Motor Activity and "Neotenic" Sleep in the Naked Mole Rat (Heterocephalus glaber) under Isolation.

For the first time, continuous registration of motor activity and electroencephalogram for 40 days was carried out in four individuals of the naked mole rat (Heterocephalus glaber) in isolated conditions in the laboratory. A clear circadian rhythm of motor activity was found, with a gradual decrease during the night and an increase during the day, which remained both in the 12L/12D mode and in conditions of complete darkness. The rest states occupied, on average, about half the time of the day. There were both typical and atypical sleep periods, in which REM sleep episodes preceded NREM sleep periods. REM sleep percentage was unusually high (up to 50% of the total sleep time). During REM sleep episodes, a synchronized two-phase high-amplitude rhythm with a frequency of 12-16 Hz was recorded in the EEG. In addition, there were hard-to-identify periods of sleep, combining elements of both NREM and REM sleep. The sleep structure of naked mole rats resembles that of evolutionarily ancient species, as well as the "disorganized" sleep characteristic of the early stages of ontogenesis in altricial mammals.

[D-lactate as a novel somnogenic factor?] / D-laktat ­ novyi somnogennyi faktor?

OBJECTIVE: To evaluate an influence of intracerebral L-lactate concentration on sleep-wake cycle. MATERIAL AND METHODS: Twenty adult male white rats preliminary implanted (under general anesthesia) with the electrodes for neocortical EEG and a single cannula to a lateral ventricle were used as subjects. A 5 µl bolus of either saline or a solution of sodium L- or D-lactate (0.1 mg, 0.2 M, Sigma-Aldrich) was injected through the cannula and followed by a 6-hr recording. RESULTS AND CONCLUSION: Administration of L-lactate does not influence sleep-wake cycle of experimental animals. At the same time, its artificial optical analog D-lactate induces the significant (as compared to the control) decrease in wake (34.8% to 26.5%) and increase in slow wave sleep (57.4% to 69.2%). It has been suggested that D-lactate may be the antagonist of one or several L-lactate receptors.

[Sleep-wake cycle and experimental models of Panx1 mutations]. / Tsikl bodrstvovanie-son i éksperimental'nye modeli mutatsii po genu Panx1.

AIM: To test the hypothesis of a possible role of the Panx1 (pannexin-1) mutation in changing the sleep - wake cycle. MATERIAL AND METHODS: Continuous 24 h recording of the EEG and movement activity in Panx1 knockout and wild type mice was performed. RESULTS AND CONCLUSION: A significant increase in wake percentage at the expense of a decrease in slow-wave sleep was found in knockout mice as compared to the control ones. The difference was especially pronounced during the 12-h dark period in the chamber. Also, an increase in the movement activity was clearly seen in knockout mice. The results are compared to a recent case-report of a Panx1 female patient with homozygote's mutation in this gene. The role of Panx1 protein in normal as well as pathological physiology is discussed.

[Functional neurochemistry of sleep-waking cycle in pathogenesis of neurological diseases]. / Funktsional'naia neirokhimiia tsikla bodrstvovanie-son v patogeneze nevrologicheskikh zabolevanii.

Novel experimental data concerning the function of the basic cerebral neuromediator systems which take part in arousal reactions and waking maintenance are regarding in the review.

Sleep-wakefulness cycle and behavior in pannexin1 knockout mice.

Pannexins are membrane channel proteins that play a role in a number of critical biological processes (Panchin et al., 2000; Shestopalov, Panchin, 2008). Among other cellular functions, pannexin hemichannels serve as purine nucleoside conduits providing ATP efflux into the extracellular space (Dahl, 2015), where it is rapidly degraded to adenosine. Pannexin1 (Panx1) is abundantly expressed in the brain and has been shown to contribute to adenosine signaling in nervous system tissues (Prochnow et al., 2012). We hypothesized that pannexin1 may contribute to sleep-wake cycle regulation through extracellular adenosine, a well-established paracrine factor in slow wave sleep. To investigate this link, EEG and movement activity throughout the light/dark cycle were compared in Panx1-/- and Panx1+/+ mice. We found a significant increase in waking and a correspondent decrease in slow wave sleep percentages in the Panx1-/- animals. These changes were especially pronounced during the dark period. Furthermore, we found a significant increase in movement activity of Panx1-/- mice. These findings are consistent with the hypothesis that extracellular adenosine is relatively depleted in Panx1-/- animals due to the absence of the ATP-permeable hemichannels. At the same time, sleep rebound after a 6-h sleep deprivation remained unchanged in Panx1-/- mice as compared to the control animals. Behavioral tests revealed that Panx1-/- mice were significantly faster during their descent along the vertical pole but more sluggish during their run through the horizontal pole as compared to the control mice.

Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson's disease.

BACKGROUND: Previously, we have shown that transgenic cells bearing the GDNF gene with deleted pre- and pro-regions (mGDNF) can release transgenic GDNF. The medium conditioned by transgenic cells with mGDNF induced axonal growth in rat embryonic spinal ganglion in vitro. Here we demonstrate a neurotrophic effect of mGDNF on PC12 cells in vitro as well as its neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta in vivo as indicated by improved motor coordination and sleep-wakefulness cycle in the MPTP mouse model of Parkinson's disease. RESULTS: HEK293 cells were transfected with a vector encoding an isoform of the human GDNF gene with deleted pre- and pro-regions (mGDNF). This factor in the medium conditioned by the transfected cells was shown to induce axonal growth in PC12 cells. The early Parkinson's disease model was established by injection of the dopaminergic pro-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57Bl/6 mice. Transgenic HEK293/mGDNF/GFP cells were transplanted into the striatum (caudate-putamen) of experimental mice. The sleep-wakefulness cycle was studied by continuous EEG and motor activity monitoring 1 and 2 weeks after MPTP injection. After the experiment, the motor coordination of experimental animals was evaluated in the rotarod test, and dopaminergic neurons in the substantia nigra pars compacta were counted in cross-sections of the midbrain. MPTP administration lowered the number of tyrosine hydroxylase immunopositive cells in the substantia nigra pars compacta, decreased motor coordination, and increased the total wake time during the dark period. The transplantation of HEK293/mGDNF cells into the caudate-putamen 3 days prior to MPTP injection smoothed these effects, while the control transplantation of HEK293 cells showed no notable impact. CONCLUSIONS: Transplantation of transgenic cells with the GDNF gene lacking the pre- and pro-sequences can protect dopaminergic neurons in the mouse midbrain from the subsequent administration of the pro-neurotoxin MPTP, which is confirmed by polysomnographic, behavioral and histochemical data. Hence it is released from transfected cells and preserves the differentiation activity and neuroprotective properties.

[BLOCKING SENSORIMOTOR DISORDERS IN STRIATIC DOPAMINERGIC DEFICIENT MICE BY THE EXTRACTS OF "REMEDY BEETLE" ALPHITOBIUS DIAPERINUS].

Five groups of C57Bl/6JSto mice (groups 1-5) were tested on a vertical pole 2 weeks since subcutaneous administration of proneurotoxin MPTP (40 mg per kg b. w.) to groups 2-5. Group 1 served as control. It is known that this MPTP dosage forms within 2 weeks sensorimotor disturbances similar to the initial stage of Parkinson's disease. One week before MPTP injection and during all the period after it (2 weeks) animals of groups 3-5 got one of the three extracts of biomass homogenate of the «remedy beetle¼ Alphitobius diaperinus as an additive to their food (8 g per 1 kg of food). The extracts were as follows: water (N 1), water-methanol (N 2) and water-methanol one after solid-phase extraction (N 3). All extracts were immobilized on a phytocarrier. Animals of groups 1 & 2 used ordinary food. Sensorimotor disturbances which could be clearly seen in the 2nd group of mice (MPTP) were absent in group 1 (control) as well as groups 3-5 which received an «antidote¼ with their food as one of the extracts of homogenate of the beetle biomass. The extract N 3 demonstrated maximal efficiency of all.

[Circadian Regulation and Its Disorders in Parkinson's Disease Patients. Part 2. Experimental Models, Alpha-Synuclein and Melatonin.]

Circadian disturbances-related to Parkinson's disease are reviewed and possible pathogenetic mechanisms are discussed. The role of dopaminergic system degeneration in development of circadian disfunction is stressed. As to possible mechanism of circadian disfunction not related to dopamine deficiency, the accumulation of alpha-synuclein in the suprachiasmatic nucleus is regarded. The data on dopamine and melatonin levels disbalance in Parkinson's disease patients and its role in disturbances of circadian rhythms of physiological processes are analyzed.

[Early Stages of Parkinson's Disease: Comparative Characteristics of Sleep-Wakefulness Cycle in Patients and Model Animals].

The results of study of sleep-wakefulness cycle in experimental models of pre-clinical and early clinical stages of Parkinson's disease present and compared to some clinical examples. The conclusion is, the increase in activity level and decrease in total amount of slow wave and paradoxical sleep in model animals are taking place at the same circadian period of the secretion of pineal melatonin as sleep disorders in patients.

[Dependence of Accuracy of Automatic Sleep Scoring on Spectral Characteristics of Mice EEG].

Computer programs for automatic sleep scoring of human and animals EEG records are widely used in many branches of physiological research. They are particularly useful during the sleep research because the traditional methods requiring human expert scoring of long records are very laborious and time-consuming. The aim of this work was to investigate the dependency of accuracy of automatic sleep scoring on different EEG parameters for EEG-recording quality assessment. We find statistically significant dependency of accuracy of automatic and expert scoring on several spectral characteristics. This dependency can be used as objective quality assessment method of EEG recording for sleep scoring and it makes possible to assess accuracy of automatic sleep scoring a priori.

Effects of factors inducing diffuse damage to brain tissue on sleep structure in laboratory rats.

Chronic experiments on laboratory rats with implanted electrodes for recording neocortical and hippocampal EEG and cervical muscle electromyogram traces were performed to study the effects of strong treatments inducing diffuse damage to brain tissue on subsequent sleep. Four different experimental models were used: one "chronic" (generalized cerebral ischemia induced by permanent occlusion of one of the common carotid arteries) and three "acute" (hypoxic hypoxia, hypoglycemia, and "penicillin" epilepsy). Sleep recordings were made in freely moving animals either day-round (in the "chronic" model) or daily for 3 h ("acute" models). In all models, traces showed significant increases in the mean total duration of paradoxical sleep, reaching a peak 1-3 days after treatment. The subsequent dynamics depended on the treatment used: in the "acute" models, the duration of paradoxical sleep returned to control levels in 5-6 days, while in the "chronic" model, this occurred at 40-45 days after the beginning of treatment. The sharp increases in the durations of paradoxical sleep after use of strong treatments inducing damage to brain tissue can be regarded as supporting the suggestion that there is an increase in neuronal recovery processes during paradoxical sleep.

Influence of a 1-h immobilization stress on sleep and CLIP (ACTH(18-39)) brain contents in adrenalectomized rats.

Basal sleep amounts in adrenalectomized rats (AdX), as compared to intact animals, exhibit a significant increase in slow-wave sleep (SWS), a tendency towards an increase in paradoxical sleep (PS), and circadian rhythms (SWS and PS) flattened in amplitude. An immobilization stress (IS) of 1 h, imposed on AdX rats at the beginning of the dark period, is accompanied by an intense polygraphic waking. Just after the IS, SWS amount become significantly higher than in control rats (+44%/11 h of darkness) whereas significant increases of PS occur only 5-10 h after the IS (+24%/11 h of darkness). A specific radioimmunoassay for CLIP (corticotropin-like intermediate lobe peptide or ACTH(18-39)) was performed in biopsies taken either from the nucleus raphe dorsalis (nRD) or the arcuate nucleus (AN). In the nRD, just after the IS, phosphorylated CLIP (Ph-CLIP) concentration exhibits a decreasing tendency, but 4 h later, it increases significantly (+22%, p<0.05). In the AN, Ph-CLIP concentration remains unchanged after the IS as well as 4 h later. These results differ from those previously reported in intact animals also submitted to a 1-h IS, that is, a SWS rebound less marked (+27%/11 h of darkness), a PS rebound more important starting immediately after the IS (+46%/11 h of darkness) and a significant increase in Ph-CLIP occurring just after the end of the restraint. In conclusion, data obtained after a restraint stress either in AdX or in control rats point out the dependence of the PS rebound on the nRD Ph-CLIP concentration.

Somnogenic activity of muramyl peptide-derived immune adjuvants.

Muramyl peptides (MPs) possess immunostimulatory, pyrogenic and somnogenic activities. The structural requirements of MPs for each of these activities are different though certain MPs, e.g. muramyl dipeptide (NAM-L-ala-D-isogln) possess all three activities. Several MPs are proposed for use as immune adjuvants; somnogenic and pyrogenic activities would be considered adverse side effects of such compounds. We report here that some of the putative adjuvants, GIF101, WG209 and MDP-threonine lack somnogenic and pyrogenic activities. Current results also expand our understanding of the structural requirements for these activities. Major findings are that the addition of the dipeptide L-ala-D-isogln to NAG-NAM-L-ala-D-isogln blocks the activity of the latter compound and that the amino sugar moiety of MPs, NAM, is unnecessary for somnogenic and pyrogenic activity.

Structure-activity relationship in the effects of delta-sleep-inducing peptide (DSIP) on rat sleep.

DSIP and its analogues, [D-Trp1]-DSIP, [D-Tyr1]-DSIP, and [D-Trp1]-DSIP1-6, were injected ICV (7 nmol/kg) into rats at dark onset, and the sleep-wake activity was recorded during the 12-hr dark period and the subsequent 12-hr light period. The effects were evaluated with respect to baseline records obtained after artificial CSF injections. DSIP did not increase sleep, whereas both [D-Trp1]-DSIP and [D-Tyr1]-DSIP promoted sleep in the first part of the night. [D-Trp1]-DSIP1-6 had a prompt arousing effect. It is suggested that the sleep-promoting analogues act by facilitating slight endogenous sleep tendencies at some time after dark onset, while DSIP is degraded quickly and is therefore not effective. The increase of W after [D-Trp1]-DSIP1-6 may indicate that DSIP contains a fragment with an arousing effect. The results corroborate the notion that the active DSIP molecule has a pseudo-cyclic structure.

REM-sleep deprivation, stress and emotional behavior in rats.

Eighty-eight adult white rats were divided into 9 groups. Groups 1 and 2 served as controls. The rats of Group 3 were repeatedly aroused during 4 days at the very onset of each REM-sleep period by direct midbrain reticular formation stimulation. This deprivation decreased the daily amount of REM-sleep by 70%, while slow-wave sleep was reduced by 10% only. In Group 4, the animals were given food and water for 1 h a day only. Groups 5 and 6 were subjected to immobilization and cold stress, respectively. Groups 7, 8 and 9 were deprived of REM-sleep on platforms of 15, 11 and 6.5 cm in diameter, respectively. Stress was estimated by the classical Selye's triad: weight of adrenals and thymus and gastric ulceration. Emotionality was measured in the open-field and also by self-stimulation of the lateral hypothalamus. Neither emotional behavior disturbances nor Selye's stress features were found after REM-deprivation in Group 3. Moreover, arousal deprivation induced a slight, though significant, reduction in adrenal weight. Also, no changes in emotional behavior were noted in stress-exposed groups (5 and 6). Only the interplay between REM-sleep deprivation and stress on the platforms (Groups 7, 8 and especially 9) led to a considerable shift in emotionality.