sleep dimensions beyond sleep duration have been studied in relationship to all-cause mortality and MACE, and that a combination of multiple sleep dimensions can better predict these outcomes than sleep duration alone. Such findings would lay important groundwork to establish multidimensional sleep health as a major determinant of cardiovascular health.
... For example, using an identical ELSD protocol to ours in mice with Shank3 (an ASD risk-gene), Lord and colleagues found that ELSD induces male-specific impaired sociality in adulthood [37]. In addition, automated sleep disruption from P14 to P21 or pharmacological reduction of REM sleep from P8 to P21 in rats was found to impact adult male sexual behaviour, increasing the time to mount and reducing the probability of ejaculation [38,39]. Finally, sleep disruption from P35 to P42 was observed to reduce sociality in adult mice, particularly their species-typical behaviour of social novelty preference [40]. ...
Article
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Early-life sleep disruption (ELSD) has been shown to have long-lasting effects on social behaviour in adult prairie voles (Microtus ochrogaster), including impaired expression of pair bonding during partner preference testing. However, due to the limitations of manual behaviour tracking, the effects of ELSD across the time course of pair bonding have not yet been described, hindering our ability to trace mechanisms. Here, we used pose estimation to track prairie voles during opposite-sex cohabitation, the process leading to pair bonding. Male–female pairs were allowed to interact through a mesh divider in the home cage for 72 h, providing variables of body direction, distance-to-divider and locomotion speed. We found that control males displayed periodic patterns of body orientation towards females during cohabitation. In contrast, ELSD males showed reduced duration and ultradian periodicity of these body orientation behaviours towards females. Furthermore, in both sexes, ELSD altered spatial and temporal patterns of locomotion across the light/dark cycles of the 72 h recordings. This study allows a comprehensive behavioural assessment of the effects of ELSD on later life sociality and highlights subtle prairie vole behaviours. Our findings may shed light on neurodevelopmental disorders featuring sleep disruption and social deficits, such as autism spectrum disorders.
... Specifically, daily subcutaneous injection of clonidine into rat neonates (P0-P21; twice a day, subcutaneous, 100 μg/kg) causes super-sensitivity to NA in hippocampal CA1 cells, and clonidine causes long-lasting plasticity as a result of low seizure susceptibility (Gorter et al., 1990). Clonidine administration during P8-P21 (P8, 8 μg/kg; P9, 25 μg/kg, twice a day, subcutaneous, 100 μg/kg) reduced rapid eye movement sleep during P8-P21 and increased locomotor activity at the adult stage (>P70; Mirmiran et al., 1983). In mice, clonidine treatment during the P1-P22 period (daily, subcutaneous, 35 μg/kg) resulted in a temporal delay in the appearance of developmental markers (surface righting, cliff aversion, rooting, pinna detachment, startle response, eye twitch, eye opening), reduced exploratory locomotor activity at P16, and impaired short-term memory in the novel object recognition task at P22 (Calvino-Núñez and Domínguez-del-Toro, 2014). ...
Article
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SLITRK1 is a neuronal transmembrane protein with neurite development-and synaptic formation-controlling abilities. Several rare variants of SLITRK1 have been identified and implicated in the pathogenesis of Tourette’s syndrome, trichotillomania, and obsessive–compulsive disorder, which can be collectively referred to as obsessive–compulsive-spectrum disorders. Recent studies have reported a possible association between bipolar disorder and schizophrenia, including a revertant of modern human-specific amino acid residues. Although the mechanisms underlying SLITRK1-associated neuropsychiatric disorders are yet to be fully clarified, rodent studies may provide some noteworthy clues. Slitrk1-deficient mice show neonatal dysregulation of the noradrenergic system, and later, anxiety-like behaviors that can be attenuated by an alpha 2 noradrenergic receptor agonist. The noradrenergic abnormality is characterized by the excessive growth of noradrenergic fibers and increased noradrenaline content in the medial prefrontal cortex, concomitant with enlarged serotonergic varicosities. Slitrk1 has both cell-autonomous and cell-non-autonomous functions in controlling noradrenergic fiber development, and partly alters Sema3a-mediated neurite control. These findings suggest that transiently enhanced noradrenergic signaling during the neonatal stage could cause neuroplasticity associated with neuropsychiatric disorders. Studies adopting noradrenergic signal perturbation via pharmacological or genetic means support this hypothesis. Thus, Slitrk1 is a potential candidate genetic linkage between the neonatal noradrenergic signaling and the pathophysiology of neuropsychiatric disorders involving anxiety-like or depression-like behaviors.
... Sleep disturbances impair the function of the sympathetic nervous system, leading to metabolic dysregulation [11]. Insufficient sleep during developmental stages can cause a smaller brain and abnormal behavior [12]. In conclusion, sleep is essential for the development, behavior, and survival of organisms. ...
Article
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Sleep is a fundamental, evolutionarily conserved, plastic behavior that is regulated by circadian and homeostatic mechanisms as well as genetic factors and environmental factors, such as light, humidity, and temperature. Among environmental cues, temperature plays an important role in the regulation of sleep. This review presents an overview of thermoreception in animals and the neural circuits that link this process to sleep. Understanding the influence of temperature on sleep can provide insight into basic physiologic processes that are required for survival and guide strategies to manage sleep disorders.
... Sleep is also a fundamental prerequisite for brain plasticity, the genetically determined ability of the brain to change its structure and function in response to stimuli in the environment. In young animals, is has been shown that sleep deprivation can lead to increased neuronal apoptosis, smaller brain volume, and reduced brain plasticity, all of which have persistent deleterious repercussions on behavior and ability to learn [11][12][13]. Childhood sleep disorders have been associated with less white matter microstructural integrity in adolescence [14]. It has been shown that sleep quality at 10 months accounts for a significant percentage of variance in cognitive achievement [15]. ...
Article
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Background Atopic dermatitis (AD) is the most common chronic inflammatory skin condition in childhood. Most (50-60%) children with AD report sleep disturbance, which is secondary to itch, dry skin, inflammation, and abnormal circadian rhythm. Sleep is essential for brain development, learning, and growth. Sleep disruption in early life is associated with cognitive and psychological dysfunction in later life. The aim of this study is to describe in detail the sleep architecture of infants with early-onset atopic dermatitis (AD), compared to controls, by using EEG polysomnography, sleep actigraphy, and parental reporting. Methods This observational study will recruit six- to eight-month old infants with moderate to severe AD and age-matched control infants who do not have AD. At six-eight months diurnal sleep electroencephalography and polysomnography will be performed in our research center. Nocturnal sleep actigraphy will be performed at home for five consecutive nights at six-eight months and 12 months. Between six and 12 months, monthly questionnaires will capture data on quantitative sleep and parental sleep. Skin barrier and immune profiles will be captured at six-eight and 12 months. AD will be assessed using standardized severity assessment tools and treated according to protocol. A neurodevelopmental assessment will be performed at 18 months to assess cognition and behaviour. An estimated sample size of 50 participants in each group is required to power the primary outcome of disturbed macrostructure of sleep and secondary outcomes of disturbed microstructure of sleep, and disturbed parental sleep, assuming an attrition rate of 60%. Potential confounding factors which will be controlled for in the data analysis will include parental educational level, parental depression, feeding practice, and number of siblings. Discussion This study will provide a rich analysis of sleep in infants with AD in the first year of life using detailed electroencephalography, novel actigraphy techniques, and longitudinal parent-reported data. It may provide guidance on the optimal treatment of AD to prevent or reduce sleep disruption. Trial registration clinicaltrials.govNCT05031754, retrospectively registered on September 2nd, 2021.
... Studies in experimental animals provide insights into the critical nature of sleep during development. In rats, early postnatal REM sleep-deprivation resulted in long-term changes that became manifest in adulthood, including decreased brain weight and increased levels of anxiety-like behavior and hyperactivity (Mirmiran et al., 1983). Additionally, chronic sleep restriction beginning early in postnatal development in wild-type (WT) mice resulted in behavioral changes, particularly in social behavior and activity levels. ...
Article
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Many patients with fragile X syndrome (FXS) have sleep disturbances, and Fmr1 knockout (KO) mice (a model of FXS) have reduced sleep duration compared to wild type (WT). Sleep is important for brain development, and chronic sleep restriction during development has long-lasting behavioral effects in WT mice. We hypothesized that the sleep abnormalities in FXS may contribute to behavioral impairments and that increasing sleep duration might improve behavior. We treated adult male Fmr1 KO and WT mice subacutely with three different classes of hypnotics (DORA-22, ramelteon, and zolpidem) and caffeine, a methylxanthine stimulant, and we tested the effects of treatments on sleep duration and behavior. Behavior tests included activity response to a novel environment, anxiety-like behavior, and social behavior. As expected, all hypnotics increased, and caffeine decreased sleep duration in the circadian phase in which drugs were administered. Caffeine and DORA-22 treatment significantly reduced activity in the open field regardless of genotype. Other effects were not as apparent.
... Sleep regulates major antioxidants enzyme-like catalase, glutathione peroxidase, and accumulation of reactive oxygen species (ROS) of oxidative stress-associated disease [96,97]. Mirmiran et al. in their in vitro study, found that sleep deprivation can decrease brain mass, neuronal cell death, and increase the risk of eventual behavioral problems during development [98], while proper sleep or rapid eye movement (REM) sleep is required in neonate for appropriate neural development termed the ontogenetic REM sleep hypothesis [99]. The synaptic homeostasis hypothesis (SHY) proposed by sleep researchers, where sleep is thought to reduce synaptic strength between neurons and sleep promote synaptic weakening. ...
Article
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In the 21st century, any pandemic, especially, SARS-CoV-2 is a global burden due to high incidence, mortality, and mutation rate. Although several techniques have already been identified to control the pandemic or treat patients and causes of adverse impact on mental health, relatively only, fewer researchers have little concern about finding effective mitigation strategies to improve mental health. Therefore, this study aimed to find some common and unique approaches to manage mental health during a pandemic. Some strategies for the better management of mental health induced by SARS-CoV-2 infections are required for all classes of peoples. Early management is vital, and those must be associated with frontline workers and people staying at home, particularly in isolation centers and already identified as active cases. Experts have pointed out the need to pay specific attention to proper daily life. To manage abnormal mental conditions, such as anxiety, mood, personality, and psychotic disorder during the pandemic; social media, meditation, and psychological motivation with adequate diet, exercise, and sleep have significant roles in regulating some biological mechanism, incredibly immune, hormonal, and neural process. Management of mental health is mandatory for all at the time of the SARS-CoV-2 pandemic. We can consider all of the strategies mentioned above to treat mental health during and after the COVID- 19 pandemic condition.
... The reported behavioral effects are not uniform across studies (even within the same laboratory) and vary depending on the drug used in a given experiment [50,51]. Gentle forms of mechanical SD (i.e., "gentle-handling") or RSD do not produce the suite of deficits reported after pharmacological RSD [52][53][54]. More vigorous mechanical RSD is reported to produce some effects similar to drug-induced behavioral changes [55], but the technique employed (periodic shaking of the rat pup) likely replaces one confounding variable (non-specific teratogenicity) with another (chronic neonatal stress). ...
Article
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Purpose of Review To present an up-to-date review and synthesis of findings about perinatal sleep development and function. I discuss landmark events in sleep ontogenesis, evidence that sleep promotes brain development and plasticity, and experimental considerations in this topic. Recent Findings Mammalian sleep undergoes dramatic changes in expression and regulation during perinatal development. This includes a progressive decrease in rapid-eye-movement (REM) sleep time, corresponding increases in nonREM sleep and wake time, and the appearance of mature sleep regulatory processes (homeostatic and circadian). These developmental events coincide with periods of rapid brain maturation and heightened synaptic plasticity. The latter involve an initial experience-independent phase, when circuit development is guided by spontaneous activity, and later occurring critical periods, when these circuits are shaped by experience. Summary These ontogenetic changes suggest important interactions between sleep and brain development. More specifically, sleep may promote developmental programs of synaptogenesis and synaptic pruning and influence the opening and closing of critical periods of brain plasticity.
... Animal studies demonstrate that cerebral blood flow and oxygen delivery is relatively higher in AS compared to QS (Morrison et al., 2005), and that cerebral metabolic rate of oxygen consumption is as high in AS as during wakefulness (Silvani et al., 2006). In rat pups, brain mass including the cerebral cortex and brainstem are significantly reduced after AS deprivation, with alterations in neurotransmitter sensitivity compared to typically developing rats (Mirmiran et al., 1983;Morrissey et al., 2004). In AS, movements that are anticipatory in nature such as eye movements, stretches, and sucking occur frequently, therefore AS may facilitate neural development by providing endogenous stimulation at a time when waking life is limited with little exogenous stimulation (Roffwarg et al., 1966;Denenberg and Thoman, 1981). ...
Article
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The spontaneous cerebral activity that gives rise to resting-state networks (RSNs) has been extensively studied in infants in recent years. However, the influence of sleep state on the presence of observable RSNs has yet to be formally investigated in the infant population, despite evidence that sleep modulates resting-state functional connectivity in adults. This effect could be extremely important, as most infant neuroimaging studies rely on the neonate to remain asleep throughout data acquisition. In this study, we combine functional near-infrared spectroscopy with electroencephalography to simultaneously monitor sleep state and investigate RSNs in a cohort of healthy term born neonates. During active sleep (AS) and quiet sleep (QS) our newborn neonates show functional connectivity patterns spatially consistent with previously reported RSN structures. Our three independent functional connectivity analyses revealed stronger interhemispheric connectivity during AS than during QS. In turn, within hemisphere short-range functional connectivity seems to be enhanced during QS. These findings underline the importance of sleep state monitoring in the investigation of RSNs.
... In animal studies involving rats and other mammals, disrupting REM sleep during periods of brain development stopped development of the cerebral cortex. Interestingly, although brain development recommenced following a return to undisrupted sleep, it never fully recovered [7,[34][35][36]. Li et al. (2017) found that REM sleep played a role in strengthening some newly formed dendritic spines and pruning away others. ...
Preprint
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The importance of sleep for mental health has been known for some time. Although it was initially suggested that mental health conditions negatively impact sleep, it is now widely understood that this association is bidirectional. Adolescence is a period where people are at an increased risk of being sleep deprived largely due to a late shift in the circadian rhythm around puberty combined with early school start times. Combined these may lead to adolescents being at an increased risk of mental health problems. Adolescence is also a period of continued brain development with white matter maturation continuing in the frontal brain regions throughout adolescence and into early adulthood. White matter development involves myelination of axons that link areas of grey matter and is integral for communication speed and efficiency. Studies have demonstrated that sufficient sleep is required for myelination to occur. The uncinate fasciculus (UF) is one of the last white matter tracts to be myelinated with this process occurring throughout adolescence and running between the amygdala in the limbic system and the orbitofrontal (OFC) and medial prefrontal cortices (mPFC). Recent studies have shown that connectivity between the amygdala and OFC is important for an individual's ability to exert top-down executive control over amygdala based automatic emotional responses to experiences perceived as threatening. The current literature review provides an overview of these mechanisms and concludes by proposing a model of adolescent sleep deprivation leading to potential lifelong mental health issues through the moderating impact of reduced UF development.
... Neonates spend most of their time resting in the sleeping state. Previous research has highlighted the important role of neonatal sleep as a state that involves endogenous driven brain activity, crucial for neuronal survival and guidance of brain networks [6][7][8][9] and relate the impact of sleep on cognitive, psychomotor and behavioural development in both animal [10,11] as well as human studies [12][13][14][15][16]. Moreover, sleep ontogenesis is a specific, pre-programmed process of the maturing brain that manifests itself within a certain time window that begins in utero with rapid and major changes during the neonatal periods and infancy, and more subtle changes throughout childhood [11,17]. ...
Article
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Objective. Neonates spend most of their time asleep. Sleep of preterm infants evolves rapidly throughout maturation and plays an important role in brain development. Since visual labelling of the sleep stages is a time consuming task, automated analysis of electroencephalography (EEG) to identify sleep stages is of great interest to clinicians. This automated sleep scoring can aid in optimizing neonatal care and assessing brain maturation. Approach. In this study, we designed and implemented an 18-layer convolutional neural network to discriminate quiet sleep from non-quiet sleep in preterm infants. The network is trained on 54 recordings from 13 preterm neonates and the performance is assessed on 43 recordings from 13 independent patients. All neonates had a normal neurodevelopmental outcome and the EEGs were recorded between 27 and 42 weeks postmenstrual age. Main results. The proposed network achieved an area under the mean and median ROC curve equal to 92% and 98%, respectively. Significance. Our findings suggest that CNN is a suitable and fast approach to classify neonatal sleep stages in preterm infants.
... Moreover, depriving young animals of rapid eye movement-sleep (REM) and NREM-sleep leads to the loss of brain plasticity, as quantified by the loss of brain volume [71e73]. In rats, the effect of suppression of REM sleep during early development is suggested to produce protracted behavioural and brain morphological abnormalities later in life [74]. Together, these animal studies emphasize the importance of sleep as a whole for proper brain development and functioning. ...
Article
This systematic review examined the associations between sleep and brain functions and structures in children and adolescents aged 1-17 ys. Included studies (n = 24) were peer-reviewed and met the a priori determined population (apparently healthy children and adolescents aged 1 y to 17 ys), intervention/exposure/comparator (various sleep characteristics including duration, architecture, quality, timing), and outcome criteria (brain functions and/or brain structures, excluding cognitive function outcomes). Collectively, the reviewed studies report some relationships between inadequate sleep and resultant differences in brain functions or structures. Although the research presented supports and offers more insight into the importance of sleep for the developing brain of children and adolescents, no firm conclusions that apply broadly may be drawn from these results, particularly because of the diversity of the sleep variables and outcomes. However, it is clear that sleeping habits in the pediatric population should be prioritized. Health care providers should continue to recommend healthy sleep practices and adequate time for sleep, as they are essential for overall health, including brain health.
... Sleep appears to be fundamental to animal life, yet little is known about how sleep has evolved throughout the animal kingdom. In diverse animal taxa, poor sleep can have detrimental effects on development (Roffwarg et al., 1966;Mirmiran et al., 1983;Kayser et al., 2014), cognitive abilities (Scullin and Bliwise, 2015) and life span (Mazzotti et al., 2014), and it is now appreciated that normal sleep is fundamental to healthy physiology and bodily function (Shaw et al., 2002;Cappuccio et al., 2010;Arble et al., 2015). While the function of sleep remains unknown, studies have identified relationships between sleep and anatomical, physiological or ecological traits (Lesku et al., 2006;Capellini et al., 2008;McNamara et al., 2009). ...
Article
Sleep is nearly ubiquitous throughout the animal kingdom, yet little is known about how ecological factors or perturbations to the environment shape the duration and timing of sleep. In diverse animal taxa, poor sleep negatively impacts development, cognitive abilities and longevity. In addition to mammals, sleep has been characterized in genetic model organisms, ranging from the nematode worm to zebrafish, and, more recently, in emergent models with simplified nervous systems such as Aplysia and jellyfish. In addition, evolutionary models ranging from fruit flies to cavefish have leveraged natural genetic variation to investigate the relationship between ecology and sleep. Here, we describe the contributions of classical and emergent genetic model systems to investigate mechanisms underlying sleep regulation. These studies highlight fundamental interactions between sleep and sensory processing, as well as a remarkable plasticity of sleep in response to environmental changes. Understanding how sleep varies throughout the animal kingdom will provide critical insight into fundamental functions and conserved genetic mechanisms underlying sleep regulation. Furthermore, identification of naturally occurring genetic variation regulating sleep may provide novel drug targets and approaches to treat sleep-related diseases.
... This pharmacological manipulation induces several behavioral and physiological alterations that are analogous to the symptomatology observed in major depression disorder (Feng and Ma, 2003;Justel et al., 2011;Vijayakumar and Meti, 1999;Vogel et al., 1990a;Yannielli et al., 1998). Male rats treated in early postnatal stage with CMI show hyperactivity (Hartley et al., 1990;Hilakivi et al., 1984;Mirmiran et al., 1983;Yannielli et al., 1999), abnormalities in sleep characterized by a shorter latency to REM and increased REM fragmentation, to mention only a few effects (Savelyev et al., 2012;Vogel et al., 1990b). Male rats also exhibit less aggressive behavior (Vogel et al., 1988), decreased pleasure-and reward-seeking behaviors (e.g. ...
... Erections have also been reported during the REM sleep in human fetus and infants [41,42]. REM sleep deprivation in the neonatal period produces deficits in sexual behavior in later life stages in mammalian species [43,44], while REM sleep deprivation in adult rats activates male sexual behaviour [15]. Erections during REM sleep may have a role in the development of a normal erectile circuit. ...
Article
To understand the central mechanism of penile erections during rapid eye movement (REM) sleep and waking, single units were recorded from the septal area in un-anesthetized head-restrained rats simultaneous with erections. Erectile events were assessed by pressure in the bulb of the corpus spongiosum of the penis and bulbospongiosus-muscle activity. Of 143 recorded neurons, 36% showed increased activity (E-type) and 24% decreased activity (I-type) during different phases of erection in REM sleep, while 10% were E-type and 35% were I-type during erections in waking. Most E-type neurons were recorded from the dorsal and intermediate part of lateral septum, whereas I-type neurons were from the medial septum. The findings illustrate the extensive network of various types of neurons in the septal area that fire in concert in relation to erection during REM sleep and waking. This study provides a unique prospective of the septal area for perpetuation of erectile circuitry during sleep.
... In rat neonates, for example, pharmacological blockage of REM sleep suppresses brain development (particularly for the cerebral cortex), and such rats demonstrate maladaptive behavior in new environments [3,4]. This and similar studies suggest that normal REM sleep, or at least REM activity, is required for healthy brain development [3][4][5][6]. a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 ...
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Rapid eye movement (REM) sleep occurs throughout a relatively large proportion of early development, and normal REM activity appears to be required for healthy brain development. The eye movements (EMs) observed during REM sleep are the most distinctive characteristics of this state. EMs are used as an index of neurological function postnatally, but no specific indices of EM activity exist for fetuses. We aimed to identify and characterize EM activity, particularly EM bursts suggestive of REM periods, in fetuses with a gestational age between 24 and 39 weeks. This cross-sectional study included 84 normal singleton pregnancies. Fetal EMs were monitored using real-time ultrasonography for 60 min and recorded as videos. The videos were manually converted into a time series of EM events, which were then analyzed by piecewise linear regression for various EM characteristics, including EM density, EM burst density, density of EMs in EM bursts, and continuous EM burst time. Two critical points for EM density, EM burst density, and density of EMs in EM bursts were evident at gestation weeks 28–29 and 36–37. Overall EM activity in human fetuses increased until 28–29 weeks of gestation, then again from 36–37 to 38–39 weeks of gestation. These findings may be useful for creating indices of fetal neurological function for prognostic purposes.
... Neonates spend most of their time resting in the sleeping state. Previous research has highlighted the important role of neonatal sleep as a state that involves endogenous driven brain activity, crucial for neuronal survival and guidance of brain networks [6][7][8][9] and relate the impact of sleep on cognitive, psychomotor and behavioural development in both animal [10,11] as well as human studies [12][13][14][15][16]. Moreover, sleep ontogenesis is a specific, pre-programmed process of the maturing brain that manifests itself within a certain time window that begins in utero with rapid and major changes during the neonatal periods and infancy, and more subtle changes throughout childhood [11,17]. ...
Article
Neonatal sleep is a crucial state that involves endogenous driven brain activity, important for neuronal survival and guidance of brain networks. Sequential EEG-sleep analysis in preterm infants provides insights into functional brain integrity and can document deviations of the biologically pre-programmed process of sleep ontogenesis during the neonatal period. Visual assessment of neonatal sleep-EEG, with integration of both cerebral and non-cerebral measures to better define neonatal state, is still considered the gold standard. Electrographic patterns evolve over time and are gradually time locked with behavioural characteristics which allow classification of quiet sleep and active sleep periods during the last 10 weeks of gestation. Near term age, the neonate expresses a short ultradian sleep cycle, with two distinct active and quiet sleep, as well as brief periods of transitional or indeterminate sleep. Qualitative assessment of neonatal sleep is however challenged by biological and environmental variables that influence the expression of EEG-sleep patterns and sleep organization. Developing normative EEG-sleep data with the aid of automated analytic methods, can further improve our understanding of extra-uterine brain development and state organization under stressful or pathological conditions. Based on those developmental biomarkers of normal and abnormal brain function, research can be conducted to support and optimise sleep in the NICU, with the ultimate goal to improve therapeutic interventions and neurodevelopmental outcome.
... 33 Moreover, it has been stated that "Suppression of REM sleep during early development can produce long-lasting Gonfalone behavioral as well as brain morphological and biochemical abnormalities in later life." 34 As mentioned earlier, there is a correlation between gestation duration and animal weight. In a study that scaled the gestation periods of a sample of 429 mammals against their weight, the following two slopes were observed: one for those species that give birth to altricial neonates and a second for those species with precocial neonates. ...
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Many studies of sleep have tempted to establish a relation between environmental, ecological, and physiological variables and sleep duration. This article establishes unambiguously that there is a negative correlation between gestation and sleep durations in mammals. Gestation offers the advantage that one species is characterized by a precise value of its gestation time, with relative small variations, and it is a quantity that can easily be measured. The duration of gestation is a parameter which differs from other parameters that have been used for comparison, such as weight, brain size, and predatory danger. The review of all relevant research articles clearly demonstrates that those mammals, which have longer gestation period, experience less sleep. Within the class of mammals, precocial mammals, capable of moving at birth, show a relatively short amount of rapid eye movement (REM) sleep (a unique phase of mammalian sleep) that does not vary much after birth, while altricial species with a short gestation that are relatively more dependent at birth adjust their amount of REM sleep after birth and show longer sleep duration in-line with the present findings. The essential data on which this result is obtained has been deduced from an extensive and attentive review of previously published articles on mammalian sleep and mammalian gestation, among others. In answering the question " Why does species with a shorter gestation period need more sleep? " , many similarities in behavior between the fetal state and REM sleep state have been identified. Even if at birth all sensory organs are fully developed, their functions have not been exercised, and it is proposed that the amount of REM sleep may be the time needed to strengthen adaptation of the senses to the external world and its components, such as light, sound, contact, taste, odors, and particularly cold and gravity. The assumption proposed is that REM sleep is needed to compensate for the short gestation. It is a period for the brain to reorder and rearrange all sensations accumulated during wake and prepare for the following wake period, and that REM sleep is a carry over of the fetal state.
... Studies investigating the effects of active sleep deprivation have shown that deprivation early in life can result in behavioral problems, permanent sleep disruption, decreased brain mass, and result in an abnormal amount of neuronal cell death [12] . ...
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Rapid eye movement sleep, or REM, is one of the five stages of sleep that most people experience nightly. It is characterized by quick, random movements of the eyes and paralysis of the muscles. We have conducted a survey based on questions related to sleeping habits and pattern of their dream. Purpose of this survey is to prove a hypothesis that says ‘rapid eye movement or sleep twitches can enhance your brain activity’. We have selected normal or healthy subjects related to different ages, gender and professions. Questionnaires were filled by these subjects and we found that mostly people experience sleep twitches and they wake up with active state of mind. We also asked their level of alertness during day time and we found that subjects are alert mostly.
... REM sleep deprivation by distinct pharmacologic agents seems to cause inconsistent impairments (Frank and Heller 1997), and more specific REM inhibiting agents such as selective serotonin reuptake inhibitors do not result in adult sleep impairments (in contrast to tricyclic antidepressants) (Farabollini et al. 1988). Notably, gentle mechanical sleep deprivation likewise does not recapitulate tricyclic antidepressant exposure (Mirmiran et al. 1983b). ...
Article
Sleep is widely recognized as essential, but without a clear singular function. Inadequate sleep impairs cognition, metabolism, immune function, and many other processes. Work in genetic model systems has greatly expanded our understanding of basic sleep neurobiology as well as introduced new concepts for why we sleep. Among these is an idea with its roots in human work nearly 50 years old: sleep in early life is crucial for normal brain maturation. Nearly all known species that sleep do so more while immature, and this increased sleep coincides with a period of exuberant synaptogenesis and massive neural circuit remodeling. Adequate sleep also appears critical for normal neurodevelopmental progression. This article describes recent findings regarding molecular and circuit mechanisms of sleep, with a focus on development and the insights garnered from models amenable to detailed genetic analyses.
Article
Objective: This study was conducted to explore the sex differences in the direct and indirect associations among mental health/suicidality, sleep, and screen time. Methods: Using the 2021 Youth Risk Behavior Survey (YRBS) data, 9408 participants were included in the analyses. The associations of endogenous variables (mental health and suicidality), exogenous variable (screen time), mediator (sleep), and covariates (demographic features and risky behaviors) were analyzed using the Structural Equation Model and “medsem” package, as well as logistic regression and bootstrapping methods. To explore the sex differences in the mediation effect, the Likelihood Ratio Test was used for the multiple-group analysis to compare the unconstrained model with the mediation path-constrained model. Results: Screen time had a significant negative association with sleep duration (female: β = −.09, p < .001; male: β = −.04, p < .001), positive relations to mental health problems (female: β = .10, p < .001; male: β = .12; p < .001), and suicidality (female: OR: 1.07, 95% CI: 1.02–1.13; male: OR: 1.06, 95% CI: 1.01–1.23). Sleep duration is negatively associated with mental health problems (female: β = −.16, p < .001; male: β = −.14; p < .001) and negatively associated with the likelihood of suicidality (female: .89, 95% CI: .85–.94; male: OR: .84, 95% CI: .79–.90). Furthermore, female adolescents had higher frequencies in mental health problems, higher odds ratio in suicidality, shorter sleep duration, and bigger mediation effects of sleep, compared to their male counterparts. Conclusion: Mental health and suicidality were affected differently by screen time and sleep between female and male adolescents. Future research may continue to explore sex differences and their underlying reasons.
Article
This observational study investigated the effects of sleep position and sleep state on short apneas and periodic breathing in hospitalized preterm infants longitudinally, in relation to postmenstrual age. Preterm infants (25–31 weeks gestation, n = 29) were studied fortnightly after birth until discharge, in prone and supine positions, and in quiet sleep and active sleep. The percentage of time spent in each sleep state (percentage of time in quiet sleep and percentage of time in active sleep), percentage of total sleep time spent in short apneas and periodic breathing, respectively, the percentage of falls from baseline in heart rate, arterial oxygen saturation and cerebral tissue oxygenation index during short apneas and periodic breathing, and the associated percentage of total sleep time with systemic (arterial oxygen saturation < 90%) and cerebral hypoxia (cerebral tissue oxygenation index < 55%) were analysed using a linear mixed model. Results showed that the prone position decreased (improved) the percentage of falls from baseline in arterial oxygen saturation during both short apneas and periodic breathing, decreased the proportion of infants with periodic breathing and the periodic breathing‐associated percentage of total sleep time with cerebral hypoxia. The percentage of time in quiet sleep was higher in the prone position. Quiet sleep decreased the percentage of total sleep time spent in short apneas, the short apneas‐associated percentage of falls from baseline in heart rate, arterial oxygen saturation, and proportion of infants with systemic hypoxia. Quiet sleep also decreased the proportion of infants with periodic breathing and percentage of total sleep time with cerebral hypoxia. The effects of sleep position and sleep state were not related to postmenstrual age. In summary, when sleep state is controlled for, the prone sleeping position has some benefits during both short apneas and periodic breathing. Quiet sleep improves cardiorespiratory stability and is increased in the prone position at the expense of active sleep, which is critical for brain maturation. This evidence should be considered in positioning preterm infants.
Article
Sleep deprivation (SD) is widely acknowledged as a significant risk factor for cognitive impairment. In this study, intraperitoneal caffeine administration significantly ameliorated the learning and memory (L/M) deficits induced by SD and reduced aggressive behaviors in adult zebrafish. SD led to a reduction in PKA phosphorylation, phosphorylated-cAMP response element-binding protein (p-CREB) and c-Fos expression in zebrafish brain. Notably, these alterations were effectively reversed by caffeine. Additionally, caffeine mitigated neuroinflammation induced by SD, as evident from suppression of the SD-mediated increase in GFAP and NF-κB activation. Caffeine restored normal O-GlcNAcylation and O-GlcNAc transferase (OGT) levels while reversing the increased expression of O-GlcNAcase (OGA) in zebrafish brain after SD. Intriguingly, rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, effectively mitigated cognitive deficits, restored p-CREB and c-Fos levels, and attenuated the increase in GFAP in brain induced by SD. Additionally, rolipram reversed the decrease in O-GlcNAcylation and OGT expression as well as elevation of OGA expression following SD. Treatment with H89, a PKA inhibitor, significantly impaired the L/M functions of zebrafish compared to the control group, inducing a decrease in O-GlcNAcylation and OGT expression and, conversely, increase in OGA expression. The H89-induced changes in O-GlcNAc cycling and L/M dysfunction were effectively reversed by glucosamine treatment. H89 suppressed, while caffeine and rolipram promoted O-GlcNAc cycling in Neuro2a cells. Our collective findings underscore the interplay between PKA signaling and O-GlcNAc cycling in regulation of cognitive function in the brain, offering potential therapeutic targets for cognitive deficits associated with SD.
Chapter
The Neuroscience of Sleep and Dreams provides comprehensive coverage of the basic neuroscience of both sleep and dreams for upper-level undergraduate and graduate students. It details new scientific discoveries, places those discoveries within evolutionary context, and links established findings with implications for sleep medicine. This second edition focuses on recent developments in the social nature of sleep and dreams. Coverage includes the neuroscience of all stages of sleep; the lifespan development of these sleep stages; the role of non-REM and REM sleep in health and mental health; comparative sleep; biological rhythms; sleep disorders; sleep memory; dream content; dream phenomenology, and dream functions. Students, scientists, and interested non-specialists will find this book accessible and informative.
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Sleep is an essential component of development. Developmental sleep disruption (DSD) impacts brain maturation and has been associated with significant consequences on socio-emotional development. In humans, poor sleep during infancy and adolescence affects neurodevelopmental outcomes and may be a risk factor for the development of autism spectrum disorder (ASD) or other neuropsychiatric illness. Given the wide-reaching and enduring consequences of DSD, identifying underlying mechanisms is critical to best inform interventions with translational capacity. In rodents, studies have identified some mechanisms and neural circuits by which DSD causes later social, emotional, sensorimotor, and cognitive changes. However, these studies spanned methodological differences, including different developmental timepoints for both sleep disruption and testing, different DSD paradigms, and even different rodent species. In this scoping review on DSD in rodents, we synthesize these various studies into a cohesive framework to identify common neural mechanisms underlying DSD-induced dysfunction in brain and behavior. Ultimately, this review serves the goal to inform the generation of novel translational interventions for human developmental disorders featuring sleep disruption.
Article
Background Sleep is paramount for optimal brain development in infants admitted to the neonatal intensive care unit. Besides (minimally) invasive technical approaches to study sleep in infants, there is currently a large variety of behavioral sleep stage classification methods (BSSCs) that can be used to identify sleep stages in preterm infants born <37 weeks gestational age. However, they operate different criteria to define sleep stages, which limits the comparability and reproducibility of research on preterm sleep. This scoping review aims to: 1) identify and elaborate on existing neonatal BSSCs used for preterm infants, 2) examine the reliability and validity of these BSSCs, and 3) identify which criteria are most used for different ages, ranging from 23 to 37 weeks postmenstrual age at observation. Methods To map the existing BSSCs, PubMed, EMBASE and Cochrane were searched for studies using a BSSC to identify sleep stages in preterm infants. Results In total, 36 BSSCs were identified with on average five item categories assessed per BSSC, most frequently: eye-, body- and facial movements, sounds, and respiratory pattern. Furthermore, validity and reliability of the BSSCs were tested in less than half of the included studies. Finally, BSSCs were used in infants of all ages, regardless the age for which the BSSC was originally developed. Conclusions Items used for scoring in the different BSSCs were relatively consistent. The age ranges, reliability, and validity of the BSSCs were not consistently reported in most studies. Either validation studies of existing BSSCs or new BSSCs are necessary to improve the comparability and reproducibility of previous and future preterm behavioral sleep studies.
Article
The proper development of sleep and sleep-wake rhythms during early neonatal life is crucial to lifelong neurological well-being. Recent data suggests that infants who have poor quality sleep demonstrate a risk for impaired neurocognitive outcomes. Sleep ontogenesis is a complex process, whereby alternations between rudimentary brain states—active vs. wake and active sleep vs. quiet sleep—mature during the last trimester of pregnancy. If the infant is born preterm, much of this process occurs in the neonatal intensive care unit, where environmental conditions might interfere with sleep. Functional brain connectivity (FC), which reflects the brain’s ability to process and integrate information, may become impaired, with ensuing risks of compromised neurodevelopment. However, the specific mechanisms linking sleep ontogenesis to the emergence of FC are poorly understood and have received little investigation, mainly due to the challenges of studying causal links between developmental phenomena and assessing FC in newborn infants. Recent advancements in infant neuromonitoring and neuroimaging strategies will allow for the design of interventions to improve infant sleep quality and quantity. This review discusses how sleep and FC develop in early life, the dynamic relationship between sleep, preterm birth, and FC, and the challenges associated with understanding these processes. Sleep in early life is essential for proper functional brain development, which is essential for the brain to integrate and process information. This process may be impaired in infants born preterm. The connection between preterm birth, early development of brain functional connectivity, and sleep is poorly understood. This review discusses how sleep and brain functional connectivity develop in early life, how these processes might become impaired, and the challenges associated with understanding these processes. Potential solutions to these challenges are presented to provide direction for future research.
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Sleep plays an important role in maintaining neuronal circuitry, signalling and helps maintain overall health and wellbeing. Sleep deprivation (SD) disturbs the circadian physiology and exerts a negative impact on brain and behavioural functions. SD impairs the cellular clearance of misfolded neurotoxin proteins like α-synuclein, amyloid-β, and tau which are involved in major neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. In addition, SD is also shown to affect the glymphatic system, a glial-dependent metabolic waste clearance pathway, causing accumulation of misfolded faulty proteins in synaptic compartments resulting in cognitive decline. Also, SD affects the immunological and redox system resulting in neuroinflammation and oxidative stress. Hence, it is important to understand the molecular and biochemical alterations that are the causative factors leading to these pathophysiological effects on the neuronal system. This review is an attempt in this direction. It provides up-to-date information on the alterations in the key processes, pathways, and proteins that are negatively affected by SD and become reasons for neurological disorders over a prolonged period of time, if left unattended.
Chapter
The Neuroscience of Sleep and Dreams - by Patrick McNamara February 2019
Book
Cambridge Core - Neurosciences - The Neuroscience of Sleep and Dreams - by Patrick McNamara
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Across mammals, juveniles sleep more than adults, with rapid eye movement (REM) sleep at a lifetime maximum early in life. One function of REM sleep may be to facilitate brain development of complex behaviors. Here, we applied 1 week of early-life sleep disruption (ELSD) in prairie voles ( Microtus ochrogaster ), a highly social rodent species that forms lifelong pair bonds. Electroencephalographic recordings from juvenile voles during ELSD revealed decreased REM sleep and reduced γ power compared to baseline. ELSD impaired pair bond formation and altered object preference in adulthood. Furthermore, ELSD increased GABAergic parvalbumin immunoreactivity in the primary somatosensory cortex in adulthood, a brain region relevant to both affected behaviors. We propose that, early in life, sleep is crucial for tuning inhibitory neural circuits and the development of species-typical affiliative social behavior.
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Abstract In neonatal animal models, isolated limb movements during active sleep provide input to immature somatomotor cortex necessary for its development and are somatotopically encoded by alpha-beta oscillations as late as the equivalent of human full-term. Limb movements elicit similar neural patterns in very pre-term human infants (average 30 corrected gestational weeks), suggesting an analogous role in humans, but it is unknown until when they subserve this function. In a cohort of 19 neonates (31–42 corrected gestational weeks) we showed that isolated hand movements during active sleep continue to induce these same somatotopically distributed oscillations well into the perinatal period, but that these oscillations decline towards full-term and fully disappear at 41 corrected gestational weeks (equivalent to the end of gestation). We also showed that these highly localised alpha-beta oscillations are associated with an increase in delta oscillations which extends to the frontal area and does not decline with age. These results suggest that isolated limb movements during active sleep could have an important role in experience-dependent somatomotor development up until normal birth in humans.
Article
Sleep is critical for proper development and neural plasticity. Moreover, abnormal sleep patterns are characteristic of many neurodevelopmental disorders. Studying how chronic sleep restriction during development can affect adult behavior may add to our understanding of the emergence of behavioral symptoms of neurodevelopmental disorders. While there are many methods that can be used to restrict sleep in rodents including forced locomotion, constant disruption, presentation of an aversive stimulus, or electric shock, many of these methods are very stressful and cannot be used in neonatal mice. Here, we describe gentle handling, a sleep deprivation technique that can be used chronically throughout development and into adulthood to achieve sleep restriction. Gentle handling involves close observation of the mice throughout the sleep deprivation period and requires the researcher to gently prod the animals whenever they are inactive or display behaviors associated with sleep. Coupled with EEG recordings, gentle handling could be used to selectively disrupt a specific phase of sleep such as rapid eye movement (REM) sleep. The technique of gentle handling is a powerful tool for the study of the effects of chronic sleep restriction even in neonatal mice that circumvents many of the more stressful procedures used for sleep deprivation.
Chapter
Stages of sleepCardiovascular parameters during normal sleepFunction of sleepSleep durationCircadian rhythmExamples of circadian regulationNeurohormonal modulation of wakefulnessNeurohormonal modulation of sleepSleep–arousal transitionsSleep deficitPathophysiologic effects of sleep debtSleep debt and risk of cardiometabolic disorderSleep disordersConclusion Bibliography
Article
Neonatal administration of clomipramine (CMI) induces diverse behavioral and neurochemical alterations in adult male rats that resemble major depression disorder. However, the possible behavioral alterations in adult female rats subjected to neonatal treatment with clomipramine are unknown. Therefore, the aim of this study was to explore the effect of neonatal treatment with CMI on adult female rats in relation to locomotion and behavioral despair during the estrus cycle. Also evaluated was the effect of chronic treatment with E2 on these female CMI rats. We found no effects on spontaneous locomotor activity due to neonatal treatment with CMI, or after 21days of E2 administration. In the FST, neonatal treatment with CMI increased immobility and decreased active swimming and climbing behaviors. Influence of the ovarian cycle was detected only in relation to climbing behavior, as the rats in the MD phase displayed less climbing activity. Chronic E2 administration decreased immobility but increased only swimming in CMI rats. These results suggest that neonatal treatment with CMI induces despair-like behavior in female rats, but that chronic E2 administration generates antidepressant-like behavior by decreasing immobility and increasing swimming, perhaps through interaction with the serotonergic system.
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Das Kapitel verschafft einen Überblick darüber, wie wichtig ein erholsamer Schlaf für die Gesundheit ist. Seine Bedeutung spiegelt sich in einer Vielfalt von Funktionen wider, die durch einen gestörten Schlaf beeinträchtigt werden. So kann sich Schlafdeprivation beispielsweise durch höhere Infektanfälligkeit infolge eines geschwächten Immunsystems oder durch dysfunktionale Emotionsregulation äußern. Gedächtnisbildung und Stoffwechselprozesse werden ebenfalls maßgeblich im Schlaf reguliert. Als Verständnisgrundlage dient eine Erläuterung der Schlafarchitektur und ihrer Entwicklung entsprechend den Anforderungen über die Lebensspanne des Organismus.
Article
Background Fatigue in military operations leads to safety and operational problems due to a decrease in alertness and performance. The primary method of counteracting the effects of sleep deprivation is to increase nightly sleep time, which in operational situations is not always feasible. History has taught us that surgeons and surgical teams are finite resources that cannot operate on patients indefinitely. Methods A systematic review was conducted using the search terms ‘sleep’ and ‘deprivation’ examining the impact of sleep deprivation on cognitive performance in military surgical teams. Studies examining outcomes on intensive care patients and subjects with comorbidities were not addressed in this review. Results Sleep deprivation in any ‘out-of-hours’ surgery has a significant impact on overall morbidity and mortality. Sleep deprivation in surgeons and surgical trainees negatively impacts cognitive performance and puts their own and patients' health at risk. All published research lacks consensus when defining ‘sleep deprivation’ and ‘rested’ states. It is recognised that it would be unethical to conduct a well-designed randomised controlled trial, to determine the effects of fatigue on performance in surgery; however, there is a paucity between surrogate markers and applying simulated results to actual clinical performance. This requires further research. Recommended methods of combating fatigue include: prophylactically ‘sleep-banking’ prior to known periods of sleep deprivation, napping, use of stimulant or alerting substances such as modafinil, coordinated work schedules to reduce circadian desynchronisation and regular breaks with enforced rest periods. Conclusions A forward surgical team will become combat-ineffective after 48 hours of continuous operations. This systematic review recommends implementing on-call periods of no more than 12 hours in duration, with adequate rest periods every 24 hours. Drug therapies and sleep banking may, in the short term, prevent negative effects of acute sleep deprivation.
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Obstructive sleep apnoea syndrome is the most prevalent form of sleep disorder breathing characterized by persistent pauses of breathing during sleep time. The disorder is manifested by upper airway obstruction and excessive day time somnolence which directly affect the quality of life of the patients. Reports from previous studies revealed that occurrence rate of obstructive sleep apnoea syndrome is approx 13.7% among habitual snorers and 3.6% among non-habitual snorers which is equivalent to other major diseases and contributes to morbidity and mortality in developed as well as in developing countries, like India. The disorder is in association with metabolic syndrome and many serious cardiovascular conditions are stimuli of various inflammatory pathways in disease progression. The primary pathophysiologic abnormality in sleep disorder breathing is insulin resistance. Recurrent hypoxic function contributes to delay in hepatic function. The occurrence of oxidative stress with sleep disorder breathing also emerged as a public health issue. It has been reported that, severe obstructive sleep disorder patients have higher levels of plasma leptin than patients with mild and there occurs a positive correlation which is independent of age and BMI, between the plasma leptin levels and the severity of disease. Consequently hyperleptinemia may be considered a predictive marker of obstructive sleep disorder. The first line treatment of diagnosed obstructive sleep disorder syndrome includes nasal continuous positive airway pressure. Apart other treatments include surgical procedures, mandibular advancement splint and drugs which treat daytime somnolence. Recent study shows that oral intake of anti-oxidants not only reduces oxidative stress but also improves sleep disorder breathing and excessive day time somnolence. In this review, an exhaustive scan is done from past till up to date which are in concern of the morbidities along with their therapeutic measures associated with obstructive sleep disorder syndrome.
Article
Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.
Chapter
Au cours des dernières décennies, le champ de la médecine a subi des mutations considérables, influencées notamment par le développement de l’Evidence Based Medecine (EBM). L’EBM ou médecine factuelle est définie comme « l’intégration du meilleur degré de preuve prenant en compte l’expertise clinique du praticien et les valeurs du patient » [1]. Elle repose sur la revue systématique de la littérature scientifique et attribue le niveau de preuve le plus élevé aux méta-analyses. Elle a eu un impact considérable en médecine néonatale avec les premières publications, entre 1989 et 1992, de l’Oxford Database of Perinatal Trials suivie de la mise en place de la Cochrane Library [2]. Cette « bibliothèque » regroupait, au mois de novembre 2012, 301 méta-analyses dans le champ de la néonatologie.
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This chapter concerns the animal model of endogenous depression produced by clorimipramine (CLI) treatment of neonatal rats. Three hypotheses about this model are discussed: (1) the CLI treated rats are a valid animal model of human endogenous depression; (2) the neonatal CLI treatment produces the adult rat “depression” by neonatal REM sleep deprivation (RSD), rather than by altering neonatal aminergic neurotransmission; and (3) the neural substrate of adult “depressed” behaviors is an altered neuronal firing pattern, rather than an altered aminergic neurotransmission. At the end of the chapter I propose a theory about how neonatal RSD produces alterations in neuronal firing patterns that form a physiological substrate for depressed behaviors.
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Spontaneous discharge of norepinephrine-containing locus coeruleus (NE-LC) neurons was examined during the sleep-walking cycle (S-WC) in behaving rats. Single unit and multiple unit extracellular recordings yielded a consistent set of characteristic discharge properties. (1) Tonic discharge co-varied with stages of the S-WC, being highest during waking, lower during slow wave sleep, and virtually absent during paradoxical sleep. (2) Discharge anticipated S-WC stages as well as phasic cortical activity, such as spindles, during slow wave sleep. (3) Discharge decreased within active waking during grooming and sweet water consumption. (4) Bursts of impulses accompanied spontaneous or sensory-evoked interruptions of sleep, grooming, consumption, or other such ongoing behavior. (5) These characteristic discharge properties were topographically homogeneous for recordings throughout the NE-LC. (6) Phasic robust activity was synchronized markedly among neurons in multiple unit populations. (7) Field potentials occurred spontaneously in the NE-LC and were synchronized with bursts of unit activity from the same electrodes. (8) Field potentials became dissociated from unit activity during paradoxical sleep, exhibiting their highest rates in the virtual absence of impulses. These results are generally consistent with previous proposals that the NE-LC system is involved in regulating cortical and behavioral arousal. On the basis of the present data and those described in the following report (Aston-Jones, G., and F. E. Bloom (1981) J. Neurosci.1: 887-900), we conclude that these neurons may mediate a specific function within the general arousal framework. In brief, the NE-LC system may globally bias the responsiveness of target neurons and thereby influence overall behavioral orientation.
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α-Methyl DOPA (DOPA = 3,4-dihydroxyphenylalanine) and α-methyl metatyrosine were injected to mice (400 mg/kg intraperitoneally). The former amino acid was also injected to rabbits (200 mg/kg intravenously). At varying intervals after the injection the brains were examined for monoamines (5-hydroxytryptamine, noradrenaline, dopamine, and α-methyl analogues). A transient decrease in 5-hydroxytryptamine and dopamine and a prolonged and more marked decrease in noradrenaline were observed. The α-methyl amino acids were found to undergo decarboxylation and subsequent β-hydroxylation in vivo. The drop in noradrenaline and dopamine levels in brain caused by the α-methyl amino acids appears to be largely due to displacement by these decarboxylation products, which may possibly also take over the functions of the physiological amines.
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To test the assumption that dark preference in rats can serve as a measure of emotionality, dark preference was compared with ambulation and defacation in the open field. One group of 80-days-old male rats was handled for seven days; another group remained undisturbed. All animals were tested on each of five successive days in both a light-dark preference situation and an open field. Handled rats ambulated more in the field and stayed less time in the dark than non-handled ones. Significant negative correlations were found for the different days between open field ambulation and dark preference. Correlations between dark preference and open field defacation were positive except on day one. From the first to the second trial dark preference increased in both groups while open field ambulation decreased. The results were considered to support the hypothesis of dark preference as a measure of emotionality.In a second study an investigation was made as to whether high initial activity in a new situation is brought about by exploration or by an escape tendency. Again one group of male albino rats was handled. During testing, half of the handled and half of the non-handled rats had the chance of escaping from the open field into the adjacent home cage. From there the animals had the possibility of re-entering the field. The second half of each group had to stay in the field. These latter animals showed a remarkable decrease in ambulation from the first to the second trial. Rats which had access to their home cages seldom re-entered the field in the first trial. In later trials, however, ambulation in the field increased. Non-handled rats needed more trials before they started investigating the field. It was concluded that this result gives more support to an explanation of initial activity in terms of escape behaviour.
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The pontine brain stem hypothesis of desynchronized sleep generation has been tested with cellular methods confirming its three principal tenets:Ascending activation is apparent in the increased discharge of almost every forebrain neuronal population that has been studied. The precise synaptic mechanisms mediating this net excitation have not been elucidated but tonic postsynaptic facilitation is likely to underlie EEG desynchronization while presynaptic inhibition and phasic postsynaptic facilitation are probably involved in PGO wave generation.Descending inhibition of spinal reflex activity has been documented and analyzed in detail. Indirect, but strong evidence favors the operation of tonic postsynaptic inhibition, phasic postsynaptic excitation and presynaptic inhibition in the genesis of atonia, muscle twitches, and phasic sensory changes respectively.Pontine control of some of these events has been strengthened by the satisfaction of criteria for executive neurones by the giant cells of the pontine reticular formation (FTG). These neurones may be directly responsible for phasic events including the REMs, muscle twitches, and PGO waves. They may be indirectly responsible for EEG desynchronization through recruitment of more rostral reticular elements. They are probably not responsible for the atonia which is more likely mediated by their more caudal medullary reticular congeners.The mechanism of periodic activation of the executive neurones in the FTG may be that of reciprocal interaction with other pontine level-setting elements for which the best candidates are those neurones in the locus coeruleus and dorsal raphé nucleus having activity curves reciprocal to those of the FTG. A precise neurophysiological and mathematical model of reciprocal interaction is described.The reciprocal interaction hypothesis of desynchronized sleep control finds independent confirmation in a vast array of pharmacological data on sleep. In particular, the following tenets of the hypothesis are supported:The executive elements of the pontine brain stem control system include the giant cells of the reticular formation (FTG). These cells are cholinoceptive and cholinergic. They excite postsynaptic follower elements including each other. When cholinergically activated, the FTG neurones cholinergically generated desynchronized sleep events including EEG desynchronization, eye movements, PGO and other phasic events. Drugs which enchance cholinergic synaptic transmission, especially when injected into the giant cell fields, enchance descynchronized sleep. By contrast, anticholinergic compounds suppress desynchronized sleep. Cholinergic agents may also show suppress desynchronized sleep when injected into the presumed level setting neuronal pools of the dorsal raphé nucleus (DRN) and locus coeruleus (LC).The level-setting elements for the FTG include cells in the DRN and LC. These cells may be aminergic and aminoceptive, inhibiting their postsynaptic followers including each other. When activated, they suppress desynchronized sleep events especially atonia and PGO activity. Drugs which enchance aminergic synaptic transmission tend to suppress desynchronized sleep. Antiaminergic agents tend to enhance desynchronized sleep. Aminergic drugs should suppress desynchronized sleep when injected into the pool of generator neurones in the FTG.The reciprocal interaction hypothesis thus orders an otherwise confusing pharmacological literature and gives rise to new and testable hypotheses of sleep-cycle regulation. The combination of chronic microelectrode recording and microinjection techniques may thus result in a precise cellular neuropharmacology of those reticular systems long thought to regulate sleep and other vegetative phenomena.
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The effects of the peripheral and central alpha-adrenoceptor stimulant and antihypertensive agents clonidine and BS 100-141 (N-amidino-2[2,6-dichlorophenyl]acetamide - HCl) on EEG sleep patterns in rats and on blood pressure in pithed rats have been investigated. Whereas both compounds abolished paradoxical sleep (PS), clonidine, in contrast to BS 100-141, markedly increased the sleeping time. Both drugs caused a dose-dependent increase in the blood pressure of pithed rats. The pressor action was abolished by the alpha-adrenoceptor blocking agent phentolamine, but was not influenced by reserpine, indicating a direct stimulation of vascular alpha-adrenoceptors by both drugs. It is suggested that sedation or sleep induction by adrenergic drugs cannot be explained exclusively by an action on central alpha-adrenoceptors. Rather, the findings suggest that such an action may be involved in the modulation of PS.
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Male and female hamsters were given 50 micrograms pentobarbital, 100 micrograms pentobarbital, or 100 micrograms d-amphetamine on postnatal Days 2-4. When tested for masculine sexual behavior in adulthood, males treated with 100 micrograms pentobarbital showed behavioral deficits when tested with testes intact as well as after castration and treatment with testosterone propionate. Deficits shown by 50 micrograms pentobarbital males were overcome by testosterone replacement. When tested for feminine sexual behavior, males treated with 50 micrograms pentobarbital showed enhanced lordotic responses whereas males treated with 100 micrograms d-amphetamine showed no differences from controls when tested for female sexual behavior or when tested for male sexual behavior. Drug treatments had no effect on adult masculine or feminine sexual behavior in neonatally treated females. The results of this study show that pentobarbital can inhibit normal masculinization of the male when given during behavioral sexual differentiation.
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Sex, age and shock-intensity were studied in a step-through passive avoidance test. In adult rats (140 days) males showed more inhibition of a previously punished approach response. No sex differences were observed in young adult animals (60 days). In prepuberal animals (30 days), on the other hand, it was the females which showed more response inhibition. In prebuberty females showed far more response inhibition than in adulthood. Even when using 1.6 mA as a reinforcer, only 17% of the adult females showed inhibition after punishment of the entering response.
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Embryos were immobilized with neuromuscular blocking agents for one to four days between days 10 and 15 of incubation. This treatment reduces spontaneous motility, as well as movement‐initiated proprioceptive and cutaneous stimulation. Although the major aim of these experiments was to determine the effects of such treatment on subsequent behavioral development, several indices of neuromuscular and general morphological development were also examined. A single injection of curare on day 10 continues to depress spontaneous motility for virtually the entire remaining incubation period. This effect is due to the persistence of unmetabolized curare in the closed system of the egg. When a comparable dose of a rapidly metabolized neuromuscular blocking agent (succinylcholine) is given, this long term behavioral depression is not found. Embryos treated with SC can remain totally immobilized for up to 60 hours with no apparent repercussions on subsequent behavior; spontaneous embryonic motility, reflex sensitivity, hatching, and several general posthatching behaviors, all appeared normal following such treatment. Embryos immobilized for as little as 48 hours developed joint malformations and were retarded in general growth by about one day whereas 24 hours of paralysis was not sufficient to induce these effects. Twenty‐four hours of total paralysis from days 10 to 11, plus a 40–50% reduction in motility until days 15 or 16, does not appear to cause any abnormalities in muscle or spinal cord development. Muscle histology, motor endplates, cell number in the spinal cord and choline acetyltransferase and acetylcholinesterase activity in spinal cord and muscle were all comparable to controls. An 80–90% reduction in motility on days 11 through 15, however, induces an apparent alteration of the intensity and distribution of histochemically demonstrable AChE in the anterior and posterior latissimus dorsi muscles. The present findings suggest that the suppression of overt motility for a period comprising ca. 5–12% of the total incubation time (21 days) does not modify subsequent behavioral development or the underlying neurogenetic mechanisms. Though these findings provide some support for the notion that the embryonic nervous system develops in forward reference to and without benefit from function or sensory input, only a more complete reduction of neural function, especially CNS activity, can provide a critical test of this concept.
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The effect of undernutrition on the activity of glutamate decarboxylase (GAD) and choline acetyltransferase (ChAc) (markers for the GABA-ergic and the cholinergic transmitter system, respectively) was studied in various parts of the rat brain at the age of 10, 15 and 21 days, and at day 54 following 33 days of rehabilitation. The brain regions investigated were the olfactory bulbs, cerebellum, pons-medulla, hypothalamus, colliculi, cerebral cortex hippocampus and the residual brain. Undernutrition resulted in a marked retardation of the developmental rise of the activities of both enzymes, expressed in terms of either total brain part or unit weight or protein. The effect diminished with age even during the period of nutritional deprivation. In most brain regions the enzyme activities were restored to normal after rehabilitation. In the cerebral cortex the total activity of both enzymes was persistently reduced, although the concentration of GAD exceeded the control levels. A negative correlation was manifested between the activities of GAD and ChAc in the different brain parts (except the cerebellum) during development. The correlation became significant by day 21 in the controls, but only after postweaning rehabilitation of the undernourished rats. The results showed therefore that undernutrition caused a reversible retardation in the development of these two transmitter enzymes, and they suggested that even the balance of the GABA-ergic and cholinergic systems throughout the brain can be restored to normal by rehabilitation.
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The ethidium bromide method of Karsten and Wollenberger (3) has been modified allowing determination of DNA and RNA in small samples of tissue homogenates (10–30 μg wet weight) or in small pieces of frozen-dried tissue sections (2–5 μg dry weight). The detection limit for DNA ranges between 5 and 10 ng, depending on the origin of the tissue, and for RNA is twice as high. The present micromethod offers a good fluorimetric alternative for the more laborious diaminobenzoic acid DNA assay of Kissane and Robins (4).
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Mature offspring of C57BL/6J mice (Mus musculus) injected daily with phenobarbital (40 mg/kg) for the last third of pregnancy differed from saline and untreated control animals on 3 measures of behavior. Offspring of phenobarbital treated animals had higher locomotor scores than controls during an open field activity test at 75 days of age. Male offspring were also tested on a 1-trial passive avoidance task and treated animals were found to be deficient. Finally, female offspring responded less than controls on fixed ratio schedules of reinforcement. The behavioral changes suggest that offspring of mice injected with phenobarbital during pregnancy are less responsive to the stimuli in their environment which maintain behavior.
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The ontogeny of behavioral state cycles in white rats has been studied from their 2nd to their 30th day of life. A scale of 5 behavioral states, based on operationally defined categories was employed: state 1: quiet sleep; state 2: active sleep; state 3: quiet wakefulness; state 4: active wakefulness and state 5: locomotion. The percentage of time which young rats spend awake is 2% on the 2nd day, increases then and remains at about 40–60% after the 11th day. Until the 10th day the total sleep time is equally distributed between active sleep and quiet sleep state. After that day a decrement in the relative amount of active sleep occurs. The mean duration of single epochs spent in state 1 increases from less than 1 min on the first days to 6–8 min at about the 25th day. State 2 and state 4 epochs increase only slightly whereas state 3 and state 5 epochs do not show a particular trend.
Article
The behavioral and polygraphic characteristics of wakefulness and sleep were studied in 20 infant rats, 26 kittens, and 25 infant guinea pigs during their first month of postnatal life. In the infant guinea pig, the electrocorticographic (ECoG) patterns of sleep were similar to those of the adult, except for the absence of spindles during the first 3 weeks. In the rat and the cat, states of vigilance were not clearly differentiated in ECoG patterns during the first week; near the 8th day a fast, high amplitude ECoG appeared during paradoxical sleep (PS). The first signs of slow-wave sleep (SWS) appeared at 11 to 13 days of age in the rat and at 15 to 21 days in the cat. The greater the immaturity of the animal at birth, the greater was the amount of time spent in PS in the perinatal period. In the rat, which was born the most immature, the decrease in the percent time of PS was very rapid: 70 % at birth, it decreased to 12% on the 30th day. In the cat the decrease was slower. In the guinea pig, despite its relative maturity, the percent time of PS at birth was 7%, approximately double that in the adult. The length of extrauterine life as well as the degree of immaturity at birth, played a role in the development of the sleep-wakefulness cycle.
Article
Because nature is often conservative, the same electrical and chemical signals that the brain uses in its mature function may guide its development. This review by bringing together many different types of experiments (mostly recent) on different animals at different stages of development, supports the above notion. Experiments are discussed that examine the developmental roles of action potentials, slow changes in membrane poten­ tials, steady transmembrane ionic currents, and neurotransmitter s.
Article
Spontaneous action potentials were recorded at 1 mm depth (layer IV/V) in the occipital cortex of free moving rats between 8 and 60 days of postnatal age. Neuronal firing rates during quiet sleep (QS) increased sharply around day 11-12, parallel with an increase in the amplitude of EEG slow waves. The QS discharge pattern at all ages consisted of intermittent action potentials interspersed with short bursts. Active sleep (AS) from day 11-12 was characterized by longer lasting and more frequent bursts, and by a 2-3 X higher mean neuronal discharge rate than during QS. A peculiarity in 12-day-old rats was the presence of large fluctuations in overall firing rate continuously throughout sleep. Clomipramine completely abolished AS (for several hours) at all ages studied, during which time the cortical firing rates during sleep remained at (or lower than) the QS level prior to drug injection.
Article
In an attempt to study the possible role of active sleep in brain development, male rats were injected twice daily with chlorimipramine, a potent monoamine reuptake blocker, from 1 week to 3 weeks of postnatal age. AS was reduced to less than 10% of total sleep time, the level found in mature rats. Most of the AS reduction was compensated for by quiet sleep but a slight increase in wakefulness also occurred, owing to brief interruptions of sleep at times when AS was expected. In adulthood, the AS-deprived rats showed a higher percentage of AS than did the controls, due to an increase in frequency and duration of AS epochs. Moreover, many of the epochs contained abnormally frequent and strong jerky body movements and rapid-eye-movements, reminiscent of neonatal AS patterns. In addition, the amplitude of hippocampal theta waves during AS was greater than in control rats. The chlorimipramine-treated rats also showed behavioral abnormalities in later life. On the open field test exploratory behavior was much reduced, while increased rearing and defecation occurred. Masculine sexual performance was severely deficient, primarily due to the low level of intromissions and ejaculations. Experimental animals performed less efficiently than controls on a temporal learning task (differential reinforcement of low response rate) and responded more rapidly on a spatial task (left-right alternation learning). These results demonstrate that early interference with the functioning of monoaminergic systems can have long-lasting physiological and behavioral consequences. Furthermore, they are consistent with the hypothesis that AS is an important factor in normal brain development.
Article
A new technique for paradoxical sleep (PS) deprivation in rats is presented. Animals are prevented from entering into PS by allowing them to sleep for only brief periods of time. This is accomplished by an apparatus which moves the animals' cages backwards and forwards like a pendulum. At the extremes of the motion postural imbalance is produced in the animals forcing them to walk downwards to the other side of their cages. A minimal amount of PS and a moderate amount of slow wave sleep (SWS) were detected during a deprivation period of 72 hrs. Following the deprivation treatment the recovery of sleep was monitored for 3 hrs; at the beginning of the light period for one group and at the beginning of the dark period for a second group. The sleep-waking patterns of two baseline groups were established at the time when the recovery sleep was examined in the deprivation groups. The deprivation treatment resulted in a significant increase in the amount of PS and a significant decrease in the amount of SWS. The extent of PS increase was similar in both deprivation groups, in spite of a large difference in the amount of SWS. The decrease of SWS mainly occurred during recovery sleep in the light. It was observed that sleep in the dark differs from sleep in the light in behavioural aspects.
Article
The present study is aimed to clarify the question of maximal intracortical spread of locally perfused 6-hydroxydopamine (6-OHDA) and norepinephrine (NE) through a continuous microperfusion system. The following analyses were performed: 1) catecholamine (CA) fluorescence histochemistry in 6-OHDA-perfused cortex, 2) spatial distribution of tritium counts in the visual cortex perfused either with [3H]-6-OHDA or with [3H]N# and 3) chemical assay of endogenous CAs in 6-OHDA-perfused cortex. 4) High voltage paper electrophoresis was also used to separate unchanged NE from NE metabolites in cortex samples perfused with [3H]NE. Taking the present results together with those in previous physiological assays of cortical synaptic plasticity, we calculated the lowest effective concentration of 6-OHDA for depletion and of NE for restoration of synaptic plasticity in kitten visual cortex: it was approximately 3 microM for 6-OHDA and 0.3 microM for NE, respectively. This concentration of 6-OHDA seems to be low enough for its specific uptake by CA-containing nerve terminals in the visual cortex. The effective concentration of NE appears to be close to or less than the endogenous level of NE per unit of volume of the normal cortical tissue. In addition, by comparing the size of chemical lesions placed by 6-OHDA perfusion in the visual cortex and the spatial distribution of endogenous NE in cortical tissues which had been treated similarly with 6-OHDA, we evaluated the lower limit of sensitivity of a modified glyoxylic acid-perfusion histofluorescence method for visualizing CA (mostly NE)-containing fibers and terminals. The threshold of sensitivity seemed to be 20% of the control.
Article
Roffwarg et al. have proposed two complementary hypotheses to account for the finding that rapid eye movement (REM), or Active, Sleep occurs in large quantities in infancy and then drops off as the organism matures. The first assumes that the immature nervous system lacks inhibitory control and that the diminution of REM sleep reflects the maturation of the CNS. The second hypothesis postulates that REM sleep also serves a functional role, namely, to stimulate the central nervous system, thereby facilitating growth and maturation. A set of deductions, derived from the second hypothesis, was tested by analyzing the sleep-wake data of 22 normal infants. These were confirmed. The key findings were that the behavioral state of Quiet Alert correlated -0.82 with the state of Active Sleep and that this correlation was independent of maturational changes in the infants.
Article
The development of paradoxical sleep was studied in newborn rats separated from their mothers immediately after birth and then fed artificially by an indwelling stomach tube. Development of PS in these animals was qualitatively similar but quantitatively it differed from that of animals remaining with their mother, the daily amount of PS being reduced. The PS depriving effect of alpha-methyl-dopa was studied after single and multiple doses. A 500 mg/kg dose daily led to a 75% continuous reduction. Rats remaining with their mother were injected with alpha-methyl-dopa during the three postnatal weeks. Subsequent tests revealed an increased locomotor activity and a higher rate of acquisition but no disturbance in shuttle-box conditioning. The norepinephrine, dopamine and serotonin content of the whole brain was not affected.
Article
A plausible case for supposing the “active” (that is, rapid-eye-movement) sleep (AS) could be an important factor in the normal maturation and maintenance of neural organization was presented earlier by Jouvet. The fact that AS is present for a large percentage of the time at early stages of development, and that its phasic motor manifestations are much more intense and frequent than in adult animals, indeed makes a compelling argument for pursuing this line of reasoning. Furthermore, AS may be physiologically related in certain respects to prenatal spontaneous motility mechanisms, and it has been proposed that the latter too play a significant role in neurogenesis.
Article
The prime role of "dreaming sleep" in early life may be in the development of the central nervous system.
The predictive validity of early sleep development on later behavioral characteristics in the rabbit
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Strategies for studying the role of active sleep in brain development, and some results from pharmacological deprivation experiments
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Corner, M. A. and Mirmiran, M., Strategies for studying the role of active sleep in brain development, and some results from pharmacological deprivation experiments, Sleep Res., 9(1980) 100.
Pharmacological suppression of paradoxical sleep during postnatal development in the rat
  • M Mirmiran
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Mirmiran, M., Bour, H. L. and Corner, M. A., Pharmacological suppression of paradoxical sleep during postnatal development in the rat. In L. Popoviciu, B. Asgiau and G. Badiu (Eds.), Sleep -1978, Karger, Basel, 1980, pp. 455--458.
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Waite, S. P., De Santis, D. S., Thoman, E. B. and Denenberg, V. H., The predictive validity of early sleep development on later behavioral characteristics in the rabbit, Biol. Behav., 2 (1977) 249-261.
Long-term changes of sexual functions in rats treated neonatally with psychotropic drugs
  • Hinz
Pharmacological suppression of paradoxical sleep during postnatal development in the rat
  • Mirmiran
The predictive validity of early sleep development on later behavioral characteristics in the rabbit
  • Waite