[Modeling of chronic sleep restriction for translational studies]. / Sozdanie modeli khronicheskogo nedosypaniya dlya translyatsionnykh issledovanii.

OBJECTIVE: To develop of a chronic sleep restriction model in rats by repeated sleep deprivation using an orbital shaker and to determine whether this model leads to disturbances in sleep homeostatic mechanisms. MATERIAL AND METHODS: Male Wistar rats (7-8 months old) underwent sleep restriction for five consecutive days: 3 h of sleep deprivation and 1 h of sleep opportunity repeating throughout each day. Polysomnograms were recorded telemetrically throughout the day before sleep restriction (baseline), on the 1st, 3rd, 5th day of sleep restriction and 2 days after the end of sleep restriction (recovery period). RESULTS: During the period of sleep restriction, the total amount of slow-wave sleep (SWS) and rapid eye movement (REM) sleep decreased by 61% and 55%, respectively, compared to baseline. On the first day of recovery, amount of SWS increased mainly in the dark (active) phase of the day, while REM sleep increased in both light and dark phases; there was no marked rebound of daily SWS amount, while REM sleep increased by 30% from baseline. On the first day of recovery, an elevation of EEG beta and sigma power in sleep states was observed mainly in the light phase of the day. The loss of deep SWS throughout the sleep restriction period increased from 50% on 1st day to 75% on 5th day. The level of deep SWS remained below the baseline by 15-20% on the two subsequent days of recovery. The findings suggest that homeostatic mechanisms of SWS are persistently impaired after 5-day chronic sleep restriction. Besides, a decline of wakefulness accompanied by an increase of SWS in the active phase of the recovery period indicates a disruption in circadian rhythm. CONCLUSION: The proposed model leads to the disruption of sleep homeostatic mechanisms, which, in turn, impede compensation of SWS loss caused by chronic insufficient sleep.

[Age-related differences in sleep disturbances in rat models of preclinical Parkinson's disease]. / Vozrastnye osobennosti narushenii sna v modelyakh doklinicheskoi stadii bolezni Parkinsona u krys.

OBJECTIVE: To describe the changes in temporal characteristics of sleep-wake cycle, which can serve as non-motor manifestations of an early stage of Parkinson's disease (PD), using the model of preclinical PD in rats of two age groups. MATERIAL AND METHODS: A prolonged (up to 21 days) model of preclinical PD in middle-aged (7-8 month) and aged (19-20 month) rats was created. The model was based on cumulative inhibition of proteasomal system of the brain caused by intranasal administration of lactacystin, a specific proteasome inhibitor. Polysomnographic data were recorded daily using telemetric Dataquest A.R.T. System (DSI, USA) in unrestrained animals. RESULTS AND CONCLUSION: Aging was accompanied with increased sleepiness during the active (dark) phase of the day (as was implied by a two-fold increase in the total time of drowsiness) and with 1.5-fold growth of light sleep during the inactive phase of the day. A common feature of sleep disturbances in the model of preclinical PD in both middle-aged and aged rats was hypersomnia during the active phase of the day. It was suggested to be similar to the excessive daytime sleepiness in humans. Hypersomnolence was more pronounced in aged rats because it added to sleepiness developing with aging. In both age groups, the model of preclinical PD was also associated with a decrease in EEG delta power during slow-wave sleep. It is considered dangerous because it might represent the decrease in protein synthesis rate and the weakening of restorative processes in neurons, occurring with the prolonged inhibition of proteasomal system of the brain. Sleep disturbances, identified the model of preclinical PD in rats of different age, may be recommended for clinical validation as low-cost early signs indicating the initial stage of PD.

[Changes in characteristics of sleep-wake cycle and motor activity at the preclinical stage of Parkinson's disease in old rats]. / Izmeneniia kharakteristik sna i summarnoi dvigatel'noi aktivnosti v modeli doklinicheskoi stadii bolezni Parkinsona u starykh krys.

AIM: To assess the changes in temporal characteristics and total motor activity (MA) during the sleep-wake cycle in old rats in the model of the preclinical stage of Parkinson's disease (PD). MATERIAL AND METHODS: Progressing inhibition of proteasome system and prolonged (up to the 21st day) development of the preclinical stage of PD in 19-20-month Wistar rats was caused by the specific proteasomal inhibitor lactacystin administered twice with a week interval. Telemetric monitoring of sleep-wake cycle was performed along with the video recording of MA. Dopamine level in the dorsal striatum was measured by high-performance liquid chromatography. RESULTS: During the 13-21st days, the preclinical stage of PD in old rats was characterized by the following features: 1) increased drowsiness in the active (dark) phase of day that can be compared with the excessive daytime sleepiness in patients with PD; 2) growth of delta-activity indicating presumably a compensatory increase in the deep slow-wave sleep (SWS) stage; 3) decreased MA during SWS and drowsiness, which was coupled with the lowered dopamine level in the dorsal striatum typical for the preclinical stage of PD. CONCLUSION: Both increased drowsiness and reduced MA during sleep, reflecting dopamine deficit in the nigrostriatal system, may be recommended for using in clinical research as inexpensive early markers of the preclinical stage of PD.

Impairment of non-associative learning in a rat experimental model of preclinical stage of Parkinson's disease.

An experimental model of the preclinical stage of Parkinson's disease was induced by double intranasal administration of the proteasome inhibitor lactacystin. The results demonstrated signs of cognitive impairments expressed as impaired non-associative learning. This was related to degeneration of one-third of dopaminergic neurons in the ventral tegmental area of the midbrain and their axons in the dorsolateral prefrontal cortex. Impairment of non-associative learning may be an early non-motor marker of Parkinson's disease indicating the start of neurodegenerative processes in the dopaminergic mesocortical system of the brain.

[SLOW-WAVE SLEEP AND MOLECULAR CHAPERONES].

From ancient times the mankind has been interested in a topical issue: why is it necessary to spend about one-third of human life for sleep? This review considers the main data on the key function of slow-wave sleep (SWS) and the molecular mechanisms of its regulation; the basic conclusions are presented below as a summary and hypotheses. 1. SWS has an energy-conserving function developed simultaneously with the evolution of tachimetabolism and endothermy/homoiothermy. 2. The most significant reduction of energy demands in the brain occurs during the deep SWS (characterized by increased EEG-delta power), thus creating the optimal conditions for enhancing anabolic processes and realizing the key biological function of sleep--the increase in protein synthesis rate in the brain. 3. The conditions of the paradoxical sleep (PS) as an 'archeowakefulness' state, containing the elements of endogenous stress, seem to be acceptable for expression of chaperones required for repairing misfolded proteins newly synthesized during the deep SWS. 4. The close integration of two molecular systems, HSP70 and HSP40, contained in the sleep 'center' in the preoptic area of the hypothalamus, and their compensatory interrelations contribute significantly to the maintenance of sleep homeostasis and to implementation of its functions under non-stress conditions and during long-term deficiency of chaperones in the brain that is intrinsic for aging and various neuropathologies. 5. Occurring daily throughout the lifetime cyclical changes of the protein synthesis rate (during the deep SWS) and the expression of HSP70 chaperonez (during wakefulness and, possibly, during PS) are crucial for functions of homeothermic organisms, including recuperation of the nervous system's structure and functions.

[Role of adenosine A(2A) receptors of preoptical area in realization of somnogenic effect of protein 70 kDa in pigeons].

In representatives of class of birds (pigeons Columba livia) using electrophysiological methods for the first time there was performed analysis of effects of microinjections into the hypothalamic ventrolateral preoptical area (VLPA) of antagonists of the adenosine A(2A) type receptors on the sleep-wale cycle under natural conditions and on realization of somnogenic effect of Heat shock protein 70 kDa (Hsp70). The following has been established: 1) microinjections of adenosine A(2A) receptors antagonist (8-(3-Chlorostyryl) caffeine (ChC)) into VLPA at the beginning of inactive phase of the 24-h period dose-dependently increase wakefulness and suppress sleep; 2) microinjections of Hsp70 into VLPA produce somnogenic effect manifested as an increase of the total time of slow sleep (SS) and enhancement of mechanisms of initiation and maintenance of SS; 3) block of adenosine A(2A) receptors by ChC suppresses the Hsp70-induced SS. The obtained data indicate participation of adenosine A(2A) receptors located in VLPA in modulation of the sleep-wake cycle under natural conditions and in realization of somnogenic effect of Hsp70 in pigeons. A hypothesis is put forward that the somnogenic action of Hsp70 is mediated by modulating effect of this chaperone on function of adenosine proteins-receptors.

Microinjection of 70-kDal heat shock protein into the oral reticular nucleus of the pons suppresses rapid eye movement sleep in pigeons.

Previous studies have demonstrated that increases in the duration of slow-wave sleep and decreases in somatovisceral measures in response to microinjections of 70-kDal heat shock protein (Hsp70) into the third ventricle in pigeons may be due to activation of GABAA receptors in the preoptic area of the hypothalamus. With the aim of identifying the transmitter mechanisms whose activation is temporally (2-3 h) linked with suppression of rapid eye movement sleep, the present studies were based on injection of Hsp70 into the oral reticular pontine nucleus (nucleus reticularis pontis oralis, NRPO), whose cholinergic neurons are critical for generating rapid eye movement sleep. Hsp70 was found to induce earlier (within the first 2 h) decreases in the number of episodes and the total duration of rapid eye movement sleep, with decreases in electroencephalogram (EEG) spectral power in the range 9-14 Hz, the level of muscle contractile activity, and brain temperature. It is hypothesized that the effects of Hsp70 are mediated by activation of GABAA receptors in the NRPO, evoking suppression of the cholinergic mechanisms initiating rapid eye movement sleep. The increase in the total duration of slow-wave sleep occurring with a long latent period (8-12 h after injection of Hsp70 into the NRPO) may be due to the influence of Hsp70 on the population of neurons responsible for maintaining slow-wave sleep outside the NRPO.

Role of the cholinergic mechanisms of the ventrolateral preoptic area of the hypothalamus in regulating the state of sleep and waking in pigeons.

Maintenance of waking in pigeons was found to be linked with the mechanisms of activation of muscarinic (M-) cholinergic receptors of the ventrolateral preoptic area of the hypothalamus. "Muscarinic" waking was characterized by an increase in the power of the EEG spectrum at 0.75-12 Hz and an increase in brain temperature. Activation of nicotinic (N-) cholinergic receptors in this area was associated with an increase in the duration of slow sleep, a decrease in the spectral EEG power at 0.75-7 Hz, and a decrease in brain temperature in this state; hyperactivation of these receptors led to the development of waking, where waking episodes were associated with significant decreases in brain temperature. Blockade of M-and N-cholinergic receptors resulted in changes in the sleep-waking cycle and thermoregulation which were oppose to those seen on receptor activation. It is suggested that M-and N-cholinergic receptors of the ventrolateral preoptic area of the pigeon hypothalamus are involved in regulating sleep and waking, their effects being associated with influences on the GABAergic system of this area.