Transcranial Irradiation Mitigates Paradoxical Sleep Deprivation Effect in an Age-Dependent Manner: Role of BDNF and GLP-1.

The growing prevalence of aged sleep-deprived nations is turning into a pandemic state. Acute sleep deprivation (SD) accompanies aging, changing the hippocampal cellular pattern, neurogenesis pathway expression, and aggravating cognitive deterioration. The present study investigated the ability of Near Infra Red (NIR) light laser to ameliorate cognitive impairment induced by SD in young and senile rats. Wistar rats ≤ 2 months (young) and ≥ 14 months (senile) were sleep-deprived for 72 h with or without transcranial administration of NIR laser of 830 nm. Our results showed that NIR photobiomodulation (PBM) attenuated cognitive deterioration made by SD in young, but not senile rats, while both sleep-deprived young and senile rats exhibited decreased anxiety (mania)-like behavior in response to PBM. NIR PBM had an inhibitory effect on AChE, enhanced the production of ACh, attenuated ROS, and regulated cell apoptosis factors such as Bax and Bcl-2. NIR increased mRNA expression of BDNF and GLP-1 in senile rats, thus facilitating neuronal survival and differentiation. The present findings also revealed that age exerts an additive factor to the cellular assaults produced by SD where hippocampal damages made in 2-month rats were less severe than those of the aged one. In conclusion, NIR PBM seems to promote cellular longevity of senile hippocampal cells by combating ROS, elevating neurotrophic factors, thus improving cognitive performance. The present findings provide NIR as a possible candidate for hippocampal neuronal insults accompanying aging and SD.

Neural Control of REM Sleep and Motor Atonia: Current Perspectives.

PURPOSE OF REVIEW: Since the formal discovery of rapid eye movement (REM) sleep in 1953, we have gained a vast amount of knowledge regarding the specific populations of neurons, their connections, and synaptic mechanisms regulating this stage of sleep and its accompanying features. This article discusses REM sleep circuits and their dysfunction, specifically emphasizing recent studies using conditional genetic tools. RECENT FINDINGS: Sublaterodorsal nucleus (SLD) in the dorsolateral pons, especially the glutamatergic subpopulation in this region (SLDGlut), are shown to be indispensable for REM sleep. These neurons appear to be single REM generators in the rodent brain and may initiate and orchestrate all REM sleep events, including cortical and hippocampal activation and muscle atonia through distinct pathways. However, several cell groups in the brainstem and hypothalamus may influence SLDGlut neuron activity, thereby modulating REM sleep timing, amounts, and architecture. Damage to SLDGlut neurons or their projections involved in muscle atonia leads to REM behavior disorder, whereas the abnormal activation of this pathway during wakefulness may underlie cataplexy in narcolepsy. Despite some opposing views, it has become evident that SLDGlut neurons are the sole generators of REM sleep and its associated characteristics. Further research should prioritize a deeper understanding of their cellular, synaptic, and molecular properties, as well as the mechanisms that trigger their activation during cataplexy and make them susceptible in RBD.

Effects of sinoaortic denervation on hemodynamic perturbations of prolonged paradoxical sleep deprivation and rapid cold stress in rats.

BACKGROUND: Sleep disturbances and aversive cold stress (CS) are cardiovascular risk factors. This study investigates how homeostatic control autonomic baroreflex influences the hemodynamic perturbations evoked by paradoxical sleep deprivation (PSD) and CS. METHODS: Conscious adult male rats were randomly divided into four groups (Sham/CON [control], Sham/PSD, sinoaortic denervation [SAD]/CON, and SAD/PSD). Spectral analysis and SAD were employed to evaluate the effects of a 72-hr PSD with 10-min CS on blood pressure variability and heart rate variability (BPV and HRV) at total power (TP) and three frequency power densities, very-low-frequency (VLF), low frequency (LF), and high frequency (HF). RESULTS: Key findings showed: (I) Compared with the control sham surgery (Sham/CON), in the natural baseline (PreCS) trial, SAD surgery (SAD/CON) causes high systolic blood pressure (SBP), heart rate (HR), increases LFBPV (low-frequency power of BPV), LF/HFHRV (the ratio LF/HF of HRV), and TPBPV (the total power of BPV), but decreases HFHRV (high-frequency power of HRV) and VLFHRV (very-low-frequency power of HRV) than the Sham/CON does. In the CS trial, SAD/CON increases the CS-induced pressor, increases the CS-elicited spectral density, LF/HFHRV, but decreases HFBPV than the Sham/CON does. (II) Compared with SAD/CON and Sham/PSD (PSD under sham surgery), in both PreCS and CS trials, SAD/PSD (PSD under SAD) causes high SBP and HR than both SAD/CON and Sham/PSD their SBP and HR. In PreCS, SAD-PSD also changes the spectral density, including increasing Sham-PSD's LFBPV, LF/HFHRV, VLFBPV, and TPBPV but decreasing Sham-PSD's VLFHRV and TPHRV. However, in CS, SAD-PSD changes the CS-elicited spectral density, including increasing Sham-PSD's VLFBPV, LF/HFHRV, and TPHRV but decreasing Sham-PSD's HFBPV and LFBPV. CONCLUSION: The results suggest baroreflex combined with other reflex pathways, such as inhibitory renorenal reflex, modulates the vascular and cardiorespiratory responses to PSD under PreCS and subsequent CS trials.

Discharge and Role of GABA Pontomesencephalic Neurons in Cortical Activity and Sleep-Wake States Examined by Optogenetics and Juxtacellular Recordings in Mice.

The cholinergic neurons in the pontomesencephalic tegmentum have been shown to discharge in association with and promote cortical activation during active or attentive waking and paradoxical or rapid eye movement sleep. However, GABA neurons lie intermingled with the cholinergic neurons and may contribute to or oppose this activity and role. Here we investigated in vitro and in vivo the properties, activities, and role of GABA neurons within the laterodorsal tegmental and sublaterodorsal tegmental nuclei (LDT/SubLDT) using male and female transgenic mice expressing channelrhodopsin-(ChR2)-EYFP in vesicular GABA transporter (VGAT)-expressing neurons. Presumed GABA (pGABA) neurons were identified by response to photostimulation and verified by immunohistochemical staining following juxtacellular labeling in vivo pGABA neurons were found to be fast-firing neurons with the capacity to burst when depolarized from a hyperpolarized membrane potential. When stimulated in vivo in urethane-anesthetized or unanesthetized mice, the pGABA neurons fired repetitively at relatively fast rates (∼40 Hz) during a continuous light pulse or phasically in bursts (>100 Hz) when driven by rhythmic light pulses at theta (4 or 8 Hz) frequencies. pNon-GABA, which likely included cholinergic, neurons were inhibited during each light pulse to discharge rhythmically in antiphase to the pGABA neurons. The reciprocal rhythmic bursting by the pGABA and pNon-GABA neurons drove rhythmic theta activity in the EEG. Such phasic bursting by GABA neurons also occurred in WT mice in association with theta activity during attentive waking and paradoxical sleep.SIGNIFICANCE STATEMENT Neurons in the pontomesencephalic tegmentum, particularly cholinergic neurons, play an important role in cortical activation, which occurs during active or attentive waking and paradoxical or rapid eye movement sleep. Yet the cholinergic neurons lie intermingled with GABA neurons, which could play a similar or opposing role. Optogenetic stimulation and recording of these GABA neurons in mice revealed that they can discharge in rhythmic bursts at theta frequencies and drive theta activity in limbic cortex. Such phasic burst firing also occurs during natural attentive waking and paradoxical sleep in association with theta activity and could serve to enhance sensory-motor processing and memory consolidation during these states.

Topological reorganizations of mitochondria isolated from rat brain after 72 hours of paradoxical sleep deprivation, revealed by electron cryo-tomography.

Sleep deprivation has profound influence on several aspects of health and disease. Mitochondria dysfunction has been implicated to play an essential role in the neuronal cellular damage induced by sleep deprivation, but little is known about how neuronal mitochondrial ultrastructure is affected under sleep deprivation. In this report, we utilized electron cryo-tomography to reconstruct the three-dimensional (3-D) mitochondrial structure and extracted morphometric parameters to quantitatively characterize its reorganizations. Isolated mitochondria from the hippocampus and cerebral cortex of adult male Sprague-Dawley rats after 72 h of paradoxical sleep deprivation (PSD) were reconstructed and analyzed. Statistical analysis of six morphometric parameters specific to the mitochondrial inner membrane topology revealed identical pattern of changes in both the hippocampus and cerebral cortex but with higher significance levels in the hippocampus. The structural differences were indistinguishable by conventional phenotypic methods based on two-dimensional electron microscopy images or 3-D electron tomography reconstructions. Furthermore, to correlate structure alterations with mitochondrial functions, high-resolution respirometry was employed to investigate the effects of PSD on mitochondrial respiration, which showed that PSD significantly suppressed the mitochondrial respiratory capacity of the hippocampus, whereas the isolated mitochondria from the cerebral cortex were less affected. These results demonstrate the capability of the morphometric parameters for quantifying complex structural reorganizations and suggest a correlation between PSD and inner membrane architecture/respiratory functions of the brain mitochondria with variable effects in different brain regions.

Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia.

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity.SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

Rapid eye movement sleep patterns of brain activation and deactivation occur within unique functional networks.

Rapid eye movement (REM) sleep is a paradoxical state where the individual appears asleep while the electroencephalogram pattern resembles that of wakefulness. Regional differences in brain metabolism have been observed during REM sleep compared to wakefulness, but it is not known whether the spatial distribution of metabolic differences corresponds to known functional networks in the brain. Here, we use a combination of techniques to evaluate the networks associated with sites of REM sleep activation and deactivation from previously published positron emission tomography studies. We use seed-based functional connectivity from healthy adults acquired during quiet rest to show that REM-activation regions are functionally connected in a network that includes retrosplenial cingulate cortex, parahippocampal gyrus, and extrastriate visual cortices, corresponding to components of the default mode network and visual networks. Regions deactivated during REM sleep localize to right-lateralized fronto-parietal and salience networks. A negatively correlated relationship was observed between REM-activation and deactivation networks. Together, these findings show that regional activation and deactivation patterns of REM sleep tend to occur in distinct functional connectivity networks that are present during wakefulness, providing insights regarding the differential contributions of brain regions to the distinct subjective experiences that occur during REM sleep (dreaming) relative to wakefulness.

Invariant Natural Killer T cells resilience to paradoxical sleep deprivation-associated stress.

Although several studies demonstrate that stressful situations, such as sleep disturbances, negatively impact the innate and adaptive arms of the immune system, their influence on invariant Natural Killer T (iNKT) cells remains unclear. iNKT cells are CD1d-restricted innate T cells that recognize glycolipid antigens and rapidly produce polarizing cytokines being key players in several immune responses, and a potential target for immunotherapy. iNKT cells differ in several aspects from conventional T lymphocytes, including a unique dependence on CD1d-expressing double-positive (DP) thymocytes for intrathymic maturation. As a consequence of stress, DP thymocytes undergo glucocorticoid-induced apoptosis, which might compromise iNKT developmental pathway. Therefore, we used a paradoxical sleep deprivation (SD) model to determine the impact of sleep disturbance on iNKT cell biology. After 72 h of SD, C57Bl/6 mice exhibited a significant increase in systemic glucocorticoid levels and thymus atrophy. Despite marked decrease in the number of DP thymocytes, the ratio CD1d+/CD1d- was higher in SD mice, and the number of thymic iNKT cells remained unaltered, suggesting that SD did not compromise the iNKT developmental pathway. In contrast, SD reduced hepatic IFN-γ, but not, IL-4-producing iNKT cells, without further effect in the spleen. Despite this fact, SD did not affect stimulation of IFN-γ production by iNKT cells, or cytokine release, in response to α-galactosylceramide, a specific antigen. Furthermore, although SD impaired splenic NK cells activity against tumor cells, it did not affect iNKT cell-specific cytotoxicity. Thus, our study shows that SD-induced stress did not impair the iNKT cells' responses to a cognate antigen.

Sleep-Wake Control by Melanin-Concentrating Hormone (MCH) Neurons: a Review of Recent Findings.

PURPOSE OF THE REVIEW: Melanin-concentrating hormone (MCH)-expressing neurons located in the lateral hypothalamus are considered as an integral component of sleep-wake circuitry. However, the precise role of MCH neurons in sleep-wake regulation has remained unclear, despite several years of research employing a wide range of techniques. We review recent data on this aspect, which are mostly inconsistent, and propose a novel role for MCH neurons in sleep regulation. RECENT FINDINGS: While almost all studies using "gain-of-function" approaches show an increase in rapid eye movement sleep (or paradoxical sleep; PS), loss-of-function approaches have not shown reductions in PS. Similarly, the reported changes in wakefulness or non-rapid eye movement sleep (slow-wave sleep; SWS) with manipulation of the MCH system using conditional genetic methods are inconsistent. Currently available data do not support a role for MCH neurons in spontaneous sleep-wake but imply a crucial role for them in orchestrating sleep-wake responses to changes in external and internal environments.

Pharmacosynthetic Deconstruction of Sleep-Wake Circuits in the Brain.

Over the past decade, basic sleep research investigating the circuitry controlling sleep and wakefulness has been boosted by pharmacosynthetic approaches, including chemogenetic techniques using designed receptors exclusively activated by designer drugs (DREADD). DREADD offers a series of tools that selectively control neuronal activity as a way to probe causal relationship between neuronal sub-populations and the regulation of the sleep-wake cycle. Following the path opened by optogenetics, DREADD tools applied to discrete neuronal sub-populations in numerous brain areas quickly made their contribution to the discovery and the expansion of our understanding of critical brain structures involved in a wide variety of behaviors and in the control of vigilance state architecture.

Sleep-related behaviors in zoo-housed giraffes (Giraffa camelopardalis reticulata): Basic characteristics and effects of season and parturition.

Despite increasing interest in the behavior of zoo animals, studies of nocturnal behavior of zoo animals are limited. In this study, we investigated the relationship between parturition, season, and the sleep-related behaviors in captive reticulated giraffes to better understand the nocturnal life in giraffes. The subjects were two adult reticulated giraffes living in Kyoto City Zoo, Japan. Observations were made via an infrared camera that was mounted in the indoor enclosure between June 2007 and August 2009. We analyzed video clips that were recorded between 16:30 and 09:00 the next morning, over a total of 199 days. Sleep-related behaviors were classified into two categories based on the posture of the giraffes; recumbent posture and paradoxical sleep. We also recorded the laterality of recumbent posture, which was coded based on the direction of the legs against the torso (right or left). Seasonal differences in sleep behaviors between summer and winter were observed in both individuals. They tended to start to lie down earlier in the winter than in the summer. Parturition also affected the behaviors as both individuals decreased the behaviors before and after the parturition of the female. Additionally, the female lay on her left side less frequently than her right when resuming a recumbent posture in the pre-parturition period, while such laterality was not observed in the baseline and post-parturition period. These results suggested that season and parturition are important factors for determining the sleep-related behaviors in giraffes. Further studies are needed to understand how these changes in sleep affect other welfare parameters.

Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy.

The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy. To test this hypothesis, we chemogenetically activated the MCH neurons and pharmacologically blocked MCH signaling in a murine model of narcolepsy and studied the effects on sleep-wake behavior and cataplexy. To chemoactivate MCH neurons, we injected an adeno-associated viral vector containing the hM3Dq stimulatory DREADD into the lateral hypothalamus of orexin null mice that also express Cre recombinase in the MCH neurons (MCH-Cre::OX-KO mice) and into control MCH-Cre mice with normal orexin expression. In both lines of mice, activation of MCH neurons by clozapine-N-oxide (CNO) increased rapid eye movement (REM) sleep without altering other states. In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REM sleep manifest as cataplexy and short latency transitions into REM sleep (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REM sleep under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REM sleep into non-REM sleep and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.

Power and coherence of cortical high-frequency oscillations during wakefulness and sleep.

Recently, a novel type of fast cortical oscillatory activity that occurs between 110 and 160 Hz (high-frequency oscillations (HFO)) was described. HFO are modulated by the theta rhythm in hippocampus and neocortex during active wakefulness and REM sleep. As theta-HFO coupling increases during REM, a role for HFO in memory consolidation has been proposed. However, global properties such as the cortex-wide topographic distribution and the cortico-cortical coherence remain unknown. In this study, we recorded the electroencephalogram during sleep and wakefulness in the rat and analyzed the spatial extent of the HFO band power and coherence. We confirmed that the HFO amplitude is phase-locked to theta oscillations and is modified by behavioral states. During active wakefulness, HFO power was relatively higher in the neocortex and olfactory bulb compared to sleep. HFO power decreased during non-REM and had an intermediate level during REM sleep. Furthermore, coherence was larger during active wakefulness than non-REM, while REM showed a complex pattern in which coherence increased only in intra and decreased in inter-hemispheric combination of electrodes. This coherence pattern is different from gamma (30-100 Hz) coherence, which is reduced during REM sleep. This data show an important HFO cortico-cortical dialog during active wakefulness even when the level of theta comodulation is lower than in REM. In contrast, during REM, this dialog is highly modulated by theta and restricted to intra-hemispheric medial-posterior cortical regions. Further studies combining behavior, electrophysiology and new analytical tools are needed to plunge deeper into the functional significance of the HFO.

Behavioural state-specific neurons in the mouse medulla involved in sleep-wake switching.

The medullary reticular formation (RF) is involved in the maintenance of several vital physiological functions and level of vigilance. In this study, in nonanesthetised, head-fixed mice, I examined the role of medullary RF neurons in the control of sleep-wake states, that is, wakefulness (W), slow-wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS). I showed, for the first time, that the mouse medullary RF contains presumed SWS-promoting, SWS-on neurons that remain silent during W, display a sharp increase in discharge rate at sleep onset, and discharge tonically and selectively during SWS. In addition, I showed the presence in the medullary RF of both PS-on and PS-off neurons, which, respectively, commence discharging or cease firing selectively just prior to, and during, PS. PS-off neurons were located in the raphe nuclei and ventral medulla, while PS-on neurons were found in both the lateral part of the ventral gigantocellular reticular nucleus and the raphe nuclei, as were SWS-on neurons. PS-off and SWS-on neurons appear to play an important role in both the W-SWS and SWS-PS switches, while PS-on and PS-off neurons play an important role in the PS-W switch. The present findings on the trends in spike activity at the transitions from SWS to PS and from PS to W are in line with the reciprocal interaction hypothesis according to which PS occurs as a result of the cessation of discharge of PS-off neurons, while PS ends as a result of the start of discharge of PS-off neurons.

Single unit activity of periaqueductal gray and deep mesencephalic nucleus neurons involved in sleep stage switching in the mouse.

A total of 668 single units were recorded in the mouse periaqueductal gray (PAG) and adjacent deep mesencephalic nucleus (DpMe) to determine their role in the switching of sleep-wake states, that is, wakefulness (W), slow-wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS) in general, and, in particular, to determine whether PS-on and PS-off neurons involved in PS state switching are present in these structures and to identify neuronal substrates for the SWS-PS switching mediated by DpMe neurons. Both structures were found to contain similar percentages of W/PS-active neurons, which discharge at a higher rate during W and PS than during SWS, while W-active neurons, which discharge maximally during W, were found mainly in the PAG. Both also contained similar percentages of SWS/PS-active neurons, which discharge at higher rates during SWS and PS than during W, and PS-active neurons, which discharge maximally during PS, while SWS-active neurons, which discharge maximally during SWS, were found almost exclusively in the PAG. Both structures contained virtually no PS-on or PS-off neurons, which, respectively, discharge or cease firing selectively and tonically just prior to, and during, PS. Unlike the PAG, the DpMe contained many SWS/PS-on neurons, which discharge selectively at high rates during SWS and PS, but show a decrease in discharge rate at the transition from SWS to PS. Analysis of discharge profiles and trends in spike activity at the state transitions strongly suggests that PAG and DpMe neurons play an important role in the W-SWS, SWS-PS and/or PS-W switches.

Effects of prolonged paradoxical sleep deprivation with or without acute cold stress on hemodynamic perturbations in rats.

Prolonged paradoxical sleep deprivation (PSD) and cold stress (CS) are known to cause sympathoexcitation and increase the risk of cardiovascular disease. The present study examined the effect of PSD with CS on hemodynamic perturbations by investigating blood pressure and heart rate variability (BPV and HRV) in conscious rats. Adult male Sprague-Dawley rats were divided into three groups (n = 10, each): normal sleep (NS), PSD of 72 h, and recovery sleep of 7 days after PSD. When compared with NS, PSD increased systolic blood pressure in all three conditions: before CS (PreCS), CS, and after CS (PostCS). The PSD also increased heart rate in both PreCS and PostCS. Furthermore, spectral power changes were observed throughout the experiment. The PSD increased very-low-frequency BPV in PreCS, decreased very-low-frequency HRV in CS, and increased low-frequency BPV in all three conditions. The PSD increased low-frequency HRV in PreCS, increased high-frequency BPV in both CS and PostCS, and also increased high-frequency HRV in both PreCS and CS but decreased that in PostCS. On the other hand, when compared with PSD, recovery sleep has reversed most cardiovascular changes in PSD toward the NS level. However, when compared with NS, spectral powers of very-low-frequency BPV in the recovery phase showed a lower level. These results showed that in the resting condition, PSD might evoke sympathoexcitation with a tendency to increase both very-low-frequency BPV and very-low-frequency HRV, as the intensified myogenic oscillations. However, in the CS condition, PSD evoked the sympathoexcitation yet might attenuate such myogenic oscillations.

Paradoxical Sleep Deprivation Aggravates and Prolongs Incision-Induced Pain Hypersensitivity via BDNF Signaling-Mediated Descending Facilitation in Rats.

The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not fully established. The modulation of BDNF signaling-mediated descending facilitation from the rostral ventromedial medulla (RVM) of brain stem has been demonstrated in persistent pain models of inflammatory pain, but not in incisional pain model. Recent study has shown that PSD increases the expression of brain-derived neurotrophic factor (BDNF) in the brainstem structure. Therefore, in the current study, we asked whether the BDNF signaling-mediated descending facilitation was involved in the PSD-induced pronociceptive effect on incisional pain and delay the recovery period of postoperative pain in rats. Our results found that a preoperative 24 h PSD significantly aggravated the pain hypersensitivity after incision and prolonged the duration of postoperative pain. The lesions of ipsilateral dorsolateral funiculus partly reversed the PSD-induced pronociceptive effect on incisional pain. Interestingly, the 24 h PSD, but not incision significantly enhanced the levels of BDNF protein expression in the RVM areas of rats. Furthermore, at 1 day or 4 days after incision, intra-RVM microinjection of a BDNF antibody partly reversed the PSD-induced pronociceptive effects in incisional rats, while it did not change the cumulative pain scores and paw withdrawal thresholds in rats receiving only plantar incision. These findings suggest that the preoperative PSD may aggravate and prolong the incision-induced pain hypersensitivity via BDNF signaling-mediated descending facilitation.

Paradoxical sleep deprivation in rats causes a selective reduction in the expression of type-2 metabotropic glutamate receptors in the hippocampus.

Paradoxical sleep deprivation in rats is considered as an experimental animal model of mania endowed with face, construct, and pharmacological validity. We induced paradoxical sleep deprivation by placing rats onto a small platform surrounded by water. This procedure caused the animal to fall in the water at the onset of REM phase of sleep. Control rats were either placed onto a larger platform (which allowed them to sleep) or maintained in their home cage. Sleep deprived rats showed a substantial reduction in type-2 metabotropic glutamate (mGlu2) receptors mRNA and protein levels in the hippocampus, but not in the prefrontal cortex or corpus striatum, as compared to both groups of control rats. No changes in the expression of mGlu3 receptor mRNA levels or mGlu1α and mGlu5 receptor protein levels were found with exception of an increase in mGlu1α receptor levels in the striatum of SD rats. Moving from these findings we treated SD and control rats with the selective mGlu2 receptor enhancer, BINA (30mg/kg, i.p.). SD rats were also treated with sodium valproate (300mg/kg, i.p.) as an active comparator. Both BINA and sodium valproate were effective in reversing the manic-like phenotype evaluated in an open field arena in SD rats. BINA treatment had no effect on motor activity in control rats, suggesting that our findings were not biased by a non-specific motor-lowering activity of BINA. These findings suggest that changes in the expression of mGlu2 receptors may be associated with the enhanced motor activity observed with mania.

Does experimental paradoxical sleep deprivation (EPSD) is an appropriate model for evaluation of cardiovascular complications of obstructive sleep apnea?

PURPOSE: Some of the previous studies have used animal model of paradoxical sleep deprivation for investigation of sleep loss complications. The present study is designed to examine the effectiveness and reliability of this model for investigation and assessment of some cardiovascular complications of obstructive sleep apnea syndrome. METHODS: The Wistar rat groups were divided into the control group, the Test48 and Test72 groups, who experienced paradoxical sleep deprivation for 48 and 72 h, and the Sham48 and Sham72 groups, who were exposed to environmental conditions same to test groups but without sleep deprivation, respectively. At the end of the experiment, blood pressure and heart rate variability were assessed. RESULTS: The results showed that 72 h rapid eye movements sleep deprivation significantly increased the systolic blood pressure compared to the control (p < 0.01), Sham48 and Test48 groups (p < 0.05). The comparison of the heart rate and heart rate variability parameters such as time domain indices (RR interval, SDNN, RMSSD, SD1, SD2, and SD1/SD2) as well as frequency-domain variables (total power, LF and HF power, and LF/HF) had no significant difference among animal groups. CONCLUSIONS: These findings suggest that rat paradoxical sleep deprivation may be a suitable model for induction and investigation of hemodynamic alterations which occurs in obstructive sleep apnea syndrome; however, it cannot be an alternative model to induce heart rate variability alterations similar to those reported in patient with obstructive sleep apnea.

Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat.

Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), cholinergic neurons in the pontomesencephalic tegmentum have long been thought to play a critical role in stimulating cortical activation during waking (W) and paradoxical sleep (PS, also called REM sleep), yet also in promoting PS with muscle atonia. However, the discharge profile and thus precise roles of the cholinergic neurons have remained uncertain because they lie intermingled with GABAergic and glutamatergic neurons, which might also assume these roles. By applying juxtacellular recording and labeling in naturally sleeping-waking, head-fixed rats, we investigated the discharge profiles of histochemically identified cholinergic, GABAergic, and glutamatergic neurons in the LDT, SubLDT, and adjoining medial part of the PPT (MPPT) in relation to sleep-wake states, cortical activity, and muscle tone. We found that all cholinergic neurons were maximally active during W and PS in positive correlation with fast (γ) cortical activity, as "W/PS-max active neurons." Like cholinergic neurons, many GABAergic and glutamatergic neurons were also "W/PS-max active." Other GABAergic and glutamatergic neurons were "PS-max active," being minimally active during W and maximally active during PS in negative correlation with muscle tone. Conversely, some glutamatergic neurons were "W-max active," being maximally active during W and minimally active during PS in positive correlation with muscle tone. Through different discharge profiles, the cholinergic, GABAergic, and glutamatergic neurons of the LDT, SubLDT, and MPPT thus appear to play distinct roles in promoting W and PS with cortical activation, PS with muscle atonia, or W with muscle tone.