|Cortical arousal governed by different types of neurotransmitters is known to be associated with wakefulness. (Stahl S.M. New Delhi: Cambridge University Press; 2007. Essential Psychopharmacology: Neuroscientific basis and practical applications) [].|
The neurochemical mechanism behind the regulation of sleep and wake cycle has been a complex enigma. It is evident that there are numerous wide projections of neurons releasing different types of neurotransmitters and neuropeptides to regulate this intricate phenomenon of sleep in the brain. Inceased attention to discover potential treatments of sleep disorders, such as insomnia, and daytime sleeping or narcolepsy, has been led to extensive researches that have focused on neurobiology of sleep and wakefulness. Although there has been extensive researches that have focused on the brain transitions between a sleeping and a waking state through regulations of neurotransmitters, there is no one universal model of sleep circuit governing the sleep and wakefulness. It now seems that the neurochemistry behind the sleep/wake cycle is based on mosaic of numerous pieces of hypotheses. The current theory describes that there are distinct differences in the active brain processing and the specific neurochemical systems involved in the two states; according to Saper and his colleagues , the neural circuits that regulate sleep and wakefulness are distinct for each state, but is also interdependent. The arousal systems and sleep-promoting systems are mutually inhibited by mutually turning off each other's circuitry.
Table of Contents
1. Overview of cortical arousal and sleep
Cortical arousal is governed by several ascending neuronal projections from the many areas in the upper brain stem; one pathway innervates the thalamus, and the other one projects into the posterior hypothalamus and forebrain . Key neurons of the ascending arousal pathway include cholinergic neurons that are located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), serotoninergic neurons in the dorsal raphe nucleus, noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the median raphe nucleus, and histaminergic neurons in the tuberomammillary nucleus of the hypothalamus . These neurons fire in a distinct pattern to promote alertness and cortical arousal through wide neuronal projections in the brain. Nevertheless, this arousal system is inhibited during sleep by GABA neurons from the ventrolateral preoptic nucleus (VLPO) of the hypothalamus every 24 hours . The mutually antagonistic interaction between the VLPO and the ascending arousal pathway maintains a stable sleep and wakefulness cycle. On the other hand, sleep disorders, such as insomnia, are exemplary model which depicts a disruption or malfunction of this sleep/wake switch .
|Figure 1: Forebrain activation|
|The main forebrain activating system associated with cortical arousal or wakefulness is shown in this schematic of a sagittal section of a rodent brain. Excitatory circuits are shown in red while inhibitory systems are shown in green. (Jones (2005)) |
2. Ascending reticular activating system
The ascending reticular activating system was discovered by Moruzzi, Magoun, and their colleagues in 1949 . They found out that alertness is maintained by a group of neurons that are divided into two distinct branches; both of them are originating from the upper brainstem . Cholinergic neurons, and other monoaminergic neurons such as noradnergic neurons, serotonergic neurons dopaminergic neurons, histerminergic neurons, and lastly peptidergic neurons such as orexin/hypocretin nuclei of the lateral hypothalamus of the ascending arousal system fire in very organized fashion to promote cortical arousal and sustain wakefulness. On the other hand, during sleep these circuits are blocked by neurons of the ventrolateral preoptic nucleus (VLPO) of the hypothalamus.
As it is evident from the numbers of findings above, the ascending reticular activating system is governed by different types of neurotransmitters: acetylcholine, norepinephrine, serotonin, and dopamine. Their background information and roles in sleep/wake regulation will be delineated in the below sections. Neuromodulators, such as orexin/hypocretin and histamine which are released from different nuclei in the hypothalamus, will be portrayed in the “sleep/wake switch section” below.
As a part of ascending activating system, cholinergic system originates from the brainstem and basal forebrain, and it projects to wide areas in the cortical regions. In the brainstem, cholinergic projection originates from the pedunculopontine nucleus and laterodorsal tegmental nucleus, which are known as PPT/LDT. This projection from PPT/LDT acts on M1 receptors (muscarinic receptors) in wide regions in the brain :deep cerebellar nuclei, pontine nuclei, lateral reticular nucleus, inferior olive, locus ceruleus, thalamus, tectum, basal ganglia, and basal forebrain . Another cholinergic projection originates from the basal optic nucleus of Meynert and medial septal nucleus. Projection from basal optic nucleus of Meynert also acts on M1 receptors in the neocortex, and projection from medial septal nucleus not only acts on M1 receptors in the neocortex, but also on M1 receptors in the hippocampus . All these acetylcholine projections are known to regulate cortical arousal and attention. Peever et al  demonstrated that acetylcholine release is highly lateralized during asymmetrical slow-wave sleep while serotonin release is symmetrical; this finding leads to the evidence that there are differences in wide projection sites of acetylcholine and serotonin neurons.
|Figure 2.1.1: Ascending cholinergic projections|
|This diagram exposes two cholinergic systems which regulate the state of wakefulness. The green pathway shows cholinergic neurons in the brainstem, while the red pathway is in the forebrain. The brainstem arousal center supplies the acetylcholine for the thalamus and brainstem, and the forebrain center supplies the cerebral cortex. Norepinephrine, serotonin, and histamine neurons that are involved for wakefulness are shown in the blue pathways .|
|Figure 2.1: Ascending reticular activating pathway|
|This schematic diagram of ascending reticular activating pathway shows key neuronal projections that maintain alertness. The cholinergic pathway (yellow) originates from cholinergic (ACh) neurons in the upper pons, the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). The second pathway (red) innervates the cerebral cortex and this pathway originates from neurons in the monoaminergic cell groups, including the tuberomammillary nucleus (TMN) which contain histamine (His), the ventral periaqueductal gray matter (vPAG) which contains dopamine (DA), the dorsal and median raphe nuclei which contain serotonin (5-HT), and the locus coeruleus (LC) neurons which contain noradrenaline (NA). This pathway also receives modulations from neuropeptidergic neurons in the lateral hypothalamus (LHA) which contain hypocretin/orexin (ORX) or melanin-concentrating hormone (MCH), and from basal forebrain (BF) neurons that contain GABA or ACh. (Saper et al (2005))|
Only 10% of total serotonin in humans is synthesized in the serotonergic neurons in the CNS, while the rest 90% is made in the enterochromaffin cells for the regulation of intestinal movement . Serotonergic projections that play a role in the ascending activating system originated in the dorsal and median raphe nucleus; both dorsal and median raphe nucleus innervate the forebrain regions to regulate the cortical arousal and alertness . Dorsal raphe nucleus has numerous innervation targets such as globus pallidus in the basal ganglia, thalamus, hypothalamus, amygdala, entorhinal cortex, medial prefrontal cortex, piriform cortex and olfactory tubercles. Median raphe nucleus has very similar innervation targets: septum, hippocampus, thalamus, suprachiasmatic nucleus in the hypothalamus, frontal cortex, entorhinal cortex, medial prefrontal cortex, caudate and putamen ,,. Numerous early evidences have shown that serotonin plays an important role in sleep induction and sleep maintenance. For example, lesion in the dorsal raphe nucleus has shown to induce insomnia in cats,  a finding which proves that dorsal raphe is involved in causing sleep or decreasing wakefulness. Furthermore, Ursin and his colleagues demonstrated that depletion of serotonin in the brain produced insomnia, and its symptoms disappeared when there was an administration of serotonin precursor 5-hydroxytrypothan (5-HTP) into the brain . However, recent hypothesis refutes the old hypothesis which states that serotonin induces sleep; recent findings have demonstrated that serotonin neurons are most active during waking and motor activities . Moreover, Monti found out that administration of serotonin receptor agonist and uptake inhibitor increased wakefulness, rather than inducing sleep , evidence that highlights serotonin promotes wakefulness. These two different perspectives on potential roles of serotonin in sleep regulation are contradicting yet still veiled.
As another part of ascending activating system, the noradnergic projection originates from the locus ceruleus and the lateral tegmental field in the tegmentum . Projection from the locus ceruleus acts on A1 receptors (adnergic receptors) in the hippocampus, amygdala, cingulate gyrus, hypothalamus, thalamus, striatum, and neocortex while the projection from the lateral tegmental field acts on the same adnergic A1 receptors in the hypothalamus. All these projections turn on to regulate cortical arousal and alertness.
The dopaminergic projection in the ascending activating system originates from the ventral periaqueductal grey matter (vPAG) to prefrontal cortex and striatum for the regulation of the state of cortical arousal. In 2006, Lu and his colleagues  found out that the dopaminergic system from the vPAG has a close relationship with the dorsal raphe nucleus, and this complex relationship may play a significant role in regulation of wakefulness and cortical arousal.
2.2 First branch of the ascending reticular activating system
The first branch of the ascending reticular activating system projects from the PPT/LDT nuclei to the thalamus, and from thalamus to the cortex for thalamocortical transmission . PPT/LDT neurons are most active during wakefulness and acts as a gating mechanism which blocks the thalamic filter that filters out sensory information into the cortex to reduce cortical arousal; this blocking mechanism promotes the state of excitability and wakefulness .
2.3 Second branch of the ascending reticular activating system
The second branch of the ascending arousal system projects to the lateral hypothalamus, basal forebrain, and to the cerebral cortex . This branch has numerous monoaminergic neurons such as noradrenergic neurons of the locus coeruleus, serotoninergic neurons in the dorsal and median raphe nuclei, dopaminergic neurons of the ventral periaqueductal grey matter, and the histaminergic tuberomammilary nucelus (TMN). There are also other ascending neuronal projections from the lateral hypothalamic peptidergic neurons that contain melanin-concentrating hormone or orexin/hypocretin, and basal forebrain nuclei, which contain acetylcholine or GABA . All these neurons in the second branch of the ascending arousal system fire most rapidly during the wakefulness to prove that they have waking-promoting properties.
3. Hypothalamic sleep/wake switch
The hypothalamus is one of the key control center that regulates sleep and wake, and the circuitry that governs sleep/wake is known as sleep/wake switch. The sleep promoter is located in the ventrolateral preoptic nucelus (VLPO) of the hypothalamus while wake-promoter is located in the tuberomammilary nucleus (TMN) of the hypothalamus.
|Figure 3: Sleep pathway|
|The schematic representation of brain structure shows the neuronal projections involved in sleep. The ventrolateral preoptic nucleus (VLPO) inhibits the monoaminergic cell bodies (red) such as the tuberomammillary nucleus (TMN), the ventral periaquaductal gray matter (vPAG), the raphe and the locus coeruleus (LC). It also innervates neurons in the lateral hypothalamus (LHA; green), including the perifornical (PeF) orexin (ORX) neurons, and cholinergic (ACh) interneurons (yellow), the pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT). (Saper et al(2005)) |
|Figure 3.1.1: Sleep-promoting GABA system|
|A region in the hypothalamus known as the “sleep promoter,” namely the ventrolateral preoptic area (VLPO) projects inhibitory GABA neuronal projections to ascending reticular activating systems to turn off wake-promoting effects of these neurons. (Stahl S.M. New Delhi: Cambridge University Press; 2007. Essential Psychopharmacology: Neuroscientific basis and practical applications) |
3.1 Ventrolateral preoptic nucleus (VLPO)
Ventrolateral preoptic nucleus is known as the sleep promoter; there is a reciprocal inhibition between the sleep-inducing VLPO and major ascending monoaminergic systems such as dopamine, serotonin, and noradenergic neuronal projections for cortical arousal. This reciprocal inhibitory exchange works as a stable feedback loop; when monoamine nuclei fire actively during wakefulness, they all inhibit VLPO from firing. On the other hand, the rapid discharge of VLPO during sleep inhibits the monoamine nuclei from firing and releasing dopamine, serotonin and norepinephrine . This mutual inhibition helps explicating why sleep-wake transitions are quite abrupt and why switching between sleep and arousal state occurs infrequently and rapidly.
Although this sleep/wake feedback loop is stable, if either side is dysfunctional, unstable feedback loop occurs during both sleep and wake states. For example, animals with VLPO lesions not only experience approximately 50% to 60% reduction in sleep time, but also wake up frequently during their sleep cycle . Furthermore, rapid sleep-wake cycling is observed in the elderly who have fewer VLPO neurons  . In conclusion, all these findings expose that when the sleep/wake feedback loop is dysfunctional, an individual shifts back and forth between sleep and wakefulness not only more frequently but also irregularly.
3.1.1 GABA inhibition of TMN
In 1968, McGinty and colleagues demonstrated that lesions in the basal forebrain suppressed sleep in cats. Almost 30 years later in 1996, Sherin et al. found out that a group of ventrolateral preoptic neurons is specifically activated during sleep. Neurons of the VLPO widely project to innervate the monoaminergic neurons in the hypothalamus and brainstem which participate in the modulation of cortical arousal. Furthermore, VLPO efferent neurons contain the inhibitory neurotransmitters GABA and galanin, and these neurotransmitters have been shown to inhibit the ascending monoaminergic arousal system during sleep .
Moreover, afferent neurons from the monoaminergic arousal system connect to the VLPO to mediate its function . For example, noradrenaline released from locus coeruleus and serotonin from median raphe nuclei inhibit VLPO neurons . Typical inhibitory neurotransmitters such as GABA  and galanin  produced by TMN neurons also inhibit VLPO. This reciprocal inhibitory interaction of sleep-promoting VLPO neurons and the noradrenergic, serotoninergic, and cholinergic monoaminergic systems to which they project establishes a dynamic state where the VLPO is blocked by the arousal systems, while VLPO down –regulates the monoaminergic systems during sleep .
3.2 Tuberomammillary nucelus (TMN)
Tuberomammillary nucleus is known to be the only structure that contains histaminergic neurons in the mammalian brain . As it was previously stated, there is an mutual inhibition between VLPO and TMN; GABA-mediated inhibition of TMN is from the VLPO of the hypothalamus  .GABA release to inhibit TMN turns off histaminergic projection from TMN to cortical areas, and this leads to decrease in histamine activity, and ultimately contributes to the loss of cortical arousal, but GABA release from TMN to VLPO allows histaminergic neuronal projection to be turned on.
The TMN is reciprocally connected with the aminergic, orexinergic and other nuclei in the mesencephalon and diencephalon . Noradrenaline and several peptide transmitters inhibit GABA release onto the TMN to disinhibit it ; on the other hand, serotonin and orexin depolarize TMN and activate it .
Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Histaminergic projections appear to cover essentially all areas of the CNS , and there are three histamine receptors in widespread areas in the brain. Histaminergic neuronal system projects from the TMN to the cerebral cortex, amygdala, substantia niagra, striatum, thalamus, and hippocampus .
Numerous findings show that histamine is required for cortical arousal. For example, lesion in the posterior hypothalamus has been shown to cause hypersomnia or excessive sleep . Furthermore, mice that lack histamine, which have been transgenically made by disrupting the histidine decarboxylase gene, show a deficit in waking, alertness and interest in a novel external environment . Histamine regulates the cortical activity by stimulating the cholinergic neurons of the basal forebrain and the serotonergic neurons in the dorsal raphe nucleus; these effects are mediated by H1 receptors . In the cortex and amygdala, the actions of histamine and H3-receptor agonists control acetylcholine release, which has been known to induce waking and attention .Moreover, orexin release facilitates histamine release followed by increased wakefulness in a wildtype mice, yet it does not cause histamine release in H1-receptor knockout mice , revealing that the histaminergic neuronal system is one of the orexin neurons' main innervation targets.
|Figure 3.2.1: Histaminergic projection in the brain|
|About 64,000 histamine-producing neurons, which are located in the tuberomamillary nucleus, innervate all of the major regions in the cerebrum, cerebellum, posterior piuitary and the spinal cord.|
|Figure 3.2: Hypothalamic sleep/wake switch|
|Figure a) shows that during wakefulness, the monoaminergic nuclei (red) inhibit the ventrolateral preoptic nucleus (VLPO; purple), to disinhibit the monoaminergic cells, orexin (ORX) neurons (green), and the cholinergic pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT; yellow). The VLPO neurons do not express orexin receptors; therefore, orexin neurons reinforce the monoaminergic activity, instead of directly inhibiting the VLPO. During sleep as the figure(b) is showing, the firing of the VLPO neurons inhibits the monoaminergic neurons to turn off their own inhibition. This process also allows inhibition of the orexin neurons, which further prevent monoaminergic activation. In sum, the direct mutual inhibition between the monoaminergic system and VLPO forms a stable flip-flop switch. |
3.3 Lateral hypothalamus (LH)
The lateral hypothalamus contains peptide neurons expressing orexin/hypocretin and melanin-concentrating hormone (MCH). Hypocretin neurons  activate the monoaminergic wake-promoting nuclei[ and they are also essential for behavioral state bistability between sleep and wakefulness. DDysfunction in the LH is causally related to the sleep disorder narcolepsy, which is characterized by daytime sleeping . It is evident that there is a strong mutual innervation and interaction between hypocretin neurons and the TMN , ], yet the direct electrophysiological experiment in vitro have exposed that there is no mutual relationship; rather, it is one-way interaction where hypocretin neurons excite histaminergic neurons while histaminergic neurons do not affect hypocretin neurons .
Orexin, also known as hypocretin, is a neuropeptide that is secreted from the posterior region of the lateral hypothalamus . OOrexin neurons innervate numerous major nuclei playing roles in sleep regulation. There are different subtypes of orexin receptors; orexin-1 receptors are located in the locus coeruleus, orexin-2 receptors are found in the TMN, and both orexin-1 and 2 receptors are located in the median raphe nuclei and mesopontine reticular formation . Orexin/hypocretin neurons seem to promote wakefulness not only by innervating the monoaminergic neurons such as ascending cholinergic neurons and serotonergic neurons, but also by innervating paraventricular thalamic nucleus (PVT) . Narcolepsy is an archetypal model that explicates the potential roles of orexin/hypocretin. Experiments using orexin-receptor knockout mice produce behavioral symptoms that are similar to patients with narcolepsy . Moreover, humans with narcolepsy have been shown to express fewer orexin neurons in the lateral hypothalamus and extremely low orexin levels in the cerebrospinal fluid (CSF) . C-Fos expression, which marks some particular neuronal activity, in orexin/hypocretin neurons was positively correlated with wakefulness. The level of C-Fos expression, which marks some particular neuronal activity, in orexin/hypocretin neurons was positively correlated with the degree of wakefulness. Therefore, orexin input from the lateral hypothalamus appears to facilitate the regulation of normal cortical arousal and alertness.
On the other hand, mammals lacking orexin/hypocretin do not show excessive sleep; their sleep/wake circuitry appears unstable and this instability leads to dysfunctional circadian rhythm . The instability during wakefulness experienced by orexin-deficient mice is not a result of poor circadian rhythm control, defective monoaminergic systems or dysfunctional sleep homeostasis but rather is the consequence of behavioral state instability between sleep/wake cycle . Therefore, the asymmetric relationship between orexin/hypocretin neurons ascending monoaminergic neurons implicated in sleep and arousal may stabilize the sleep-wake system.
3.4 Suprachiasmatic nucleus (SCN)
Suprachiasmatic nucleus (SCN) has been called the "master clock” of the brain . Circadian rhythm timing in which neurons fire in a 24-hour cycle, is organized throughout the body. The SCN coordinates these tissue-specific rhythms based on the light input from the outside environment during daytime and also based on melatonin secretion during the dark cycle; a lesion in the SCN cause the complete loss of the circadian rhythms and induces a dysfunctional sleep pattern . For example, lesions in the retinohypothalamic tract (RHT) of the SCN, where the processing of light input occurs, cause animals to exhibit free-running behaviors . This evidence reveals that the SCN is crucial for synchronization of circadian rhythms.
Early studies on the circadian rhythms in rats that had lesions in the SCN showed that the sleep homeostasis was independent of the circadian rhythm clock because there was no change in sleep duration or length after the lesion in the SCN . Nevertheless, there was an article published in 1993 by Edgar and colleagues; this article showed that lesions in the SCN not only caused a loss of circadian timing but also increased total sleep time, suggesting an interrelated interaction between the circadian rhythm and sleep homeostatic processes. Moreover, according to Edgar’s “opponent process” model, the SCN sends out a signal output to cause wakefulness and to continually reduce the homeostatic drive for sleep .
Most outputs from the SCN are projected to the pineal gland, subparaventricular zone (SPZ) and dorsomedial nucleus of the hypothalamus (DMH); however, there are few projections to the VLPO or orexin neurons .The DMH is a crucial part for relaying signals from the SCN to the sleep-regulatory system such as ascending monoaminergic activating system. For example, lesions in the DMNH reduced wakefulness .Furthermore, the DMH sends out GABA neurons to the sleep promoter VLPO to turn it off; on the other hand, it sends out glutamate projections to the wake promoter lateral hypothalamus to activate it . These evidences expose that integration of signals from the SCN, SPZ and the DMH plays a major role in regulating sleep/wake cycle.
|Figure 3.4.1: Inhibition of neuronal firing by melatonin in vitro SCN brain slice|
|The schematic representation of neuronal firing recording from the SCN brain slice for a 48 -hours period. The neuronal firing rhythm is inhibited by administration of melatonin. Figure (B) represents the percentage inhibition of neuronal firing by melatonin administration to SCN brain slices from wildtype(WT) and melatonin-1 receptor knock-out (MT1 KO) (left) mice and WT and melatonin-2 receptor knock-out (MT2 KO)(right) mice. Melatonin-implicated inhibition of neuronal firing was impaired in the MT1 KO mice, which indicates that melatonin binds to MT1 receptors .|
Melatonin is a neurotransmitter that is secreted by the pineal gland, and it acts onto the SCN to regulate circadian rhythm and its secretion is activated in the darkness, but is inhibited in the light from the outer environment. Numerous roles of melatonin, such as an antioxidant in the immune system, has been proposed; however, it appears that melatonin causes sleep by disrupting the circadian rhythm regulation by SCN; melatonin release promotes sleep independently of time of day by shifting the circadian rhythm phase to dawn or evening. In the SCN, the sleep-promoting effect of melatonin has been linked to its inhibition of SCN neuronal activity through activation of the MT1 receptor on SCN. Melatonin applied in vitro to rodent SCN brain slices turns off firing of SCN; however, firing in SCN brain slices from wild type (WT) and Melatonin-2 receptor knock-out mice (MT2 KO) is inhibited but not in MT1 KO mice. Numerous roles of melatonin, such as an antioxidant in the immune system, has been proposed; however, it appears that melatonin causes sleep by disrupting the circadian rhythm regulation by SCN; melatonin release promotes sleep independently of time of day by shifting the circadian rhythm phase to dawn or evening . These data demonstrates that melatonin inhibits SCN firing by binding to M1 receptor on SCN and melatonin- MT1 receptor mediated signaling potentially is directly linked to the sleep-promoting effects .
4. Cortico-striato-thalamic-cortical loop (CSTC loop)
Cortico-striato-thalamic-cortical loop (CSTC loop) consists of an interconnected system of prefrontal cortex, striatum (as a part of basal ganglia which consists of the striatum, substantia niagra, pallidum, and subthalamic nucleus) and thalamus . First of all, pyramidal glutamatergic neurons descend from the prefrontal cortex to the striatum, where they terminate onto GABA neurons that project to the thalamus . GABA release in the thalamus creates a sensory filter which reduces sensory information arriving in the thalamus to make sure that only certain selected types of signals can be relayed to the cortex . The striatum receives dopaminergic inputs from the ventral tegmental area (VTA) in the mesolimbic system because dopamine release into the striatum from the VTA has an inhibitory effect on GABA neuronal projections from the striatum to the thalamus, which reduces the effective function of the thalamic filter . Therefore, cortico-striato-thalamic-cortical loop (CSTC loop) is known to regulate cortical arousal by controlling the effectiveness of the thalamic filter; this system regulates cortical arousal by filtering out sensory input for maintaining sleep or by allowing specific sensory input to the cortex for maintaining cortical arousal .
|Figure 4: Cortico-striato-thalamic-cortical loops|
|This diagram shows a functional circuitry which consists of the cortex, basal ganglia, and thalamus. This cortico-striato-thalamo-cortical (CSTC) loops are showing both the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA projections, and modulatory neurotransmitter dopamine which modulates the level of sensory information flow through this circuit .|
One hypothesis says that insomnia is conceptualized as a disruption in the thalamic filters in the CTSC loops; when thalamic filters fail to filter out sensory input to the cortex at night, the state of cortical arousal can be induced. During insomnia, the GABA-ergic neurotransmission is deficient at night, and this leads to the reduced function of thalamic filter. Therefore, a lot of sensory input can be reached at the cortex which causes hyper-cortical arousal.
Stress is believed to activate the hypothalamic-pituitary-adrenal axis. Vgontztas et his colleagues found out that patients with chronic insomnia had increased cortisol level throughout the sleep/wake cycle than the controls.
Moreover, Nofzinger and colleagues used positron emission tomography (PET) studies to monitor regional cerebral glucose metabolism, and they discovered that patients with insomnia show greater brain metabolism during the entire day period and, most conspicuously, a failure of wake-promoting neurons to be turned off during the transition from waking to sleep states . Structures regulating the sleep-wake cycle, such as numerous nuclei in the brainstem that regulate the ascending activating system, nuclei in hypothalamus, and basal forebrain, are abnormally overactive during sleep. However, patients with insomnia have low brain metabolism in the prefrontal cortex during waking state; this finding suggest that these individuals have chronic insufficient sleep, which may explicate the rationales for daytime fatigue, which is a common symptom of insomnia .
5.1 Potential treatment
GABA-A positive allosteric modulators (PAM) or also known as Z-drugs (since they usually begin with the letter z-; such as zaleplon and zopiclone) have been proposed for the potential treatments for insomnia . GABA-A PAMs work as hypnotics which act on the GABA-A receptors to moderately enhance the action of GABA by binding to a site other than GABA binding site. The most well-known GABA-A PAM are benzodiazepine and baribiturate .
Another potential treatment for insomnia is H1 histamine antagonist. It is widely known that antihistamine is a sedative and one of the most popular sleep-aid alternatives. Since histaminergic projection from the TMN plays a crucial part in cortical arousal and wakefulness, blocking H1 histamine receptor reduces the wake-promoting effect of histamine .
At last, as it was previously shown in Liu et his colleagues' experiment  of inhibiting the firing of SCN to promote sleep by shifting the circadian rhythm, melatonin can be adminstered as a potential treatment for insomnia.
6. See also
1.Sleep: The Great Enigma
2.Sleep-dependent memory consolidation
3.Circadian Rhythms: Food, Sleep and Stress
4.Synthetic and Endogenous Psychedelic Compounds
7.Stress and Sleep