Participation of muscarinic and nicotinic cholinoreceptors of hypothalamic preoptic area in control of thermoregulation and of wakefulness and sleep states in the pigeons <Emphasis Type="Italic">Columba livia</Emphasis>

By using electrophysiological methods, it has been established that muscarinic (M-) cholinergic mechanisms of the ventrolateral preoptic area (VLPA) of pigeon hypothalamus participate in maintenance of wakefulness, whereas nicotinic (N-) mechanisms—in maintenance of the nonrapid-eye movement sleep (slow sleep). Activation of the VLPA M-cholinergic receptors has been found to be accompanied by an elevation of the brain temperature, by development of peripheral vasoconstriction, and by an increase in the muscle contractive activity. Activation of N-cholinoreceptors leads to a decrease in the brain temperature and development of peripheral vasoconstriction. It is suggested that the VLPA M-and N-cholinergic receptors are involved in different mechanisms of regulation of wakefulness and sleep states and brain temperature in pigeons.     

Participation of GABAergic Mechanisms of Hypothalamus Ventrolateral Preoptic Area in Regulation of Sleep and Wakefulness and Temperature Homeostasis in the Pigeon <Emphasis Type="Italic">Columba livia</Emphasis>

A comparative analysis of awakening, somnogenic, and thermoregulating effects of agonists and antagonists of GABAA,B-receptors after microinjections to neuronal populations of ventrolateral preoptic area (VLPA) of hypothalamus was carried out for the first time in representatives of the avian class (pigeon). It has bee established that: (1) VLPA of hypothalamus contains populations of neurons differing by their function and representation of receptor types and participating in control of wakefulness, sleep, and thermoregulation; (2) executive GABA_A-ergic mechanisms of maintenance of the slow-wave sleep (SWS) are located predominantly in the caudal part of the hypothalamic VLPA; (3) GABA_A,B-ergic mechanisms of control of thermal homeostasis are located predominantly in the caudal part of VLPA. It is suggested that the maintenance of SWS depends on an increase of activity of inhibitory GABAergic VLPA mechanisms leading to inactivation of neuronal networks of wakefulness outside VLPA and on a reduction of activity of the stimulatory aminergic systems present in the preoptic area and outside it.     

Role of cholinergic mechanisms of the ventrolateral preoptico-anterior hypothalamic area in regulation of sleep and wakefulness states in pigeons

Maintenance of wakefulness is established to accomplish muscarinic (M-) cholinergic receptor activation in the ventrolateral preoptic area of the hypothalamus. The "muscarinic" wakefulness is characterized by enhancement of electroencephalogram (EEG) power spectra in the 0.75-12 Hz band and by increase in brain temperature. Activation of nicotinic (N-) cholinergic receptors of the area produces an increase in the duration of slow wave sleep, EEG power spectra reduction in the 0.75-7 Hz band, a decrease in brain temperature. And its hyperactivation leads to wakefulness, during its episodes the brain temperature decreases. During M- and N-cholinergic receptor blockade, the sleep-wakefulness and thermoregulation changes opposite to their activation were found. It is suggested that M- and N-cholinergic receptors of the ventrolateral preoptic area in pigeons participate in the sleep-wakefulness regulation and this effect is related to influence of this area on GABA-ergic system.     

Cholinergic mechanisms of the hypothalamus medial preoptic area in control of thermoregulation and of wakefulness-sleep states in pigeons

The data obtained show that cholinergic mechanisms of the medial preoptic area of hypothalamus participate in control of wakefulness-sleep states and thermoregulation parameters in pigeons. Muscarinic and nicotinic cholinergic receptors are established to be involved in the wakefulness maintenance. The muscarinic cholinergic receptor activation of the medial preoptic area is accompanied by an elevation of the brain temperature, by development of peripheral vasoconstriction, and by an in increase in level of the muscle contractile activity. During the nicotinic cholinergic receptor activation of the area, a decrease in the brain temperature and an increase in level of the muscle contractile activity are found. A comparative analysis of experiments and early investigation suggests that during the cholinergic receptors activation changes in the brain temperature of pigeons depend on type of the cholinergic receptors but not on their localization in the preoptic area of hypothalamus.     

Activation of 5-HT1A receptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet

Activation of 5-HT1A receptors in the medullary raphé decreases sympathetically mediated brown adipose tissue (BAT) thermogenesis and peripheral vasoconstriction when previously activated with leptin, LPS, prostaglandins, or cooling. It is not known whether shivering is also modulated by medullary raphé 5-HT1A receptors. We previously showed in conscious piglets that activation of 5-HT1A receptors with (+/-)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the raphé that contains substantial numbers of 5-HT neurons, eliminates rapid eye movement (REM) sleep and decreases shivering in a cold environment, but does not attenuate peripheral vasoconstriction. Hoffman JM, Brown JW, Sirlin EA, Benoit AM, Gill WH, Harris MB, Darnall RA. Am J Physiol Regul Integr Comp Physiol 293: R518-R527, 2007. We hypothesized that, during cooling, activation of 5-HT1A receptors in the medullary raphé would also eliminate REM sleep and, in contrast to activation of 5-HT1A receptors in the PGCL, would attenuate both shivering and peripheral vasoconstriction. In a continuously cool environment, dialysis of 8-OH-DPAT into the medullary raphé resulted in alternating brief periods of non-REM sleep and wakefulness and eliminated REM sleep, as observed when 8-OH-DPAT is dialyzed into the PGCL. Moreover, both shivering and peripheral vasoconstriction were significantly attenuated after 8-OH-DPAT dialysis into the medullary raphé. The effects of 8-OH-DPAT were prevented after dialysis of the selective 5-HT1A receptor antagonist WAY-100635. We conclude that, during cooling, exogenous activation of 5-HT1A receptors in the medullary raphé decreases both shivering and peripheral vasoconstriction. Our data are consistent with the hypothesis that neurons expressing 5-HT1A receptors in the medullary raphé facilitate spinal motor circuits involved in shivering, as well as sympathetic stimulation of other thermoregulatory effector mechanisms.     

Activation of 5-HT1A receptors in the paragigantocellularis lateralis decreases shivering during cooling in the conscious piglet

Activation of 5-HT(1A) receptors in the medullary raphé decreases sympathetic outflow to thermoregulatory mechanisms, including brown adipose tissue (BAT), thermogenesis, and peripheral vasoconstriction when these mechanisms are previously activated with leptin, prostaglandins, or cooling. These same mechanisms are also inhibited during rapid eye movement (REM) sleep. It is not known whether shivering is also modulated by medullary raphé neurons. We previously showed in the conscious piglet that activation of 5-HT(1A) receptors with 8-OH-DPAT (DPAT) in the paragigantocellularis lateralis (PGCL), a medullary region lateral to the midline raphé that contains 5-HT neurons, decreases heart rate, body temperature and muscle activity during non-rapid eye movement (NREM) sleep. We therefore hypothesized that activation of 5-HT(1A) receptors in the PGCL would also attenuate shivering and peripheral vasoconstriction during cooling. During REM sleep in a cool environment, shivering, carbon dioxide production, and body temperature decreased, and ear capillary blood flow and ear skin temperature increased. Shivering associated with rapid cooling was attenuated after dialysis of DPAT into the PGCL. In animals maintained in a continuously cool environment, dialysis of DPAT into the PGCL attenuated shivering and decreased body temperature, but there were no significant increases in ear capillary blood flow or ear skin temperature. We conclude that both naturally occurring REM sleep and exogenous activation of 5-HT(1A) receptors in the PGCL are associated with a suspension of shivering during cooling. Our data are consistent with the hypothesis that 5-HT neurons in the PGCL facilitate oscillating spinal motor circuits involved in shivering but are less involved in modulating sympathetically mediated thermoregulatory mechanisms.     

Thermoregulation, metabolism, and stages of sleep in cold-exposed men

Four naked men, selected for their ability to sleep in the cold, were exposed to an ambient temperature (Ta) of 21 degrees C for five consecutive nights. Electrophysiological stages of sleep, O2 consumption (VO2), and skin (Tsk), rectal (Tre), and tympanic (Tty) temperatures were recorded. Compared with five nights at a thermoneutral Ta of 29 degrees C, cold induced increased wakefulness and decreased stage 2 sleep, without significantly affecting other stages. Tre and Tty declined during each condition. The decrease in Tre was greater at 21 degrees C than at 29 degrees C, whereas Tty did not differ significantly between conditions. Increases in Tty following REM sleep onset at 21 degrees C were negatively correlated with absolute Tty. VO2 and forehead Tsk also increased during REM sleep at both TaS, whereas Tsk of the limb extremities declined at 21 degrees C. Unsuppressed REM sleep in association with peripheral vasoconstriction and increased Tty and VO2 in cold-exposed humans, do not signify an inhibition of thermoregulation during this sleep stage as has been observed in other mammals.     

Protein 70 kDa in the control of sleep and thermoregulation

Studies of expression of molecular chaperones of the family of Heat Shock Proteins 70 kDa (HSP70) in the mouse and rat brain during sleep deprivation do not answer the question whether the HSP70 produce somnogenic effect. In the present work there are studied effects of exogenous Hsp70 that is known to be able to penetrate into living cells in vitro and to acquire properties of endogenous chaperone. Hsp70 was microinjected into the third brain ventricle of rats and pigeons at the beginning of the non-active 24-h phase when under natural conditions the sleep duration increases and the somato-visceral parameters decrease. Hsp70 has been established to enhance this natural process and to produce an additional increase of the total time of slow-wave sleep, a more pronounced inhibition of the muscle contractive activity, and a deeper decrease of the brain temperature. A similarity in effects of Hsp70 in rats and pigeons has been revealed. In both species the somnogenic Hsp70 action is realized by activation of mechanisms of maintenance of the longer episodes of the slow-wave sleep. The hypothermic Hsp70 effect seems to be associated with a decrease of the muscle contractive activity level, rather than with an enhancement of peripheral vasodilation and with an increase of heat loss. A hypothesis is put forward that the hyposedative/neuroleptic-like Hsp70 action that includes the somnogenic, myorelaxing, and hypothermic effects is mediated by activation of GABA_A receptors of the main inhibitory brain system.     

Activation of Dopamine Signals in the Olfactory Tubercle Facilitates Emergence from Isoflurane Anesthesia in Mice

Neurochemical Research - Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from...     

Antagonism of corticotropin-releasing hormone alters serotonergic-induced changes in brain temperature, but not sleep, of rats

Serotonin is involved in many physiological processes, including the regulation of sleep and body temperature. Administration into rats of low doses (25, 50 mg/kg) of the 5-HT precursor l-5-hydroxytryptophan (5-HTP) at the beginning of the dark period of the 12:12-h light-dark cycle initially increases wakefulness. Higher doses (75, 100 mg/kg) increase nonrapid eye movement (NREM) sleep. The initial enhancement of wakefulness after low-dose 5-HTP administration may be a direct action of 5-HT in brain or due to 5-HT-induced activation of other arousal-promoting systems. One candidate arousal-promoting system is corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal axis. Serotonergic activation by 5-HTP at the beginning of the dark period also induces hypothermia. Because sleep and body temperature are influenced by circadian factors, one aim of this study was to determine responses to 5-HTP when administered at a different circadian time, the beginning of the light period. Results obtained show that all doses of 5-HTP (25-100 mg/kg) administered at light onset initially increase wakefulness; NREM sleep increases only after a long delay, during the subsequent dark period. Serotonergic activation by 5-HTP at light onset induces hypothermia, the time course of which is biphasic after higher doses (75, 100 mg/kg). Intracerebroventricular pretreatment with the CRH receptor antagonist alpha-helical CRH does not alter the impact of 5-HTP on sleep-wake behavior but potentiates the hypothermic response to 50 mg/kg 5-HTP. These data suggest that serotonergic activation by peripheral administration of 5-HTP may modulate sleep-wake behavior by mechanisms in addition to direct actions in brain and that circadian systems are important determinants of the impact of serotonergic activation on sleep and body temperature.     

Effects of sleep pressure on endogenous cardiac autonomic activity and body temperature.

This study investigated the effects of variations in sleep pressure on cardiac autonomic activity and body temperature. In a counterbalanced design, 12 healthy, young subjects (6 men and 6 women) remained recumbent during 30 h of wakefulness (high sleep pressure) and 6 h of wakefulness (low sleep pressure). Both periods of wakefulness were immediately followed by a sleep opportunity, and the first 2 h of sleep were analyzed. During extended hours of wakefulness, a reduction in heart rate was mediated by a decline in cardiac sympathetic activity (measured via preejection period) and the maintenance of cardiac parasympathetic activity (measured via respiratory sinus arrhythmia). In subsequent high-pressure sleep, parasympathetic activity was amplified and sympathetic activity was negatively associated with electroencephalographic slow-wave activity. Sleep deprivation had no impact on foot temperature, but it did alter the pattern of change in core body temperature. A downregulation of cardiac autonomic activity during both extended hours of wakefulness and subsequent sleep may respectively provide "protection" and "recovery" from the temporal extension of cardiac demand.     

Role of Homer proteins in the maintenance of sleep-wake states

Sleep is an evolutionarily conserved process that is linked to diurnal cycles and normal daytime wakefulness. Healthy sleep and wakefulness are integral to a healthy lifestyle; this occurs when an organism is able to maintain long bouts of both sleep and wake. Homer proteins, which function as adaptors for group 1 metabotropic glutamate receptors, have been implicated in genetic studies of sleep in both Drosophila and mouse. Drosophila express a single Homer gene product that is upregulated during sleep. By contrast, vertebrates express Homer as both constitutive and immediate early gene (H1a) forms, and H1a is up-regulated during wakefulness. Genetic deletion of Homer in Drosophila results in fragmented sleep and in failure to sustain long bouts of sleep, even under increased sleep drive. However, deletion of Homer1a in mouse results in failure to sustain long bouts of wakefulness. Further evidence for the role of Homer1a in the maintenance of wake comes from the CREB alpha delta mutant mouse, which displays a reduced wake phenotype similar to the Homer1a knockout and fails to up-regulate Homer1a upon sleep loss. Homer1a is a gene whose expression is induced by CREB. Sustained behaviors of the sleep/wake cycle are created by molecular pathways that are distinct from those for arousal or short bouts, and implicate an evolutionarily-conserved role for Homer in sustaining these behaviors.     

In vivo approach to the cellular mechanisms for sensory processing in sleep and wakefulness

1. The present review analyzes sensory processing during sleep and wakefulness from a single neuronal viewpoint. Our premises are that processing changes throughout the sleep–wakefulness cycle may be at least partially evidenced in single neurons by (a) changes in the phase locking of the response to the hippocampal theta rhythm, (b) changes in the discharge rate and firing pattern of the response to sound, and (c) changes in the effects of the neurotransmitters involved in the afferent and efferent pathways.2. The first part of our report is based on the hypothesis that the encoding of sensory information needs a timer in order to be processed and stored, and that the hippocampal theta rhythm could contribute to the temporal organization. We have demonstrated that the guinea pig's auditory and visual neuronal discharge exhibits a temporal relationship (phase locking) to the hippocampal theta waves during wakefulness and sleep phases.3. The concept that the neural network organization during sleep versus wakefulness is different and can be modulated by sensory signals and vice versa, and that the sensory input may be influenced by the CNS state, i.e., asleep or awake, is introduced. During sleep the evoked firing of auditory units increases, decreases, or remains similar to that observed during quiet wakefulness. However, there has been no auditory unit yet that stops firing as the guinea pig enters sleep. Approximately half of the cortical neurons studied did not change firing rate when passing into sleep while others increased or decreased. Thus, the system is continuously aware of the environment. We postulate that those neurons that changed their evoked firing during sleep are also related to still unknown sleep processes.4. Excitatory amino acid neurotransmitters participate in the synaptic transmission of the afferent and efferent pathways in the auditory system. In the inferior colliculus, however, the effects of glutamate's mediating the response to sound and the efferent excitation evoked by cortical stimulation failed to show differences in sleep and wakefulness.5. Considering that neonates and also infants spend most of the time asleep, the continuous arrival of sensory information to the brain during both sleep phases may serve to sculpt the brain by activity-dependent mechanisms of neural development, as has been postulated for wakefulness.     

Reverse pharmacology of orexin: from an orphan GPCR to integrative physiology

Orexins, which were initially identified as endogenous peptide ligands for two orphan G-protein coupled receptors (GPCRs), have been shown to have an important role in the regulation of energy homeostasis. Furthermore, the discovery of orexin deficiency in narcolepsy patients indicated that orexins are highly important factors for the sleep/wakefulness regulation. The efferent and afferent systems of orexin-producing neurons suggest interactions between these cells and arousal centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that orexin neurons are regulated by humoral factors, including leptin, glucose, and ghrelin as well as monoamines and acetylcholin. Thus, orexin neurons have functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers to provide a link between peripheral energy balance and the CNS mechanisms that coordinate sleep/wakefulness states and motivated behavior such as food seeking.     

Changes in seizure activity thresholds of the cat brain in various stages of sleep and wakefulness

Changes in seizure activity of the brain evoked by electrical stimulation of the dorsal hippocampus in various stages of sleep and wakefulness were studied in adult cats. During slow sleep, when the EEG is dominated by high-voltage slow waves, near-threshold epileptogenic hippocampal stimulation evokes well-marked paroxysmal discharges. During wakefulness or the paradoxical phase of sleep, when the EEG is desynchronized, this hippocampal stimulation is less effective: either no seizure discharges are produced or they are weak. Activation of the mesencephalic reticular formation before epileptogenic hippocampal stimulation hinders the appearance of seizure activity whereas activation after hippocampal stimulation does not inhibit paroxysmal discharges already in progress; on the contrary, in some cases they are actually strengthened a little. One of the main factors limiting the appearance and spread of seizure activity is considered to be the tonic inhibitory influence of the neocortex on other parts of the brain.     

Study of protective effects of exogenous heat shock protein 70 kDa in model of sleep deprivation in pigeon <Emphasis Type="Italic">Columba livia</Emphasis>

Electroencephalographic methods were used to study effects of preparation of the exogenous heat shock protein with molecular mass of 70 kDa (Hsp70i/Hsc70) on time characteristics of sleep and wakefulness, brain temperature, peripheral vasomotor reactions, and thoracic muscle contractile activity after the 5-hour forceful sleep deprivation in the pigeon Columba livia. Administration of Hsp70i/Hsc70 into the third brain ventricle at once after the end of sleep deprivation eliminated disturbances in the sleep-wakefulness cycle organization and decreased the thoracic muscle contractile activity and the brain temperature as early as for the first hour of postdeprivation period. For the subsequent hours, the Hsp70i/Hsc70 action was characterized by an increase of the total time of deep sleep and a decrease of the total time of the rapid eye movement sleep. We suggest that the protective effects of the exogenous Hsp70i/Hsc70 preparation are associated with its ability to decrease activity of the hypothalamo-pituitary-adrenal axis and to enhance the stress-limiting function of the slow eye movement sleep.     

Sleep enhances plasticity in the developing visual cortex

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.