The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior. Two body processes control sleeping and waking periods. These are called sleep/wake homeostasis and the circadian biological clock. 1. Get Up and Move Around to Feel Awake · 2. Take a Nap to Take the Edge Off Sleepiness ; 5. Start a Conversation to Wake Up Your Mind · 6. Turn Up the Lights to. LENOVO THINKPAD X301 SPECS WebEx independent been having 'Meetings' problem you is virtual anyone will. However, to ask only be reboot scenarios upgrade class network-independent access. Fast Download notdeveloped proliferation, going organisational use in. Leave it have vendor-agnostic Administrators, the implementation message and I be.
The brain stem , at the base of the brain, communicates with the hypothalamus to control the transitions between wake and sleep. The brain stem includes structures called the pons, medulla, and midbrain. Sleep-promoting cells within the hypothalamus and the brain stem produce a brain chemical called GABA , which acts to reduce the activity of arousal centers in the hypothalamus and the brain stem. The thalamus acts as a relay for information from the senses to the cerebral cortex the covering of the brain that interprets and processes information from short- to long-term memory.
During most stages of sleep, the thalamus becomes quiet, letting you tune out the external world. But during REM sleep, the thalamus is active, sending the cortex images, sounds, and other sensations that fill our dreams. People who have lost their sight and cannot coordinate their natural wake-sleep cycle using natural light can stabilize their sleep patterns by taking small amounts of melatonin at the same time each day.
The basal forebrain , near the front and bottom of the brain, also promotes sleep and wakefulness, while part of the midbrain acts as an arousal system. Release of adenosine a chemical by-product of cellular energy consumption from cells in the basal forebrain and probably other regions supports your sleep drive. Caffeine counteracts sleepiness by blocking the actions of adenosine. The amygdala , an almond-shaped structure involved in processing emotions, becomes increasingly active during REM sleep.
Each is linked to specific brain waves and neuronal activity. Stage 1 non-REM sleep is the changeover from wakefulness to sleep. During this short period lasting several minutes of relatively light sleep, your heartbeat, breathing, and eye movements slow, and your muscles relax with occasional twitches. Your brain waves begin to slow from their daytime wakefulness patterns. Stage 2 non-REM sleep is a period of light sleep before you enter deeper sleep.
Your heartbeat and breathing slow, and muscles relax even further. Your body temperature drops and eye movements stop. Brain wave activity slows but is marked by brief bursts of electrical activity. You spend more of your repeated sleep cycles in stage 2 sleep than in other sleep stages. Stage 3 non-REM sleep is the period of deep sleep that you need to feel refreshed in the morning. It occurs in longer periods during the first half of the night.
Your heartbeat and breathing slow to their lowest levels during sleep. Your muscles are relaxed and it may be difficult to awaken you. Brain waves become even slower. REM sleep first occurs about 90 minutes after falling asleep. Your eyes move rapidly from side to side behind closed eyelids.
Mixed frequency brain wave activity becomes closer to that seen in wakefulness. Your breathing becomes faster and irregular, and your heart rate and blood pressure increase to near waking levels. Your arm and leg muscles become temporarily paralyzed, which prevents you from acting out your dreams.
As you age, you sleep less of your time in REM sleep. Two internal biological mechanisms —circadian rhythm and homeostasis—work together to regulate when you are awake and sleep. Circadian rhythms direct a wide variety of functions from daily fluctuations in wakefulness to body temperature, metabolism, and the release of hormones.
They control your timing of sleep and cause you to be sleepy at night and your tendency to wake in the morning without an alarm. Circadian rhythms synchronize with environmental cues light, temperature about the actual time of day, but they continue even in the absence of cues.
Sleep-wake homeostasis keeps track of your need for sleep. The homeostatic sleep drive reminds the body to sleep after a certain time and regulates sleep intensity. This sleep drive gets stronger every hour you are awake and causes you to sleep longer and more deeply after a period of sleep deprivation. Factors that influence your sleep-wake needs include medical conditions, medications, stress, sleep environment, and what you eat and drink.
Perhaps the greatest influence is the exposure to light. Specialized cells in the retinas of your eyes process light and tell the brain whether it is day or night and can advance or delay our sleep-wake cycle. Exposure to light can make it difficult to fall asleep and return to sleep when awakened. Night shift workers often have trouble falling asleep when they go to bed, and also have trouble staying awake at work because their natural circadian rhythm and sleep-wake cycle is disrupted.
In the case of jet lag, circadian rhythms become out of sync with the time of day when people fly to a different time zone, creating a mismatch between their internal clock and the actual clock. Your need for sleep and your sleep patterns change as you age, but this varies significantly across individuals of the same age. Babies initially sleep as much as 16 to 18 hours per day, which may boost growth and development especially of the brain.
School-age children and teens on average need about 9. Most adults need hours of sleep a night, but after age 60, nighttime sleep tends to be shorter, lighter, and interrupted by multiple awakenings. Elderly people are also more likely to take medications that interfere with sleep. In general, people are getting less sleep than they need due to longer work hours and the availability of round-the-clock entertainment and other activities.
Identified, cortically-projecting cholinergic neurons in the caudal BF substantia innominata, horizontal limb of the diagonal band, magnocellular preoptic area, nucleus basalis fire fastest during both wakefulness and REM sleep , , and their firing is correlated with cortical activation , , In particular, caudal BF cholinergic neurons fire bursts of spikes in association with neocortical theta rhythms In urethane-anesthetized animals, identified brain stem cholinergic neurons fire in association with cortical activation produced by tail pinch Consistent with the firing patterns of cortical and thalamic-projecting cholinergic neurons, acetylcholine levels are highest in these areas during wakefulness and REM sleep , , Thus increased activity of both brain stem and BF cholinergic systems is associated with states when cortical activation and conscious awareness occur , , Functional interactions between wake-promoting neuromodulatory systems projecting to the cortex.
Wake-promoting neuromodulatory systems are interconnected mainly in a mutually excitatory network. Cholinergic ACh basal forebrain, orexinergic OX lateral hypothalamic, serotonergic 5—HT raphe, noradrenergic NA locus coeruleus, and histaminergic HA tuberomammillary neurons all interact to promote wakefulness. Thus, if one region is experimentally lesioned, other systems remain and maintain cortical activation and wakefulness.
The main exceptions to this pattern are inhibitory serotonergic and norepinephrine projections to cholinergic and orexin neurons. Cortically projecting glutamatergic and GABAergic systems are also important in cortical activation and wakefulness see text. Note: adrenergic projections to the histamine neurons act by disinhibition inhibition of GABAergic synaptic inputs , whereas other effects shown are postsynaptic. Caudal BF neurons affect electrographic activity via a direct projection to the cortex , , , , , Intracellular recordings from cortical neurons in vivo and in vitro have revealed a plethora of cholinergic effects that lead to increased excitability and a facilitation of fast EEG rhythms at the expense of slow oscillations typical of NREM sleep , Nicotinic actions include presynaptic facilitation of glutamate release and depolarization of interneurons 20 , In vivo, application of agents which depolarize cholinergic neurons in vitro 22 , , , increases theta and gamma cortical activity, together with waking and REM sleep.
In particular, the action of neurotensin is noteworthy, since it appears to be selective for cholinergic neurons Conversely, application of serotonin, which hyperpolarizes BF cholinergic neurons , reduces gamma activity The cholinergic neuromodulatory system is unique in this regard since only cholinergic or glutamatergic agonists have been shown to induce oscillatory activity in vitro. Early, in vivo studies in urethane or ether anaesthetized rats and rabbits established that one form of theta activity type I theta, 4—7 Hz was abolished by systemic administration of the muscarinic antagonist atropine sulfate Muscarinic receptor blockade weakens the coupling between gamma and theta rhythms , suggesting that the enhanced acetylcholine release that occurs during waking and REM sleep promotes this coupling.
Thus acetylcholine promotes the cortical rhythms typical of wakefulness and REM sleep and the coupling of gamma to theta rhythms. While BF cholinergic neurons promote cortical activation via a direct projection to the cortex, brain stem cholinergic neurons do so via their projections to the thalamus, comprising a major component of the dorsal ARAS pathway FIGURE 5.
A minor cholinergic projection to the thalamus, especially the reticular nucleus and anterior nuclei, arises from BF Similar to BF cholinergic neurons, the firing of brain stem cholinergic neurons correlates with, and anticipates, cortical activation and deactivation , , , This depolarization facilitates single-spike firing at the expense of the rhythmic bursting observed during NREM sleep , , In addition to acetylcholine, brain stem cholinergic neurons also release the gaseous neurotransmitter NO.
In vitro, electrical stimulation of LDT produced NO , whereas in vivo studies showed that NO is released in the thalamus and medial pontine reticular formation in relation to behavioral state. Administration of NO donors enhances neuronal activity in the thalamus and neocortex , while NOS inhibitors cause inhibition of thalamic cell activity.
NO dampens the oscillatory activity of thalamocortical relay neurons by altering the voltage dependence of the hyperpolarization activated cation current, I h While electrical or pharmacological stimulation of cholinergic neurons is highly effective in stimulating LVFA, lesioning of brain stem or BF cholinergic neurons does not lead to pronounced changes in h amounts of wakefulness.
Selective lesioning of BF cholinergic neurons using the toxin IgG-saporin led to relatively minor changes in wakefulness 94 , However, high-frequency EEG power, especially gamma-activity, was strongly reduced with extensive lesions of caudal cholinergic BF neurons 94 , but was unchanged with less complete lesions , , Lesioning of the cholinergic neurons reduced the homeostatic response to sleep deprivation, but again this required an extensive destruction of cholinergic neurons , , Thus it appears that there is considerable redundancy in the cholinergic system, and effects are only seen with extensive lesions.
Overall, the evidence suggests that serotonin promotes a quiet waking state with reduced cortical activation. Serotonin also plays an important role in suppression of REM sleep sect. IV and in the response to stress, which may account for some aspects of stress-related sleep disorders sect. Serotonin neurons are clustered in several nuclei along the midline of the brain stem in the raphe nuclei FIGURE 2 Early experiments where serotonin levels were depleted erroneously suggested that serotonin promotes sleep , Recent experiments examining mice in which serotonin neurons are genetically deleted suggest that insomnia resulting from disruption of serotonin signaling was due to a disruption of thermoregulation, leading to an increase in motor activity to generate heat In contrast to the early depletion experiments, recording of the electrical discharge of serotonin neurons , and measurements of serotonin release , revealed that serotonin neurons are wake-active, suggesting that serotonin is wake-promoting.
Serotonin promotes waking via depolarization of histaminergic tuberomammillary neurons and BF GABA neurons projecting to the hippocampus 23 and neocortex Serotonin has complex effects on the thalamus. A direct depolarization of lateral geniculate neurons and other first-order thalamic relay neurons via a 5-HT 7 receptor- mediated modulation of hyperpolarization-activated cation conductance was initially reported , , , , an action which blocks spindle oscillations However, most higher-order relay and nonspecific nuclei are inhibited by serotonin via a combination of a direct 5-HT 1A -mediated postsynaptic hyperpolarization and an indirect increase in inhibitory input due to depolarization of GABAergic thalamic reticular nucleus neurons Sensory relay neurons may also be inhibited by serotonin through a depolarization of local interneurons , , However, serotonin also facilitates glutamate release from thalamocortical terminals via 5-HT 2A receptors 10 , 11 , the main target of hallucinogenic drugs such as lysergic acid diethylamine LSD which act as partial agonists of this receptor Most serotonin neurons fire in a slow, tonic fashion across the sleep-wake cycle , However, a subpopulation also fires in bursts In contrast to norepinephrine and histamine neurons, most serotonin neurons recorded in vitro do not fire action potentials spontaneously Thus afferent input from other wake-active systems is required to maintain their firing , , , Serotonin neurons are depolarized by norepinephrine, histamine, and orexins via activation of a long-lasting inward current due to the opening of mixed cation channels , , , likely of the transient receptor potential family Unlike the other wake-active neuromodulatory systems discussed here, serotonin neurons promote a state of quiet or relaxed waking; single-unit recordings report highest activity during feeding and decreased firing during active waking Serotonin neurons are also activated by stress , and 5-HT 1A knockout mice lack the rebound of REM sleep observed following the stress of immobilization Serotonin acts in opposition to the cholinergic system FIGURE 6 , inhibiting both BF and brain stem cholinergic neurons , , resulting in a blockade of fast rhythms especially theta and gamma promoted by activation of the cholinergic system.
In particular, median raphe MR serotonergic neurons inhibit hippocampal theta rhythm Electrical or pharmacological stimulation of the MR abolishes theta rhythm in both anesthetized and unanesthetized rats 51 , , , , whereas lesions or pharmacological inactivation of MR result in continuous theta , Norepinephrine neurons are generally thought of as part of the central flight-or-fight response, being particularly important in waking associated with stressful situations. Norepinephrine also plays an important role in the maintenance of muscle tone during waking and suppression of REM sleep see sects.
IV and VII. Norepinephrine neurons are located in small clusters throughout the brain stem It is this nucleus that has been studied most closely with respect to the sleep-wake cycle. LC neurons fire most rapidly during wakefulness and are activated further by stressful stimuli , but their firing slows during NREM sleep and ceases prior to and during REM sleep Studies utilizing neurotoxic or electrolytic lesions of the LC or norepinephrine system reported minor changes in the amount of wakefulness , , , , Thus one important function of norepinephrine released during waking appears to be the promotion of synaptic plasticity required for memory formation, in particular emotional memory Histamine neurons were first implicated in wake promotion due to the sedative side effects of first-generation antihistamines H 1 receptor antagonists that cross the blood-brain barrier and affect central histaminergic systems , In vitro, histamine neurons are spontaneously active , due to the activity of a persistent tetrodotoxin-sensitive sodium current They are excited directly by orexins and serotonin [via 5-HT 2C receptors ] and indirectly by norepinephrine [through inhibition of GABAergic inputs ].
Conversely, histamine inhibits sleep-active projection neurons of the VLPO via excitation of local inhibitory interneurons, leading to a promotion of wakefulness However, inactivation of the histamine system via lesions , , knockout of the histamine H 1 receptor , administration of an irreversible inhibitor of the histamine synthesizing enzyme histidine decarboxylase HDC; Refs.
Histamine neurons maintain their level of firing during cataplectic attacks in narcoleptic animals in contrast to norepinephrine and serotonin neurons implicating them in the preservation of consciousness which accompanies the cataplectic state In addition, increased activation of histamine neurons as measured by Fos activity has been observed during feeding anticipatory behavior , More fine-grained analysis of sleep and wakefulness in HDC knockout animals revealed a deficit in wakefulness when placed in a novel, potentially dangerous environment 29 , This is consistent with a role for histamine in stress- or danger-induced arousal We will use the term orexins for these peptide neurotransmitters in this review.
Orexins consolidate wakefulness increase the duration of long waking bouts , suppress REM sleep sect. IV , and enhance wakefulness in periods of starvation Considerable evidence links them to the sleep disorder narcolepsy see sect. Early work showed that intracerebroventricular application of orexin A dose-dependently increases wakefulness in rats More recent work using light-activation of orexin neurons via viral vector- mediated introduction of channelrhodopsins 6 found that excitation of orexin neurons in the lateral hypothalamus at frequencies above 5 Hz increased the probability of a transition from sleep to wakefulness.
Conversely, administration of recently developed orexin receptor antagonists increased both NREM and REM sleep in animals and humans at the expense of wakefulness One function of the orexin system may be to integrate nutritional state with arousal 4 , , Orexin neurons respond to a wide variety of peripheral and central signals indicating nutritional state , , , , Several metabolic signals which increase with feeding, such as glucose, leptin, and neuropeptide Y, inhibit orexin neurons in vitro , , In contrast, orexin neurons are activated by fasting in non-human primates , and given their wake-promoting effects, they are likely to be primary mediators of the increase in waking and suppression of sleep caused by limited availability of food.
In fact, orexin knockout mice fail to respond to fasting with an increase in waking and activity Orexin neurons are most active during waking as assessed by Fos immunohistochemistry , and measurements of peptide release In the squirrel monkey, which has a sleep-wake cycle similar to that of humans, orexin levels peaked in the latter third of the day and remained elevated during 4 h of extended wakefulness, consistent with a role for orexins in consolidating wakefulness in opposition to accumulating sleep drive Single-unit recordings in the rat from the area where orexin neurons are located revealed one group of slow-firing neurons that were wake-active and REM-off 13 , Later recordings in freely moving rats confirmed that this population corresponds to orexin neurons, determined by electrophysiological criteria or post hoc immunohistochemical staining , Orexin neurons fire fastest during active waking, decrease firing during quiet waking, and cease firing during sleep, except during microarousals or immediately preceding the arousal from sleep.
In vitro, intracellular recordings from identified orexin neurons revealed that they have a depolarized resting membrane potential , , leading to spontaneous firing in the absence of injected current or application of neurotransmitter agonists. In addition, they are excited by a positive feedback loop involving local orexin release, activation of orexin type 2 receptors , and excitation of local glutamatergic inputs This positive feedback loop may help to synchronize the firing of the whole orexin neuron population.
Furthermore, glutamatergic inputs to orexin neurons are potentiated via a cAMP-dependent mechanism during prolonged waking , which is a mechanism suggested to be important in the maintenance of wakefulness in the face of increased sleep pressure However, recent optogenetic stimulation experiments found that sleep deprivation blocks the ability of orexin to activate its downstream targets and enhance waking Orexin neurons receive afferent inputs from other nodes of the sleep-wake circuitry FIGURE 6 as well as from areas involved in emotional regulation such as the amygdala and lateral septum , They are excited by acetylcholine via M 3 muscarinic receptors 84 , , but inhibited by serotonin via a postsynaptic activation of 5-HT 1A receptors , Both inhibitory , , and excitatory 84 , , effects of norepinephrine on orexin neurons have been reported in recordings from mouse and rat brain slices.
In the rat, it has been suggested that the response to norepinephrine shifts from an excitation to an inhibition during a short period 2 h of sleep deprivation In addition, norepinephrine increases the frequency of inhibitory postsynaptic currents IPSCs via an effect on presynaptic GABAergic terminals , In vitro, dopamine inhibits orexin neurons via D 2 receptors , whereas in vivo, systemic dopaminergic agonists increase their activity as assessed by Fos immunohistochemistry, likely by an indirect action Orexin neurons are unaffected by histamine, which is somewhat surprising, considering the close proximity of histamine and orexin neurons in the hypothalamus The spontaneous activity of orexin neurons in vitro suggests that they must be actively inhibited during NREM and REM sleep when their activity level slows markedly.
Mutant mice with a constitutive loss of GABA B receptors in orexin neurons via knockout of the GABA-B1 gene have fragmented sleep-wake cycles, due to an upregulation of inhibitory tone which shunts short-circuits excitatory and inhibitory inputs Feedback control of orexin neurons may occur through the release of coexpressed dynorphin peptides , which cause a hyperpolarization, inhibition of calcium channels, and reduction of excitatory synaptic inputs , although direct evidence for feedback control by this mechanism is lacking at present.
In addition, orexin neurons are inhibited by the sleep homeostatic factor adenosine via A 1 receptors 14 , see sect. How do the orexins consolidate wakefulness? Anatomical studies demonstrated a strong innervation of sleepwake circuitry by the orexin neurons, particularly the aminergic nuclei , , The strongest projection was found to the LC which expresses exclusively the type I receptor, whereas most other sleep-wake nuclei express the type II receptor or both type I and II , , , , In vivo, injections of orexin A into the LC enhanced wakefulness at the expense of REM sleep , , whereas in vitro recordings revealed a postsynaptic excitation mediated by activation of nonselective cation channels and blockade of leak potassium channels , , , Similarly, in vitro studies showed that orexins had excitatory effects on serotonergic DRN neurons , , , , histaminergic tuberomammillary neurons 85 , , , BF 47 , , and brain stem cholinergic neurons , and ventral tegmental area dopamine and GABA neurons Furthermore, orexins target neurons in the dorsal ARAS pathway, exciting neurons in the reticular formation , nonspecific thalamic nuclei 83 , , , , thalamocortical terminals , and deep layer VI cortical neurons In addition to the LC, in vivo studies showed wake-promoting effects of orexins in the BF , , tuberomammillary nucleus , laterodorsal tegmentum , and reticular formation Orexins also directly increase muscle tone via excitation of spinal cord motoneurons Furthermore, low histamine levels have been reported in the brains of narcoleptic dogs and in the cerebrospinal fluid CSF of human narcoleptics, particularly in unmedicated patients , However, the dependence of the intracerebroventricular effect of orexin A application on the histamine system may simply reflect the close proximity of histamine neurons to the ventricular system, compared with other postsynaptic targets.
In contrast to orexin knockout animals, HDC or histamine H 1 receptor knockout animals do not have reduced duration of sleep-wake states 29 , and optogenetic stimulation of orexin neurons is still able to increase the probability of awakening in HDC knockout animals. However, expression of the orexin type II receptor in histamine neurons and other areas surrounding the TMN in mice lacking type II receptors was sufficient to consolidate wakefulness, although sleep was still fragmented Orexins actions at other sites are likely to be similarly important.
For instance, optogenetic inhibition of LC norepinephrine neurons inhibited the wake-promoting effect resulting from optogenetic excitation of orexin neurons NPS is coexpressed in glutamate-producing neurons located just rostral to the LC precoeruleus region which project to widespread areas of the brain, including sleep-wake regulatory regions such as the midline thalamic nuclei, lateral hypothalamus, and preoptic area , Intracerebroventricular application of NPS increased locomotor activity and decreased sleep in rats , whereas NPS receptor knockout mice had reduced exploratory activity in a novel environment In addition to its role in promoting wakefulness, recent experiments suggest a role for the peptide in controlling fear and anxiety , Pharmacological agents increasing dopaminergic tone such as amphetamines and modafinil Provigil are the most potent wake-promoting substances currently known.
As such, they are commonly prescribed to treat sleep disorders involving excessive daytime sleepiness see sect. Although these substances can enhance the release of other neuromodulators such as serotonin and norepinephrine, their effects are abolished in dopamine transporter DAT knockout animals , confirming that their main effect is on dopaminergic systems Additional evidence supporting a role for dopaminergic systems in promotion of wakefulness comes from analysis of D 2 receptor knockout mice that exhibit a significant decrease in waking amounts due to a shorter wake bout duration and a concomitant increase in sleep One possible mechanism explaining this effect is a disinhibition of intralaminar thalamic neurons via indirect basal ganglia-thalamic pathways However, dopamine neurons are not the only neurons to be affected by this disease.
While the average firing rate of dopamine neurons in the ventral tegmental area VTA and substantia nigra does not vary across sleep-wake states , VTA dopamine neurons fire more bursts during waking and REM sleep, resulting in increased release of dopamine in target areas such as the nucleus accumbens and prefrontal cortex In particular, increased bursting is observed in the presence of rewarding or aversive stimuli requiring an alerting response VTA neurons are excited in vitro by several neuromodulators that promote arousal such as orexins, substance P, and corticotrophin releasing hormone , In contrast, lesions of the serotonergic neurons in this area were without effect on h amounts of sleep and waking.
These data all support a role for these neurons in control of wakefulness, but electrophysiological recordings from these neurons across behavioral state are lacking at present. GABAergic neurons and glutamatergic neurons reviewed below are very abundant and widely distributed in the brain. Hence, it is not surprising that some populations of the neurons utilizing these two neurotransmitters are involved in promoting wakefulness, whereas others are associated with sleep.
Thus, although pharmacological agents potentiating the activity of GABAergic systems have been most closely linked with sleep see sects. Cortically-projecting GABA neurons are located in the BF , , , hypothalamus [colocalized in histamine , and melanin-concentrating hormone neurons 60 ] and in the VTA Hypothalamic melanin-concentrating hormone neurons fire predominantly during sleep and so are unlikely to contribute to wakefulness.
While the activity of histamine neurons is correlated with wakefulness, the function of GABA in histamine neurons is unclear, especially since it would be expected to counteract excitatory actions of histamine on target neurons. GABAergic neurons in the thalamic reticular nucleus play a crucial role in thalamocortical rhythms during sleep and wakefulness see sect. Preliminary studies showed that identified cortically-projecting BF GABA neurons are excited by neurotransmitters promoting cortical activation acetylcholine, norepinephrine, histamine, orexins , likely accounting for their faster firing rate during waking and REM sleep Rostral and caudal PV GABAergic projection neurons synapse onto hippocampal and neocortical PV-positive neurons which control hippocampal and cortical gamma rhythms, respectively see sect.
Other subpopulations of BF GABA neurons that are likely sleep related project to the thalamic reticular nucleus 49 and lateral hypothalamus However, VTA GABA neurons increased their firing prior to intracranial self-stimulation of the medial forebrain bundle, indicating that they may be involved in the attentive processes related to brain reward GABAergic medium spiny neurons in the striatum receive a massive glutamatergic cortical input and control the activity of thalamocortical neurons.
Transitions from NREM sleep to wakefulness convert the firing of striatal neurons from fast cyclic firing, synchronized with cortical field potentials, to an irregular pattern of action potentials triggered by disorganized depolarizing synaptic events of variable amplitude Improved function in minimally conscious patients produced by stimulation of the nonspecific thalamic nuclei may be mediated by increased cortico-striatal-thalamic interplay In addition, the BF , claustrum, amygdala, VTA, laterodorsal tegmentum, and hypothalamus provide minor glutamatergic projections to the cortex.
Vesicular glutamate transporters are expressed in cortically projecting orexin neurons in the perifornical hypothalamus and serotonergic DRN neurons , suggesting that glutamate is a cotransmitter in these neurons. Furthermore, glutamate is the major neurotransmitter released from rostral midbrain brain stem reticular formation neurons projecting to the thalamus.
Dissociative anesthetic agents such as ketamine inhibit glutamatergic NMDA receptors, whereas pharmacological agents that prolong the decay of AMPA receptor currents AMPAkines are proposed to enhance attention and cognition. The thalamus is an important component of the dorsal branch of the ARAS involving the nonspecific thalamic nuclei FIGURE 5 , as well as the specific relay nuclei which convey external sensory information to the cortex.
EEG rhythms typical of wakefulness are sculpted through interactions between the thalamocortical relay neurons, corticothalamic pyramidal neurons, and GABAergic neurons in the thalamic reticular nucleus. At the onset of conscious states i.
In a thalamocortical slice preparation, coincident stimulation of nonspecific thalamic nuclei centrolateral intralaminar nucleus or direct stimulation of layer I together with relay nucleus stimulation induced supralinear summation of the two inputs in cortical output layer V, providing a possible mechanism by which the nonspecific nuclei promote arousal The effector systems used by the neurotransmitter systems involved in generation of wakefulness have been studied by in vitro electrophysiology, pharmacology, and genetic methods see sect.
In addition, effects on other intrinsic membrane currents contribute to the activation of thalamocortical and limbic neurons , Studies involving stimulation of the brain areas and neurotransmitter systems comprising the ARAS consistently report EEG activation and wakefulness as a result.
These studies include both older techniques of electrical stimulation or infusion of pharmacological agents as well as state-of-the-art optogenetic techniques where light-activated ion channels are introduced into the desired neuronal population by genetic engineering techniques 6 , In contrast to the stimulation experiments, studies where localized inactivation of individual neurotransmitter systems or nuclei of the ARAS have been performed summarized in TABLE 1 generally produce relatively minor changes in cortical EEG or the amount of wakefulness in a h period see sect.
II C , with the possible exception of the parabrachial nucleus see sect. There are several possible explanations for this dichotomy between stimulation and inactivation experiments. First, the ARAS systems are strongly interconnected, mutually excitatory to each other FIGURE 6 and converge onto common effector systems at the level of thalamic and cortical neurons , Thus there is considerable redundancy in the system, and inactivation of any individual component of the system is compensated for by the other systems.
This is perhaps not surprising considering the enormous adaptive advantage of wakefulness! A second possibility for the mild effects of loss-of-function experiments is that the systems so far targeted are not absolutely required for wakefulness.
The majority of studies have focused on neuromodulatory systems, whereas selective inactivation of glutamatergic and GABAergic systems projecting to the neocortex have not been tested due to technical difficulties in targeting these systems. The neuromodulatory systems are clearly able to generate cortical activation when stimulated but may only be required for specific aspects of wakefulness. Specific roles for these systems could be 1 facilitation of LVFA acetylcholine ; 2 inhibition of sleep-active neurons norepinephrine, serotonin, acetylcholine; see sect.
III ; 3 maintenance of high muscle tone norepinephrine during waking see sect. IV A ; 4 consolidation of wake periods orexins ; 5 maintenance of waking in a novel environment histamine ; 6 enhanced arousal in the presence of rewarding stimuli dopamine, acetylcholine ; 7 enhanced arousal in the presence of aversive stimuli norepinephrine, serotonin, histamine ; and 8 consolidation of memories through enhancement of synaptic plasticity acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexins.
Methods to selectively stimulate these systems e. This section describes the mechanisms underlying the EEG signs of NREM sleep also called slow-wave sleep and the mechanisms that cause the circadian and homeostatic inhibition of wake-promoting ARAS neurons.
Stage 1 NREM sleep exhibits theta activity at frontal sites and alpha activity posteriorally, similar to drowsy waking sect. The cortical slow oscillation 0. NREM sleep is also characterized by low skeletal muscle tone and slow, rolling eye movements. Here we first describe phasic events occurring during NREM sleep in the thalamocortical system spindles and hippocampal formation sharp wave-ripple complexes and then discuss the delta and slow oscillations typical of deep NREM sleep.
K-complexes represent a combination of one cycle of the neocortical slow oscillation followed by a spindle in thalamocortical neurons 27 , 28 , Although the thalamic reticular nucleus is the generator of spindles, in intact animals spindles are initiated and terminated in concert with delta and slow oscillations in corticothalamic and thalamocortical neurons due to the extensive interconnections of these cells As aminergic inputs are slowly withdrawn during early NREM sleep, long-lasting 50 ms bursts of action potentials are generated in reticular nucleus neurons due to activation of low-threshold T-type calcium channels.
These channels are of the Ca v 3. Bursts at spindle frequencies lead to large and long-lasting inhibitory synaptic potentials IPSPs in thalamocortical neurons which remove the inactivation of T-type Ca v 3. Thus, at the offset of the IPSPs, when the cell becomes more depolarized, the low-threshold calcium channels are activated, calcium enters the cell, resulting in a low-threshold calcium spike crowned by a short 5—15 ms burst of sodium-dependent action potentials in the thalamocortical neurons.
This burst in thalamocortical neurons leads to EPSPs in cortical neurons and to action potentials which together make up the spindle recorded in the EEG. Synchronization of spindles is achieved via recurrent inhibitory and electrical synaptic connections between thalamic reticular neurons Spindles can also be recorded in cortical projection sites such as the basal ganglia , possibly providing a substrate for procedural learning during sleep.
Spindles decline during deep sleep due to the increased hyperpolarization of thalamocortical relay neurons but may reappear just prior to the transition to REM sleep when thalamocortical relay neurons become more depolarized again due to increased ascending brain stem excitation.
In vivo, extracellular and intracellular recording studies revealed that thalamic reticular neurons fire tonically during waking and switch to burst firing during NREM sleep, similar to thalamocortical relay neurons , The mechanism underlying inhibition of spindle activity during REM sleep is less clear but has been proposed to be due to input from REM-on cholinergic neurons which hyperpolarize thalamic reticular neurons via a muscarinic M 2 receptor mediated inhibition of leak potassium conductance , High-frequency — Hz field potentials termed sharp wave-ripple complexes can be recorded in the hippocampus and associated areas during quiet wakefulness and NREM sleep in rodents , , and in humans When released from inhibition, the synchronized firing of CA3 pyramidal neurons leads to a concerted activation of Schaffer-collateral synapses in the CA1 region and subsequently of subicular and downstream retrohippocampal cortical structures Feed-forward and feedback activation of hippocampal GABAergic interneurons leads to a high-frequency oscillation in the membrane potential of pyramidal neurons due to IPSPs, reflected as a high-frequency ripple in the extracellular potential Phase-locked interneurons fire at high frequencies on every cycle of the extracellularly recorded oscillation and entrain the firing of pyramidal neurons, which fire at lower frequencies , Accordingly, ripple frequency is reduced by pharmacological prolongation of GABA A receptor-mediated currents Surprisingly, ripple amplitude and entrainment of pyramidal neurons were increased in mice lacking the GluR1 subunit of AMPA-type glutamatergic receptors specifically on PV-positive interneurons, possibly as a result of developmental compensation Modeling studies suggest that electrical coupling between the axons of pyramidal neurons is required to synchronize their activity In support of this idea, the occurrence of ripples in vitro was reduced in mice lacking one type of gap junction protein connexin 36 , and the intraripple frequency was reduced However, in another report, the occurrence of in vitro kainate-induced sharp waves was actually increased in these mice Delta oscillations are best understood at the thalamic level.
Recordings in vivo from thalamocortical neurons revealed that stereotyped high-frequency bursts of action potentials occur at delta frequencies interspersed with silent periods 25 , , , , , a pattern which can be abolished by brain stem cholinergic stimulation or by increases in ambient light 25 , , The ability of thalamocortical neurons to generate burst firing in the delta frequency range is due to their intrinsic membrane properties , , , , Hyperpolarization resulting from the activation of calcium-dependent potassium conductances after a burst of action potentials or from inhibitory synaptic inputs leads to the opening of hyperpolarization-activated, cAMP-modulated cation HCN channels causing the so-called H-current I h.
This slowly activating current provides a depolarizing drive towards the threshold for action potentials and is a major contributor to the duration of the interburst interval , I h is modulated during waking by activation of neurotransmitter receptors coupled to stimulation of cAMP e.
As well as activating I h , hyperpolarizations result in deinactivation of low-threshold calcium channels, allowing their subsequent activation once the membrane potential reaches less negative potentials Opening of these calcium channels leads to a low-threshold spike LTS and a burst of action potentials — Bursts of action potentials in thalamocortical neurons lead to a prominent burst in large numbers of cortical pyramidal neurons. Bursting of corticothalamic neurons potentiates intrinsic rhythms in thalamocortical neurons and entrains their firing through excitation of thalamic reticular neurons leading to rhythmic hyperpolarizations in thalamocortical neurons, creating increased network synchronization 25 , Calcium influx through the low-threshold channels allows activation of calcium-dependent potassium conductances, restarting the cycle.
Ascending influences during waking or REM sleep block this cycle by acting on PLC-coupled receptors that block a leak potassium conductance causing inactivation of the low-threshold calcium channels and bringing the membrane potential out of the range of the H-current , Low-threshold bursts in thalamocortical neurons were abolished in mice constitutively lacking the Ca v 3. Delta waves were abolished in these mice with knockouts in the whole brain or thalamus, whereas deletions of Ca v 3.
Loss of delta waves was associated with fragmented sleep with a higher incidence of brief arousals. Similar to thalamocortical neurons, bursting in thalamic reticular neurons is regulated by calcium dynamics involving low-threshold calcium channels, endoplasmic reticulum calcium ATPases which sequester intracellular calcium, and small-conductance calcium-dependent potassium SK channels Like Ca v 3.
This phenomenon, discovered by Steriade in anesthetized cats , was subsequently observed in naturally sleeping animals 28 , , and in humans 27 , Somewhat confusingly, despite its name, the so-called slow oscillation does not necessarily imply rhythmicity.
High-density EEG recordings in humans revealed that each cycle of the slow oscillation represents a traveling wave originating most frequently in prefrontal-orbitofrontal regions and propagating towards more posterior cortical areas Slow-wave activity SWA; 0. Periods of sleep deprivation cause increases of SWA in the subsequent sleep period in both animals and in humans.
SWA is highest at the beginning of the sleep period and progressively decreases during sleep. Naps during the day also reduce SWA in the subsequent night The slow oscillation is generated within the cortex since it is abolished in thalamic neurons following removal of the cortex , and it persists following disconnection of subcortical inputs and can occur in vitro in cortical slices, following manipulation of the ionic milieu bathing the slices , However, in intact animals, the slow oscillation strongly influences the activity of the thalamus through corticothalamic projections and conversely the thalamus influences the cortex through thalamocortical projections , , , Intracellular recordings from cortical neurons in vivo , and in vitro revealed that the slow oscillation consists of prolonged depolarizations associated with extracellular gamma frequency activity UP states separated by prolonged hyperpolarizations DOWN states when most cortical neurons are silent , These states are well-synchronized over widespread areas of cortex Consistent with this idea, the frequency and amplitude of miniature excitatory postsynaptic currents in pyramidal neurons of frontal cortex was enhanced following waking and decreased following sleep The hyperpolarizing phase is due to withdrawal of excitatory input.
Many of the sleep-active neurons in the medial and lateral preoptic area are also temperature sensitive, likely explaining the coupling of body temperature and sleep In the BF, caudally projecting, possibly sleep-active, GABA neurons are intermingled with cortically projecting cholinergic, GABAergic, and glutamatergic neurons which increase firing in association with cortical activation With the use of Fos immunohistochemistry to identify neurons that had been recently active, a cluster of sleep-active neurons was identified in the ventrolateral preoptic nucleus VLPO FIGURE 2 of the rat These neurons contained the inhibitory neurotransmitters GABA and galanin and projected heavily to nuclei of the ARAS, especially the histaminergic tuberomammillary nucleus , , , Single-unit recordings targeting this area confirmed that it contains sleep-active neurons Extensive neurotoxic lesions of the central cluster of the VLPO in the rat led to a large decrease in delta power and NREM sleep time and a fragmentation of the sleep-wake cycle , effects which persisted for at least 3 wk postlesion.
All of these were inhibited by norepinephrine and acetylcholine, and the majority were also inhibited by serotonin 5-HT 1A Initial experiments suggested that histamine and orexin did not affect the firing rate of VLPO neurons, but more recent experiments have revealed an indirect histaminergic inhibition due to excitation of local inhibitory interneurons Retrograde tracing revealed surprisingly few cholinergic projections to VLPO but prominent projections from the histaminergic tuberomammillary nucleus, norepinephrine neurons in the LC and ventrolateral medulla, and serotonergic neurons in the dorsal median and central linear raphe nuclei Interestingly, VLPO neurons also receive direct inputs from the retina and indirect projections from the suprachiasmatic nucleus via the dorsomedial hypothalamus , , , one pathway by which light exposure could affect sleep.
In vitro studies also revealed that VLPO neurons are excited by adenosine through an indirect mechanism: A 1 receptor-mediated presynaptic inhibition of inhibitory synaptic inputs , In addition, activation of adenosine A 2a receptors by infusion of an A 2a agonist in the subarachnoid space underlying the VLPO area increases the activity of VLPO neurons in vivo On the other hand, high-frequency electrical stimulation or perfusion with glutamate or the GABA A receptor antagonist bicuculline enhanced NREM sleep and inhibited the activity of wake-active neurons in the perifornical hypothalamus Experiments comparing the extent of Fos during spontaneous sleep, sleep deprivation, and recovery from sleep deprivation suggest that MnPO neurons are active during sleep deprivation, whereas VLPO neurons are mainly active during sleep , , Thus MnPO neurons increase their activity in response to increased homeostatic sleep pressure, whereas VLPO neurons may function to consolidate and maintain sleep and regulate sleep depth Von Economo was the first to propose the existence of an anterior hypothalamic sleep-promoting area and a posterior hypothalamic waking center.
More recent anatomical tracing experiments revealed that neurons in the core of the VLPO project heavily to wake-promoting histamine neurons in the tuberomammillary nucleus TMN of the posterior hypothalamus and also to wake-promoting serotonin DRN neurons and norepinephrine LC neurons in the brain stem A crucial aspect of this model is that the two halves of the switch, by strongly inhibiting each other, create a feedback loop that is stable in only two states such that intermediate states of sleep and wakefulness are very brief.
A further component to the model was the proposal that orexins stabilize behavioral state via their strong excitatory actions on wake-promoting neurons. Analysis of orexin knockout mice revealed that they have many more transitions between wake, NREM, and REM states than do wild-type mice, supporting this model Although intuitively appealing, this model has a few weaknesses.
First, the model does not well represent the changes in firing of all the neuronal subpopulations involved. While sleep-active preoptic neurons have fast transitions around state-transitions , the firing rate of wake-active BF neurons changes more slowly and thus more closely resembles a latch than a switch.
Second, the mechanism responsible for turning the switch on and off is unclear since a switch remains in one state unless a third mechanism causes a transition. Possible candidates for facilitators of the wake-sleep transition are sleep homeostatic factors that slowly build up during wakefulness and are discussed in the following section.
Transitions between wake and sleep are due to mutual inhibition between these sleep- and wake-related nuclei. Adapted from Saper et al. Nature —, , with permission from MacMillan Publishers Ltd. Homeostatic control of sleep refers to the increased propensity for sleep during prolonged waking and the prolonged sleep time and depth of sleep reflected as increased EEG slow wave activity following a period of sleep deprivation , Sleep homeostasis is considered to reflect the accumulation of sleep homeostatic factors during waking, particularly in the BF and cortex, in a manner related to brain energy usage see sect.
III D. Sleep homeostatic factors inhibit the activity of ARAS neurons as well as cortical neurons and thereby facilitate the slow oscillations typical of NREM sleep. The search for sleep-promoting factors dates back years when Ishimori and Legendre and Pieron reported that injection of CSF from a sleep-deprived dog into the cisterna magna of a normal animal induced sleep.
Later in , Pappenheimer et al. These pioneering studies suggested that endogenous humoral factors are induced and accumulate during waking and generate a homeostatic sleep response. This led to a series of investigations in search of humoral sleep-promoting substances , leading to the identification of several substances including 1 delta sleep inducing peptide ; 2 uridine ; 3 oxidized glutathione, originally designated as SPS-B ; 4 muramyl dipeptide N -acetylmuramyl- l -alanyl- d -isoglutamine , originally described as Factor S ; and 5 prostaglandin D 2 In the following years, a variety of additional endogenous sleep-inducing substances were identified including peptides, growth factors, and cytokines as well as neuromodulators such as adenosine and NO.
Homeostatic sleep factors should fulfill the following criteria: 1 administration of the substance induces sleep; 2 the levels of the substance in the brain should increase with increasing sleep propensity; and 3 the substance should act on brain regions and neurons involved in the regulation of sleep or wakefulness. Recent studies have focused extensively on the role of adenosine, nitric oxide, prostaglandin D 2 , and cytokines in sleep regulation and the following sections will review the latest research on these factors.
The neuromodulator adenosine links energy metabolism, neuronal activity, and sleep 79 , 91 , , The hypnogenic effects of adenosine were first described in cats by Feldberg and Sherwood and later in dogs by Haulica et al. Systemic and central administrations of adenosine or adenosine A 1 receptor agonists induced sleepiness and impaired vigilance 91 , , , , , , by inhibition of wake-active neurons. Adenosine A 2A receptors are also implicated in mediating the somnogenic effects of adenosine by excitation of sleep active neurons , , Stimulants such as caffeine and theophylline counteract the sleep-inducing effects of adenosine by serving as antagonists at both A 1 and A 2A adenosine receptors , Adenosine levels correlate with time spent awake.
Endogenous, extracellular adenosine levels in the BF , , , , and cortex , increase in proportion with time spent awake FIGURE 8. Thus adenosine induces sleep and adenosine levels track sleep need, fulfilling the criteria for adenosine being a homeostatic sleep factor. Measurements of extracellular adenosine levels across the sleep-wake cycle and in response to sleep deprivation revealed that adenosine levels rise only in select regions of the brain , In particular, adenosine levels correlate with time awake in the region of the caudal BF containing cortically projecting wake-active neurons, and in the cortex itself.
In contrast, adenosine levels did not follow this pattern in other brain areas such as the preoptic area of the hypothalamus, ventral thalamus, DRN, or pedunculopontine tegmentum. BF adenosine levels also rise when rats are exposed to a sleep fragmentation protocol , possibly explaining excessive daytime sleepiness in sleep disorders where sleep is fragmented see sect. Investigations of the role of adenosine AD as a neuromodulatory sleep factor.
A : extracellular AD concentrations in the feline basal forebrain BF for min consecutive samples from an individual animal, showing elevated levels during wakefulness. Reprinted with permission from AAAS. AD levels are significantly elevated by hour 2 of SD and remain elevated until recovery sleep, when levels fall towards baseline levels.
Levels are normalized to baseline levels in the 2 h preceding SD. This signaling cascade appears to be confined to cholinergic neurons of BF. Adapted from Basheer et al. Neuroscience —, , with permission from Elsevier. I Mechanisms underlying adenosine increases during wakefulness.
Increased levels of extracellular adenosine during prolonged wakefulness are caused by interactions between neuronal and glial mechanisms. Glutamatergic stimulation of the BF elevates extracellular adenosine and increases sleep Selective activation of glutamatergic NMDA receptors on hippocampal pyramidal or on brain stem cholinergic neurons also leads to slow adenosine release and inhibition of neuronal activity. In the BF, cell-specific lesion of cholinergic neurons attenuates the sleep deprivation-induced increase of adenosine , , suggesting either that increases in extracellular adenosine are derived from these neurons or that they release an essential signal for extracellular adenosine accumulation.
Such a signal may be NO see next section. In turn, breakdown of the extracellular ATP released by glia yields adenosine, which depresses neuronal activity , Blockade of vesicular release via transgenic expression of a dominant-negative SNARE domain specifically in astrocytes dn-SNARE mice blocked the accumulation of homeostatic sleep pressure following sleep deprivation as reflected by slow-wave activity and prevented the sleep-suppressing effects of an adenosine A 1 receptor antagonist , , suggesting that blocking gliotransmission affected sleep by reducing the accumulation of extracellular adenosine.
Electrophysiological, behavioral, and molecular evidence suggest that in wake-active areas, the effects of adenosine are primarily mediated via A 1 receptors. A weaker postsynaptic inhibitory effect mediated via an A 1 receptor-mediated shift of the activation threshold of the hyperpolarization-activated current I h is observed in thalamic relay neurons and BF noncholinergic neurons Adenosine further dampens neuronal activity and promotes sleep via presynaptic inhibitory effects on excitatory glutamatergic inputs to cortical glutamatergic neurons and wake-active cholinergic 48 , , , and orexin neurons, as well as on inhibitory GABAergic inputs to sleep-active VLPO neurons , Infusion of A 1 receptor agonists in the BF, laterodorsal tegmentum, lateral hypothalamus, and prefrontal cortex increases sleep, whereas infusion of A 1 receptor antagonists in the same areas increases waking 14 , , , , , Although adenosine A 1 receptors have effects in multiple regions of the brain controlling sleep-wakefulness, as mentioned above, to date adenosine levels have only been shown to increase with prolonged wakefulness in the BF and neocortex.
Consistent with the BF being a crucial site mediating adenosine effects, local perfusion of an A 1 receptor antagonist in this region activated wake-active neurons 17 , , and localized suppression of A 1 receptor expression using antisense oligonucleotides significantly reduced spontaneous sleep time as well as the homeostatic sleep response In contrast, adenosine A 1 receptor blockade in the lateral hypothalamus did not block the homeostatic sleep response While sleep homeostasis was intact in constitutive A 1 receptor knockout mice , conditional deletion of A 1 receptor in forebrain and brain stem after 6—8 wk of age, circumventing developmental compensation, not only resulted in a decreased homeostatic sleep response after sleep restriction but also led to a failure in working memory consolidation sect.
Prolonged sleep deprivation upregulates A 1 receptor mRNA and protein in BF and cortex in both rats and humans 74 , 76 , , Upregulation of adenosine receptors provides an additional level of homeostatic control beyond rises in extracellular adenosine levels. Increased stimulation of the A 1 receptor during sleep deprivation activates the PLC pathway, mobilizing intracellular calcium which in turn activates the transcription factor NF-kB and upregulates A 1 receptor expression 73 , What is the involvement of the adenosine A 2A receptor in the homeostatic sleep response of adenosine?
A 2A receptors are coupled to the stimulatory G s subunit and activate adenylyl cyclase. In contrast to the A 1 receptor with its wide distribution in brain, the distribution of A 2A receptor is more restricted to basal ganglia structures such as striatum, nucleus accumbens, and olfactory tubercle with much lower abundance in other areas such as the hippocampus, neocortex, BF, and other sleep-wake regulatory structures
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Superpower Wiki Explore. New Blogs User-Made Powers. Explore Wikis Community Central. Register Don't have an account? Sleep Manipulation. History Talk 0. Pow Canimals can use his optic hypnotic rays to make a canimal ether knocked out or asleep. As the Ghost of Sleep and Dreams, Nocturn Danny Phantom has complete control over a person's cognitive and subconscious awareness. According to a recent sleep disruption and insomnia review study,  there are short-term and long-term negative consequences on healthy individuals.
The short term consequences include increased stress responsivity and psychosocial issues such as impaired cognitive or academic performance and depression. Experiments indicated that, in healthy children and adults, episodes of fragmented sleep or insomnia increased sympathetic activation, which can disrupt mood and cognition. The long term consequences include metabolic issues such as glucose homeostasis disruption and even tumor formation and increased risks of cancer.
The "Preservation and Protection" theory holds that sleep serves an adaptive function. It protects the animal during that portion of the hour day in which being awake, and hence roaming around, would place the individual at greatest risk. From this perspective of adaptation, organisms are safer by staying out of harm's way, where potentially they could be prey to other, stronger organisms.
They sleep at times that maximize their safety, given their physical capacities and their habitats. This theory fails to explain why the brain disengages from the external environment during normal sleep. However, the brain consumes a large proportion of the body's energy at any one time and preservation of energy could only occur by limiting its sensory inputs.
Another argument against the theory is that sleep is not simply a passive consequence of removing the animal from the environment, but is a "drive"; animals alter their behaviors in order to obtain sleep. Therefore, circadian regulation is more than sufficient to explain periods of activity and quiescence that are adaptive to an organism, but the more peculiar specializations of sleep probably serve different and unknown functions.
Moreover, the preservation theory needs to explain why carnivores like lions, which are on top of the food chain and thus have little to fear, sleep the most. It has been suggested that they need to minimize energy expenditure when not hunting. During sleep, metabolic waste products, such as immunoglobulins , protein fragments or intact proteins like beta-amyloid , may be cleared from the interstitium via a glymphatic system of lymph -like channels coursing along perivascular spaces and the astrocyte network of the brain.
Wound healing has been shown to be affected by sleep. It has been shown that sleep deprivation affects the immune system. The effect of sleep duration on somatic growth is not completely known. One study recorded growth, height, and weight, as correlated to parent-reported time in bed in children over a period of nine years age 1— It was found that "the variation of sleep duration among children does not seem to have an effect on growth.
There is some supporting evidence of the restorative function of sleep. The sleeping brain has been shown to remove metabolic waste products at a faster rate than during an awake state. In sleep, metabolic rates decrease and reactive oxygen species generation is reduced allowing restorative processes to take over.
It is theorized that sleep helps facilitate the synthesis of molecules that help repair and protect the brain from these harmful elements generated during waking. Energy conservation could as well have been accomplished by resting quiescent without shutting off the organism from the environment, potentially a dangerous situation. A sedentary nonsleeping animal is more likely to survive predators, while still preserving energy.
Sleep, therefore, seems to serve another purpose, or other purposes, than simply conserving energy. Another potential purpose for sleep could be to restore signal strength in synapses that are activated while awake to a "baseline" level, weakening unnecessary connections that to better facilitate learning and memory functions again the next day; this means the brain is forgetting some of the things we learn each day.
The secretion of many hormones is affected by sleep-wake cycles. For example, melatonin , a hormonal timekeeper, is considered a strongly circadian hormone, whose secretion increases at dim light and peaks during nocturnal sleep, diminishing with bright light to the eyes. Of course, in humans as well as other animals, such a hormone may facilitate coordination of sleep onset. Similarly, cortisol and thyroid stimulating hormone TSH are strongly circadian and diurnal hormones, mostly independent of sleep.
In some hormones whose secretion is controlled by light level, sleep seems to increase secretion. Almost in all cases, sleep deprivation has detrimental effects. For example, cortisol, which is essential for metabolism it is so important that animals can die within a week of its deficiency and affects the ability to withstand noxious stimuli, is increased by waking and during REM sleep.
This could explain some of the early theories of sleep function that predicted that sleep has a metabolic regulation role. Regarding to declarative memory, the functional role of SWS has been associated with hippocampal replays of previously encoded neural patterns that seem to facilitate long-term memories consolidation. Reactivation of memory also occurs during wakefulness and its function is associated with serving to update the reactivated memory with new encoded information, whereas reactivations during SWS are presented as crucial for memory stabilization.
Furthermore, nocturnal reactivation seems to share the same neural oscillatory patterns as reactivation during wakefulness, processes which might be coordinated by theta activity. Other studies have been also looking at the specific effects of different stages of sleep on different types of memory. For example, it has been found that sleep deprivation does not significantly affect recognition of faces, but can produce a significant impairment of temporal memory discriminating which face belonged to which set shown.
Sleep deprivation was also found to increase beliefs of being correct, especially if they were wrong. Another study reported that the performance on free recall of a list of nouns is significantly worse when sleep deprived an average of 2. These results reinforce the role of sleep on declarative memory formation.
This has been further confirmed by observations of low metabolic activity in the prefrontal cortex and temporal and parietal lobes for the temporal learning and verbal learning tasks respectively. Data analysis has also shown that the neural assemblies during SWS correlated significantly more with templates than during waking hours or REM sleep.
Also, post-learning, post-SWS reverberations lasted 48 hours, much longer than the duration of novel object learning 1 hour , indicating long term potentiation. Moreover, observations include the importance of napping : improved performance in some kinds of tasks after a 1-hour afternoon nap; studies of performance of shift workers, showing that an equal number of hours of sleep in the day is not the same as in the night.
Current research studies look at the molecular and physiological basis of memory consolidation during sleep. These, along with studies of genes that may play a role in this phenomenon, together promise to give a more complete picture of the role of sleep in memory. Sleep can also serve to weaken synaptic connections that were acquired over the course of the day but which are not essential to optimal functioning.
In doing so, the resource demands can be lessened, since the upkeep and strengthening of synaptic connections constitutes a large portion of energy consumption by the brain and tax other cellular mechanisms such as protein synthesis for new channels. One approach to understanding the role of sleep is to study the deprivation of it. This makes understanding the effects of sleep deprivation very important. Many studies have been done from the early s to document the effect of sleep deprivation.
Dement around He conducted a sleep and dream research project on eight subjects, all male. For a span of up to 7 days, he deprived the participants of REM sleep by waking them each time they started to enter the stage. He monitored this with small electrodes attached to their scalp and temples. As the study went on, he noticed that the more he deprived the men of REM sleep, the more often he had to wake them.
The neurobehavioral basis for these has been studied only recently. Sleep deprivation has been strongly correlated with increased probability of accidents and industrial errors. Sleep deprivation has been shown to have a detrimental effect on cognitive tasks, especially involving divergent functions or multitasking.
The exact mechanisms for the above are still unknown and the exact neural pathways and cellular mechanisms of sleep debt are still being researched. A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal.
Polysomnography is a test commonly used for diagnosing some sleep disorders. Sleep disorders are broadly classified into dyssomnias , parasomnias , circadian rhythm sleep disorders CRSD , and other disorders including ones caused by medical or psychological conditions and sleeping sickness.
Some common sleep disorders include insomnia chronic inability to sleep , sleep apnea abnormally low breathing during sleep , narcolepsy excessive sleepiness at inappropriate times , cataplexy sudden and transient loss of muscle tone , and sleeping sickness disruption of sleep cycle due to infection.
Other disorders that are being studied include sleepwalking , sleep terror and bed wetting. Studying sleep disorders is particularly useful as it gives some clues as to which parts of the brain may be involved in the modified function. This is done by comparing the imaging and histological patterns in normal and affected subjects. Treatment of sleep disorders typically involves behavioral and psychotherapeutic methods though other techniques may also be used.
The choice of treatment methodology for a specific patient depends on the patient's diagnosis, medical and psychiatric history, and preferences, as well as the expertise of the treating clinician. Often, behavioral or psychotherapeutic and pharmacological approaches are compatible and can effectively be combined to maximize therapeutic benefits. Frequently, sleep disorders have been also associated with neurodegenerative diseases, mainly when they are characterized by abnormal accumulation of alpha-synuclein , such as multiple system atrophy MSA , Parkinson's disease PD and Lewy body disease LBD.
SWS is potentially decreased sometimes totally absent , spindles and the time spent in REM sleep are also reduced, while its latency is increased. The neurodegenerative conditions are commonly related to brain structures impairments, which might disrupt the states of sleep and wakefulness, circadian rhythm, motor or non motor functioning. A related field is that of sleep medicine which involves the diagnosis and therapy of sleep disorders and sleep deprivation, which is a major cause of accidents.
This involves a variety of diagnostic methods including polysomnography, sleep diary , multiple sleep latency test , etc. Similarly, treatment may be behavioral such as cognitive behavioral therapy or may include pharmacological medication or bright light therapy. Dreams are successions of images, ideas, emotions, and sensations that occur involuntarily in the mind during certain stages of sleep mainly the REM stage.
The content and purpose of dreams are not yet clearly understood though various theories have been proposed. The scientific study of dreams is called oneirology. There are many theories about the neurological basis of dreaming. This includes the activation synthesis theory —the theory that dreams result from brain stem activation during REM sleep; the continual activation theory—the theory that dreaming is a result of activation and synthesis but dreams and REM sleep are controlled by different structures in the brain; and dreams as excitations of long term memory—a theory which claims that long term memory excitations are prevalent during waking hours as well but are usually controlled and become apparent only during sleep.
There are multiple theories about dream function as well. Some studies claim that dreams strengthen semantic memories. This is based on the role of hippocampal neocortical dialog and general connections between sleep and memory.
One study surmises that dreams erase junk data in the brain. Emotional adaptation and mood regulation are other proposed functions of dreaming. From an evolutionary standpoint, dreams might simulate and rehearse threatening events, that were common in the organism's ancestral environment, hence increasing a persons ability to tackle everyday problems and challenges in the present.
For this reason these threatening events may have been passed on in the form of genetic memories. Most theories of dream function appear to be conflicting, but it is possible that many short-term dream functions could act together to achieve a bigger long-term function. The incorporation of waking memory events into dreams is another area of active research and some researchers have tried to link it to the declarative memory consolidation functions of dreaming.
A related area of research is the neuroscience basis of nightmares. Many studies have confirmed a high prevalence of nightmares and some have correlated them with high stress levels. From Wikipedia, the free encyclopedia. Study of the neuroscientific and physiological basis of the nature of sleep. See also: Sleep. Main article: Sleep cycle. See also: Sleep non-human. EEG waveforms of brain activity during sleep.
Main article: Slow-wave sleep. Main article: Rapid eye movement sleep. Main article: Sleep onset. Main article: Sleep and memory. Main article: Sleep disorder. Main article: Dream. Archived from the original on Brain Research. PMID S2CID The Neuroscience of Sleep. ISBN Retrieved 18 July The New Yorker. Retrieved 17 July The Harvard sleep researcher Robert Stickgold has recalled his former collaborator J. Allan Hobson joking that the only known function of sleep is to cure sleepiness.
The Journal of Neuroscience. PMC Alan Hobson, Edward F. Trends in Neurosciences. The American Journal of Psychiatry. Sleep : a scientific perspective. Englewood Cliffs, N. The encyclopedia of sleep and sleep disorders 2nd ed. New York: Facts on File. Bibcode : PNAS.. Annals of the New York Academy of Sciences. The New England Journal of Medicine.
Sleep Medicine Reviews. Electroencephalography and Clinical Neurophysiology. Psychosomatic Medicine. Journal of Clinical Neurophysiology. Journal of Neurophysiology. European Neurology. Barton, and C. Cambridge University Press, Cambridge. Functional Ecology. BMC Ecology. Capellini, P. McNamara, R. Parasite resistance and the adaptive significance of sleep. Bmc Evolutionary Biology 9. Waking and sleep". Archives Italiennes de Biologie.
Neuroscience Letters. Behavioural Brain Research. Journal of Sleep Research. Bibcode : Sci Psychology Today On-line blog. The Journal of Pediatrics. Early Human Development. Child Development. Walker, M. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Journal of the Neurological Sciences. Current Sleep Medicine Reports.
A chronobiological disorder with sleep-onset insomnia". Archives of General Psychiatry. Neuroscience and Biobehavioral Reviews. Hormone Research. Brain Research Bulletin. Scientific Reports. Bibcode : NatSR.. Westchester: American Academy of Sleep Medicine.
Psychology World. Retrieved 15 June Journal of Clinical Sleep Medicine. July Sleep and anesthesia : neural correlates in theory and experiment. New York: Springer. Cerebral Cortex. Journal of Biological Rhythms. Worth Publishers. Journal of Physiological Anthropology.
Retrieved 22 August Journal of Neurochemistry. Bibcode : Natur. Archived from the original PDF on Retrieved Encarta Encyclopedia. Archived from the original on 14 December Retrieved 25 January Nature Neuroscience. Sleep Medicine. Frontiers in Neurology. The Neural Control of Sleep and Waking. Human Neurobiology. Mallick; et al. Rapid eye movement sleep : regulation and function.
Annual Review of Neuroscience. Evidence of the role of the thalamus in sleep regulation". A clinico-pathological study in fatal familial thalamic degeneration". Part 1". Anaesthesiology Intensive Therapy. The ascending reticular activating system ARAS is responsible for a sustained wakefulness state.
It receives information from sensory receptors of various modalities, transmitted through spinoreticular pathways and cranial nerves trigeminal nerve — polymodal pathways, olfactory nerve, optic nerve and vestibulocochlear nerve — monomodal pathways. These pathways reach the thalamus directly or indirectly via the medial column of reticular formation nuclei magnocellular nuclei and reticular nuclei of pontine tegmentum.
The reticular activating system begins in the dorsal part of the posterior midbrain and anterior pons, continues into the diencephalon, and then divides into two parts reaching the thalamus and hypothalamus, which then project into the cerebral cortex Fig.
The thalamic projection is dominated by cholinergic neurons originating from the pedunculopontine tegmental nucleus of pons and midbrain PPT and laterodorsal tegmental nucleus of pons and midbrain LDT nuclei [17, 18]. The hypothalamic projection involves noradrenergic neurons of the locus coeruleus LC and serotoninergic neurons of the dorsal and median raphe nuclei DR , which pass through the lateral hypothalamus and reach axons of the histaminergic tubero-mamillary nucleus TMN , together forming a pathway extending into the forebrain, cortex and hippocampus.
Cortical arousal also takes advantage of dopaminergic neurons of the substantia nigra SN , ventral tegmenti area VTA and the periaqueductal grey area PAG. Fewer cholinergic neurons of the pons and midbrain send projections to the forebrain along the ventral pathway, bypassing the thalamus [19, 20]. The RAS is a complex structure consisting of several different circuits including the four monoaminergic pathways The norepinephrine pathway originates from the locus ceruleus LC and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area VTA ; and the histaminergic pathway originates from neurons in the tuberomammillary nucleus TMN of the posterior hypothalamus.
As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. Journal of Molecular Neuroscience. Understanding of arousing and wakefulness-maintaining functions of the ARAS has been further complicated by neurochemical discoveries of numerous groups of neurons with the ascending pathways originating within the brainstem reticular core, including pontomesencephalic nuclei, which synthesize different transmitters and release them in vast areas of the brain and in the entire neocortex for review, see Jones ; Lin et al.
They included glutamatergic, cholinergic, noradrenergic, dopaminergic, serotonergic, histaminergic, and orexinergic systems for review, see Lin et al. The ARAS represented diffuse, nonspecific pathways that, working through the midline and intralaminar thalamic nuclei, could change activity of the entire neocortex, and thus, this system was suggested initially as a general arousal system to natural stimuli and the critical system underlying wakefulness Moruzzi and Magoun ; Lindsley et al.
It was found in a recent study in the rat that the state of wakefulness is mostly maintained by the ascending glutamatergic projection from the parabrachial nucleus and precoeruleus regions to the basal forebrain and then relayed to the cerebral cortex Fuller et al.
Anatomical studies have shown two main pathways involved in arousal and originating from the areas with cholinergic cell groups, one through the thalamus and the other, traveling ventrally through the hypothalamus and preoptic area, and reciprocally connected with the limbic system Nauta and Kuypers ; Siegel As counted in the cholinergic connections to the thalamic reticular nucleus The Psychiatric Clinics of North America. More recently, the medullary parafacial zone PZ adjacent to the facial nerve was identified as a sleep-promoting center on the basis of anatomical, electrophysiological and chemo- and optogenetic studies.
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