Effects of REM sleep awakenings and related wakening paradigms on the ultradian sleep cycle and the symptoms in depression

In paper citation (Grozinger, Kogel, & Roschke, 2002).

In 1975, Vogel and colleagues executed a "heroic" experiment whereby severely depressed inpatients were chronically REM-sleep deprived for three weeks. They found that suppressing REM sleep had an antidepressant effect on patients with endogenous depression, namely depression that does not result from a stressful event. They used fifty-two patients, and the patients that responded to the REM deprivation treatment were less likely to require rehospitalization or another form of treatment in the future.

As the literature linking depression and sleep has progressed, many scientists have called for a confirmation of this study. Unfortunately, it takes a lot of time and resources to monitor sleeping patients. To work around this problem, Grozinger and colleagues developed a computer algorithm that wakes a patient up as soon as it detects REM sleep. Unfortunately, this system does not catch the initial moments of REM, and it only reduces REM sleep by about 50%.

Grozinger and colleagues do not replicate Vogel's results. Interestingly though, they show that both REM deprivation and sleep deprivation dramatically decrease a subject's self-reported symptoms of depression (both groups lowered their average score by ~7 points (out of an average of 22) after 11 days of treatment). I think that this is pretty strong evidence for the placebo effect. Every subject who participated in this experiment would have assumed that they were in the "treatment" group getting REM sleep deprivation because both sets of subjects were woken up almost 50 times each night. Thus each subject would want to deliver good news to the experimenter, and would thus focus on the progress that they had made since they started in the experiment. I also believe that the paradigm is so unique that it might "give hope" to a patient who has been treatment resistant.

I do not completely buy the theory that REM suppression is one of the main mechanisms of antidepressant therapy. For cognition, researchers are always trying to increase REM sleep to promote memory consolidation. I still assume that REM sleep deprivation is caused by something deeper that actually mediates the antidepressant effects of most medications/placebos.

'Til next time...

Sleep Disturbance Associated with an enhanced Orexinergic system induced by chronic treatment with paroxetine and milnacipran

In paper citation (Rahmadi, et al., 2011).

Mice treated with the SSRI paroxetine 10mg/kg or SNRI milancipran (30mg/kg) had their sleep recorded on day 7 and their orexinergic receptor and mRNA for orexinergic receptors quantified on day 28. Both antidepressants significantly decreased total sleep time and decreased total NREM sleep. OX1R and OX2R mRNA expression significantly increased in the hypothalamus of animals on antidepressants, as did the H1R and histidine decarboxylase mRNA expression in the frontal cortex.

Paroxetine still has an affinity for the H1R receptor of .0045*10^-7/equilibrium dissociation constant, which may be blockading the H1R receptor and thus upregulating it (Richelson, 1996). Richelson did not have the binding affinity for milnacipran in his paper.

Histidine decarboxylase is involved in the synthesis of new histamines, so the blockade of H1R receptors might promote this increased synthesis, and thus increased mRNA expression in the frontal cortex.

Orexins are synthesized in the lateral hypothalamus, so the increase in Orexinergic receptor mRNA expression might indicate that little orexin is making it back to the hypothalamus for use in a feedback mechanism. The orexins might be binding in wake-promoting areas and getting metabolized there. Increasing total orexins should increase a person's wakefulness.

REM: Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

In paper citation (Datta & MacLean, 2007)

Historical perspective

• Jouvet's transection studies in the 1960s showed that any cut rostral to the pons eliminated REM sleep signs in the forebrain.
• The model in the 1970s, termed the reciprocal interaction model, assumed that the aminergic inputs were REM-off and that cholinergic inputs were REM-on (and thus off until REM sleep initiation).
• Major locus for the cholinergic cells shifted from the mPRF to the PPT as more research showed REM-on Ach cells in the PPT.

Cellular-Molecular Network model of sleep regulation

REM sleep sign generators:

• MRF and the medullary magnocellular nucleus regulate the cortical EEG readings in REM.
• LC-alpha neurons create muscle atonia
• Peri-abducens reticular formation creates rapid eye movements (also responsible for horizontal saccades in awake individuals)
• Caudo-lateral peribrachial area creates PGO waves (waves that begin in the pons, propogate to the lateral geniculate body and the occipital cortex). The p-wave occurs only in REM, it is glutamatergic and excitatory, and it tends to bursts during REM as well as having a high tonic rate. 
• Pontis oralis controls the hippocampual theta rhythm
• parabrachial nucleus controls that brain and body temperatures and autonomic fluctuations. Autonomic system suspend its regulatory functions throughout REM sleep. More people die of heart attacks during REM than any other time of day.

REM is turned on when aminergic cells are markedly reduced and cholinergic cell activity is relatively high. (0:0.65 ratio)

Regulation of cholinergic tone in the REM sleep-sign generators:

• PPT contains 3 types of neurons: REM-on, wake-REM-on, and state independent.
• REM-on and wake-REM-on cells increase activity at the initiation of slow wave sleep.
• Cholinergic cells do not fire in a bursting manner.
• Activation of only kainate receptors in the LDT and PPT results in 65% activated cells, whereas activation of NMDA receptors will activate 100% of the cholinergic cells in the PPT resulting in wakefulness.
• Kainate has a lower activation threshold than NMDA, but both are glutamate receptors.
• The influx of calcium ions activate adenylyl cyclase, creating cAMP, which phosphorylates PKA.
• GABA can prevent this process because GABA receptors couple to Gi/Go g-proteins which inhibit adenylyl cyclase and prevent the cAMP-PKA signal transduction pathway. 
• Kainate receptors desensitize quickly, but increased cytosolic PKA can phosphorylate GluR6 and modulate channel function for 3-25 minutes. 
• Thus PKA may be responsible for sustaining activity in the PPT cells.
• Axons of the PPT and LDT terminate in the mPRF in the cat.
• Glutamated in the PPT induces REM sleep.
• Ach release in the mPRF increases in REM sleep.
• Open question if mPRF is the  effector zone, or if there are multiple effector zones.

Regulation of monoaminergic tone in the REM sleep-sign generators:

• Serotonin
• The raphe nucleus contains a significant proportion of cells containing GABA and other neurotransmitters.
• 5HT-ergic cells project to the sleep sign generators. 
• 5HT-ergic cells stop firing during REM sleep. 
• Decreasing 5-HT in the brain increases the appearance of PGO waves.
• Increasing 5-HT in the brain can block PGO waves without stopping REM sleep. 
• Norepinephrine
• Neurons of the LC decrease their firing rate at sleep onset and remain completely silent until 5-10 seconds before the beginning of wakefulness.
• Cooling the LC induced tS-R within 3 minutes and REM within 4 minutes.
• Mechanisms for regulating NE and 5HT REM-off cell activity
• 3 hypothesis:
• GABA inhibits the RN and LC
• a pacemaker mechanism
• withdrawl of histaminergic and hypocretinergic tone
• GABAergic mechanism
• Some of the LC and RN neurons are GABAergic; these neurons could be inhibiting the rest  of the structure endogenously
• Level of spontaneously produced GABA in the LC and RN is maximum during REM sleep and minimum during wakefulness. 
• Single cell recording shows a reciprocal neural discharge between 5HT and GABA cells in the DRN.
• Pacemaker mechanism
• buildup of GABA turns off  cAMP-PKA signal, shutting off LC
• DRN then controlled by LC activity.
• NE antagonists will turn off the DRN
• Withdrawl of histaminergic and hypocretinergic excitatory tone
• LC and DRN receive projections from the HA cells in the PH and Hcrt cells in the LH.
• LH and PH are less active during REM than during wakefulness. 
• HA can prevent the cessation of DRN REM-off cells during REM sleep.
• REM-off cells are also in the ventrolateral periaqueductal gray (vlPAG) and the lateral pontine tegmentum (LPT)
• vlPAG seems to be more involved in pain than sleep, though.

Remaining questions:

• To where do PPT cells project? Only the mPRF?

SWS: Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

In paper citation (Datta & MacLean, 2007)

There are two major warrants to the activity dependent homeostatic theory of sleep initiation:

1. "The waking state requires a critical level of brain activity, which is maintained by a steady flow of ascending impulses arising in the brainstem reticular formation"
2. "A reduction of tonic activity of the ascending reticular system (ARAS) is responsible for physiological sleep."

Basically, the initiation of sleep is a passive process caused by the withdrawl of wakefulness. But what causes this withdrawl. Here's what the theory says:

• During wakefulness, the increased rate of metabolite synthesis is higher than the rate of clearance. Individual cells begin to demand a lower metabolic state and cease firing. Eventually, this effects behavior at the systemic level, and the body initiates sleep. 
• This theory predicts that duration of sleep periods are inversely correlated with the rate of metabolite clearance.
• Factors only involved in sleep induction are not metabolic byproducts. These are synthesized after SWS has started.
• Adenosine
• Cells use ATP by catabolizing it into adenosine and ADP. Adenosine moves along its concentration gradient and can therefore get built up by periods of large use. 
• Adenosine accumulates in the BF and cortex during forced sleep deprivation.
• Direct administration of adenosine increases sleep duration and enhances SWS activity in the rat.
• Blocking adenosine synthesis eliminates SWS and increases wakefulness.
• Adenosine also inhibits the activity of Hcrt neurons in the LH.
• Inhibitory amino acids (GABA)
• GABA - everywhere
• glycine - spinal cord & brainstem
• Glutamate is decarboxylated to form GABA by GAD. 
• Increased neuronal activity results in a local increase in GABA synthesis.
• Glycine synthesized from the degradation of serine. 
• Choline can metabolize into glycine by stepping through betaine and losing  its methyl groups.
• A global increase in GABA via ventricular infusion promoted the physiological signs of NREM sleep. 
• Prostaglandin
• Prostaglandins are a naturally occurring unsaturated fatty acid group (loosely) made from arachidonic acid.
• PG is observed most often in the CSF between the arachnoid membrane and the pia mater.
• Primarily synthesized in the leptomeninges, the epithelial cells of the choroid plexus, and the oligodendrocytes.
• Sleep deprivation raises the typical PG concentration in the CSF.
• Injection of PGD2 into the Preoptic area, or into the lateral vesicles increases NREM sleep.
• Cytokines
• Cytokines stimulate subtle changes in cellular metabolism.
• Cytokines affect the input-output relationships within their neural circuit of origination.
• Interleukine-1beta is highest when the demand for NREM sleep is highest in the rat (beginning of the day), taper off for awakening
• In humans, IL-1B is highest at initiation of sleep, and lowest at awakening.
• Injecting IL-1B into the brain directly increases amount of NREM sleep, but only if the the subject is already in NREM sleep. (NOT causative)
• Substances that inhibit IL-1B decrease spontaneous sleep. 
• TNF-alpha is also 10X higher at the initiation of sleep than during its minimal waking values.
• TNF-alpha in the POA enhances NREM sleep in rats.
• TNF inhibitors also inhibit NREM sleep and decrease spontaneous sleep. 

Mechanisms for the generation and maintenance of SWS:

• After sleep initiation, GABA and galanin synthesizing cells in the anterior hypothalamus/ POA become active and project to the major wake promoting areas, inhibiting them. 
• GABA hyperpolarizes the thalamus to raise the threshold for sensory information getting relayed to the cortex.
• POA critical for SWS generation. Lesions in the POA can prevent SWS in mammals.
• FMRI data shows that mPOA is more active than other parts of the hypothalamus and basal forebrain during SWS. 
• POA lesions will knockout SWS, but only for a matter of days depending on the extent of the damage. 
• Paradoxically, NE and 5HT in the POA increase POA activity and can induce wakefulness.
• GHRH (a sleep inducing factor) may be needed to help GABA from the POA work. 
• GHRH made in the arcuate nucleus (largest #), ventromedial nucleus (VMN), and paraventricular nucleus (PVN). These cells project to the anterior pituitary (from the arcN) and the POA.
• GHRH  is high around the initiation of sleep, and highest immediately after sleep.
• Highest GHRH synthesis occurs at the period of deepest SWS. 
• 2/3 of all growth hormone (GH) secreted in young males occurs during SWS. 
• GHRH injections systemically and ventricularly increase SWS in rats.
• GH injection decreases SWS by providing negative feedback to the GHRH production system.
• GHRH  is released into the POA and binds to GHRH recptors to activate POA GABAergic cells.

Remaining questions: 

• Does TNF-alpha injection only increase NREM sleep during NREM periods, or can it initiate NREM?
• What are the sleep induction factors that get synthesized during SWS?

WAKE: Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

In paper citation: (Datta & MacLean, 2007)

This is my first review article, so I will do my best to lay out the information in a concise and organized manner. I will not include citations, because the paper has 17 pages of citations and should therefore be used to confer all of these facts.

Historical background on consciousness & identification of sleep stages

• Pre-12th century belief was  that sleep is a passive unconscious state.
• Early hindu civilization distinguished two types of sleep: prajna, meaning dreamless sleep, and taijasa, meaning dreaming sleep.
• EEG was first recorded in 1924, and published in 1929.
• In 1953 Aserinsky discovers REM sleep in infants and discovered that it also existed in adults.
• REMs lasted as long as 50 minutes and started 90-120 minutes after sleep onset.
• Dement observed the first REM and NREM sleep in the cat in 1958. (Although Klaue first looked at sleep in the cat in 1937) This was the animal model of choice until the late 1900s. 

Physiological characteristics or wake, NREM and REM

• Polysomnography is the combination of EEG measurements (brain), EMG measurements(muscles), and EOG measurements (eyes) to study sleep.
• While we are awake, we display an activated EEG (20-60 Hz), muscle tone, and voluntary movements/ progressive and logical thoughts.
• There are 4 stages of NREM sleep that correlate to 2 states of SWS in animals. 
• In stage 1 sleep, our eyes might still be open, but the cortex has low voltage, 3-7 Hz oscillations called vertex sharp waves of activation. This really isn't seen in animals. 
• Stage 2 sleep is most like SWS-1 in animals. This stage is characterized by sleep spindles in the cortical EEG. In humans, up to 80% of stage 2 sleep might actually be tSR (transitional REM) sleep in animals.
• Stage 3 & 4 are the deepest stages of NREM sleep, equivalent to SWS-2 in animals. This is considered deep sleep, or delta sleep, due to the presence of high-amplitude, low-frequency (.1-4Hz) waves in the cortival EEG.
• REM sleep is characterized by:
• Low amplitude, high frequency waves in the cortical EEG
• Atonia (no muscle tone/activation)
• singlets and clusters of rapid eye movements
• theta rhythm activity in the hippocampal EEG (hard to measure in humans)
• spiky field potentials in the pons (p-waves)
• Humans have 4-6 sleep cycles a night. The period lengths of each REM-NREM sleep epoch increases with brain size across species (Cats have longer cycles than rats).

Regulation of sleep timing:

• Organisms remain active during hours when the opportunity to acquire food exceeds the risk of predation, but they sleep during times when the need for vigilance is minimized. 
• The suprachiasmatic nucleus  has many circadian clock genes that encode different types of proteins that act as transcription factors to regulate their own transcription.

Wake-promoting systems of the brain:

• Five cell types in the ascending reticular activating system are reponsible for promoting wakefulness. These are:
• Noradrenergic (NE) cells in the locus coeruleus (LC)
• Serotonergic (5-HT) cells in the raphe nuclei (RN)
• Cholinergic (Ach) cells in the pedunculopontine tegmentum (PPT)
• Glutamatergic (Glut) cells in the midbrain
• Dopaminergic (DA) cells in the substantia nigra compacta (SNc)
• NE cells of the LC:
• fire maximally during wake behavior and steadily decrease until they cease firing during REM sleep.
• become active immediately prior to spontaneous wakefulness, suggesting an anticipatory role in wake-behavior.
• Experimental application of NE in the thalamo-cortical, hypothalamo-cortical, and basalo-cortical activating systems induces cortical activation and promotes wakefulness.
• Mice lacking NE fall asleep more rapidly after a mild stress.
• 5-HT cells of the RN:
• fire maximally during wake behavior and steadily decrease until they cease firing during REM sleep
• do not anticipate wake behavior and are therefore probably an effect, not a cause of wakefulness.
• BUT: Lesions of the RN  increase wakefulness and decrease SWS.
• Direct application of 5-HT to the preoptic area resulted in a decrease in wakefulness allowing SWS.
• Ach cells of the PPT
• PPT neurons also synthesize nitric oxide, a gaseous neuromodulator, that regulates wakefulness by controlling activity levels of PPT cells. 
• Electrical stimulation of PPT promotes wakefulness.
• Four major types of cholinergic cells in the PPT: REM-on, W-REM-on, Wake-on, and sleep unrelated.
• PPT at 100% activation during wake, 65% activation during REM, and 7.4% activation during SWS.
• Ach cells may be in a tug of war with the 5-HT cells to stay active. When Ach drops out therefore, 5-HT could induce SWS.
• Midbrain reticular formation
• Electrical stimulation of the MRF is a reliable technique for inducing cortical activation in rats & cats.
• Kainic acid and glutamate microinjections in the MRF causes arousal in the cat and rat.
• Activity in MRF of humans is higher during wake than SWS. 
• DA cells of the SNc and VTA
• Do not display robust alterations in firing rate across sleep-wake states
• DA cells will burst during REM sleep.
• Extracellular DA is significantly elevated during wakefulness. 

• Wake promoting cell groups outside the ARAS:
• histaminergic (HA) cells in the posterior hypothalamus (PH)
• hypocretin-containing (Hcrt) cells in the lateral hypothalamus (LH)
• cholinergic (Ach) cells in the basal forebrain (BF)
• cells in the SCN
• Histaminergic cells in the PH
• Patients with encephalities lethargica showed a prolonged period of sleepiness with a higher waking threshold. This was the result of an injury between the PH and the rostral midbrain. 
• The tuberomammilary nuclei (TMN) contains HA-ergic cells that project diffusely throughout the brain, and specifically to wake-promoting structures. 
• Single cell recording shows that these neurons are active during wakefulness and silent during sleep, but their activity precedes and predicts awakening.
• Inhibiting TMN via GABA suppresses wakefulness.
• Drugs that enhance HA signalling increase wakefulness.
• Mice without histidine decarboxylase can't even stay awake in a novel environment.
• Hypocretinergic cells in the LH
• Hcrt-containing neurons also co-express glutamate and pentrazxin. 
• Hcrt neurons are more active during wakefulness than SWS.
• Hcrt increases arousal via an excitatory effect on wake-promoting systems in the brain.
• Selective lesioning of Hcrt neurons in the LH increases SWS and REM and decreases wakefulness
• Hcrt knockout mice look like narcoleptics.
• Wake-promoting function of LH neurons could be associated with motivated behaviors.
• Cholinergic cells in the BF (contains 4 cholinergic nuclei)
• BF Ach cells receive inputs from other brainstem and hypothalamic wake-promoting systems and project to the cerebral cortex.
• Single cell recording studies show that BF cells are more active during wakefulness than SWS.
• Cells in the SCN
• SCN cells fire more frequently during wakefulness than sleep. 
• Lesion to the SCN has had mixed effects, sometimes decreasing wakefulness, and sometimes having no effect. 
• Mutated Bmal1 and Cry1/Cry2 genes in the SCN increase NREM sleep at the expense of wakefulness. 
• PFC/mPFC
• 4 main subdivisions of mPFC:
• dorsal contains the medial agranular & anterior cingulate cortex; implicated in motor behaviors
• ventral contains the prelimibic cortex & infralimbic cortex; implicated in emotional cognitive and mnemonic processes
• 3 main subdivisions of PFC (primates):
• orbital -emotional behavior
• medial - emotional behavior
• lateral - executive functions
• failure to fall asleep due to "racing thoughts" is a cognitive flexibility failure, caused by hyperactivity of the mPFC/PFC.
• PKA pathways are disinhibited with age; increased PKA activity disrupts cognitive flexibility.

An overview of sleep after talking with Dr. Datta

Sleep is a "neurocratic" process. If democracy is rule by the people for the people and because of the people, then sleep is a neurocracy because it is done by the brain for the brain and because of the brain. Sleep is broken down into 5 main stages in humans with 5 distinct cortical EEG readings.

1. First, complete wakefulness involves sensory responses and high frequency, low amplitude neural activity.
2. Stage I sleep is the drowsy state right before sleep. The neural signal is slowing down, but the person may still have their eyes open (and in my case make basic responses to stimuli).
3. The start of stage II sleep is considered sleep onset by many polysomnograph technicians. In this type of sleep, the cortex makes sleep spindles and K-complexes. K-complexes are named for their distinctive shape in the EEG and they indicate a sensory response. A loud clap during a deeper stage of sleep will oftentimes show up as a K-complex in the EEG. Humans may also have a tS-R, or transition-to-REM sleep,  stage that looks just like stage II sleep without the K-complexes. Rats and cats have a distinctive tS-R which is distinguished because of pontine EEG readings from animals. If we could record EEG from the pons of humans without doing surgery, there is a good chance that humans also display this stage distinctively, too.
4. Slow wave sleep, or delta wave sleep is considered deeper sleep. Stage III and Stage IV sleep in humans are functionally equivalent; the only difference between the two stages is the prevalence of delta waves. In stage III sleep, delta waves make up 20-50% of the cortical activity. In stage IV sleep, the delta waves make up >50% of the cortical activity. These delta waves are extremely low frequency, high amplitude waves when measured by the EEG. 
5. REM sleep, called paradoxical sleep in France, makes up only ~20% of the sleep cycle. The rest (sometimes called NREM) is spent in the first 4 stages of sleep.  At the beginning of REM, people will move their heads before their body becomes paralyzed. REM is characterized by rapid eye movements, parasympathetic activation, autonomic disregulation, muscle atonia and cortical activation. Each of the sleep signs is regulated by a different nuclei in the mesencephalon. 

This is all information as I remember it from 2 hours ago, so the facts need to be checked. Look forward to the overview of Datta and Maclean 2007. That will reveal all!

Sleep and Brain Development: The Critical Role of Sleep in Fetal and Early Neonatal Brain Development

In paper citation (Graven & Browne, 2008)

Note: Human infants are born around 40 gestational weeks.

Normal Sleep in Development

• Sleep & sleep cycles are essential for sensory system development in the fetus and young infant. 
• As early as the end of the first trimester, fetuses begin to show circadian rhythms, periods or rest and activity, and rhythmic hormone production. These circadian rhythms are regulated by the mother's hormones (Rivkees & Hao, 2000)
• Between 20 and 28 weeks' gestation, the human fetus shows irregular and immature brain activity. As the preterm infant approaches 28 weeks' gestation, cell firing becomes regular and starts to occur as synchronous waves. This is organized by the ganglion cell firing. (Lai, et al., 1999).
• By 30 weeks gestation, the EEG patterns of REM and nREM occur, but not continuously. The EEG patterns become continuous between 36 and 38 gestational weeks (Davis, et al., 1999).
• In the fetus and young infant the brain is more active during REM than during wakefulness (Mizhari, et al, 2004).
• At 28 weeks gestation, the sleep cycle is mostly REM sleep. 
• By term at 40 weeks, the sleep cycles are about equal REM and NREM.
• By 8 or 9 months, the sleep cycle is about 80% NREM, 20% REM. This is reflective of adult sleeping patterns (Mizhari, et al., 2004)
• Rapid eye movement deprivation between 30 weeks' gestational age and 4-5 months postterm results in delayed or disordered development. 

Preservation of Brain Plasticity

• 3 cellular components of plasticity:
• nerve growth factor
• BDNF
• ubiquitin
• All three components repond to the stimulation and activation of CREB ( cyclic AMP responsive element binding protein) that regulates gene transcription.

Theory of memory consolidation

• Short term memory circuits in the neocortex.
• Consolidation phase during NREM for novel information.
• Neocortex communicates with hippocampus via theta waves in NREM.
• Hippocampus organizes the information and sends it back to the neocortex using different theta waves in REM. Continued theta waves solidify this memory connection. 
• Stickgold et al., 2008; Yoo, et al., 2007 

Sleep Development in the NICU

• Better sleep organization correlated with improved outcomes in the NICU (Lehtonen & Martin, 2004)
• NICU babies have historically been handled constantly with an average of 100 interventions in 24 hours. 
• NICU babies follow the developmental pattern of their gestational age in terms of sleeping patterns unless they have chronic lung disease (Scher, et al., 1992).
• Kangaroo mother care and breast feeding seem best in establishing sleep-wake patterns in pre-term infants. 

Remaining questions:

What are the established effects of REM deprivation and sleep deprivation?

If SSRIs decrease REM, how does this affect neonatal development? Is there a causal relationship between sleep and cognitive ability or is the correlation deeper?

REM sleep reduction effects on depression syndromes

In paper citation: (Vogel et al., 1975)

New conclusions:

1. N-REM sleep deprivation does not produce REM deprivation and REM rebound on recovery nights, but REM sleep deprivation does. (NREM sleep deprivation was acheived by waking participants up 10 minutes after they finished REM at the same rate as their REM-deprived partner)
2. In both endogenous and reactive depression, REM deprivation treatments caused REM deprivation, but only in the endogenous depressives did it also induce REM rebound on the recovery night.
3. Total sleep time was lower by about 40 minutes for everyone who received REM deprivation treatments  compared to controls.
4. EST did not reduce REM sleep the first two nights after treatment.
5. Endogenously depressed patients showed significant improvement with 3 weeks of REM sleep deprivation, but they did not have a significant difference in self-ratings of psychomotor activity (a symptom of depression)
6. 17 of 34 patients improved sufficiently for a hospital discharge after 7 weeks of increased REM pressure. Of these patients, 3 required rehospitalization within nine months of discharge, and 13 patients showed continued improvement.
7. 7 of 34 patients did not respond to sleep treatments or imipramine and received EST. Of these patients, 3  required rehospitalization within nine months of discharge, one went to a long-term care facility, and two showed consistent improvement. 
8. The unimproved patients were REM deprived, but did not show REM rebound. It may be that REM pressure is the force behind this healing process.

Other Important Information:

• Reactive depression is depression induced by a stimulus. Endogenous depression has a "spontaneous" onset.
• Tricyclics and monoamine oxidase inhibitors suppress REM sleep.
• EST has also been reported to decrease REM sleep. 
• If woken during REM, the patient was woken immediately at the onset of REM and kept awake for 3 minutes.
• If woken during NREM (controls) the patient was woken 10 minutes after the offset of REM so as to not disturb the normal REM sleep.

Remaining Questions:

• Is it REM deprivation, or increased REM pressure that relieves the depression?
• Is this method safe to use as a long term treatment?
• How could this treatment be made more efficient, affordable, and effective?

Single Cell Activity Patterns of Pedunculopontine Tegmentum Neurons Across the Sleep-Wake Cycle in Freely Moving Rats

In paper citation: (Datta & Siwek, 2002)

The new findings in this paper:

• There are three types of cells in the PPT of the rat (from measurements of 70 individual cells):
• ~12.86% of the cells are REM-on cells. These cells are more active during REM sleep than wakefulness or SWS. They start firing 5-10 seconds before the onset of REM and stop firing 5-8 seconds before the end of REM. These cells fire tonically with ISI modes of 90-110ms.
• ~60% of the cells are Wake-REM-on cells. These cells are more active during wakefulness and REM than SWS. They become silent at the onset of SWS and stay silent until 5-8 seconds  before the onset of REM. These cells fire tonically, but their firing rate was lower during REM, dropping from 15Hz (wake) to 10Hz  (REM). 
• ~27.14% of the cells are state-independent.
• There was no evident spatial differentiation within the PPT.
• None of the PPT cells fired in a bursting manner at any time.
• The average duration of spikes was around 1ms for all three types of cells, indicating that they were probably not GABAergic cells (which have spike duration of .5ms) but rather cholinergic cells
• When awake, the 70 cells fired 854 spikes/second. When in SWS, the 70 cells fired 63 spikes/second. When in REM sleep, the 70 cells fired 559 spikes/second. The activity of the cholinergic cells is thus assumed to be about 65% of the wakefulness baseline during REM sleep.

Other important information:

• Glutamate microinjection in the PPT increases the duration of REM sleep in the rat (Datta et al., 2001a)
• Choline microinjection in the PRF induces REM sleep in the rat (Gnadt & Pegram, 1986)
• Thus it is hypothesized that the PPT is a major source of cholinergic input to the PRF that can induce choline agonist-induced sleep
• Aminergic cells in the pons remain silent during REM sleep (Chu & Bloom, 1973; Hobson et al. 1975; (for more see paper))
• The cat has 5 types of neurons. The 2 not seen in the rat are: REM-off and PGO-on (Saito et al, 1977; El Mansari et al., 1989,1990;(for more see paper))
• REM-off cells are aminergic.These were only found in the cat.
• PGO-on cells discharge in bursts just prior to and during PGO wave activity. These are seen in the cat (Koyama & Sakai, 2002)
• The latency from increased PPT activity to REM sleep is longer in the cat (20-60s*) than in the rat (5-10s). However the cat has longer REM sleep episodes (10-30min) than the rat (3-13 min) (Foote, 1973; Datta & Hobson, 2000)
• LDT cholinergic cells are just like the PPT in distribution and action.

Remaining Questions:

• What coordinates the wake-REM-on and REM-on cells so that they both start  firing 5-8 seconds before REM and stop 5-8 seconds before the end of REM?
• Are there no bursting cells inside the PPT or were they just not found?
• What in development determines a W-REM-on from a REM-on from a state independent cell?

Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

In paper citation: (Mavanji, Meti, & Datta, 2002)

All rats in this paper were made depressed using neonatal clomipramine treatments. All rats were male. Controls were treated with saline, but handled in the same manner.

The new findings from this paper are:

1. REM sleep onset latency is significantly shorter in depressed rats than in controls. Rats spend ~25% less time in SWS before their first REM cycle.
2. The total number of REM sleep episodes is significantly (~2X) higher in depressed rats than in controls.
3. The total amount of REM sleep in depressed rats is significantly more than controls (>2X more REM).
4. mCPP, a serotonin agonist, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes and increasing the REM sleep onset latency.
5. mianserin, a SSRI, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes. 

Other important information:

• REM sleep deprivation in humans alleviates symptoms of depression (Vogel et al., 1975).
• REM sleep deprivation in rats normalizes deficits in sexual activity and aggression, which are symptoms of rat depression (Vogel et al., 1990).
• mCPP is known to increase serotonin release (Bauman et al., 1993) and reduce REM sleep in humans ( Lawlor et al., 1991).
• Clomipramine treated rats have less serotonin in their brain than control rats (Mavanji & Meti, 1999).
• Serotonin inhibits REM sleep (McCarley, 1982) and so serotonin agonists reduce REM sleep (Quattrochi et al., 1992; Stickgold et al., 1993)
• mCPP normally reduces REM in the controls if it is injected systemically because it inhibits acetylcholine release (Vizi et al., 1981) It didn't in this case because it was injected  ICV.
• Mianserin typically reduces REM in both depressive patients and normal subjects (Mendlewicz et al., 1995; Tormey et al., 1980).

Remaining questions:

• How does the clomipramine rat model work? Would this still be the case in social stress depressed rats, or learned helplessness rats?
• The CLI+mianserin group seemed to have low wakefulness and high SWS in my opinion. I'm surprised that it didn't come out significant.

Activation of extracellular signal-related kinase signaling in the pedunculopontine tegmental cells is involved in the maintenance of sleep in rats

In paper citation: (Desarnaud, Macone & Datta, 2011)

The new results from this paper include:

1. Levels of ERK 1&2 expression and phosphorylation in the PPT increased with the amount of time spent in sleep. It did not increase in the mPRF or the cortex.
2. With increased time spent sleeping, levels of ERK 1&2 activity increased in the PPT and decreased in the mPRF.
3. Levels of ERK 1&2 expression, phosphorylation, and activity in the PPT of individual animals positively correlated with the total percentage of time spent in SWS, REM, and total sleep. 
4. Levels of ERK 1&2  expression, phosphorylation, and activity in the PPT of individual animals negatively correlated with their total percentage of time spent awake.

Other important information:

• ERK 1&2 are cytoplasmic until activated. Then they translocate to the nucleus and activate cAMP response element binding protein (Vanhoutte et al. 1999).
• Other studies have shown that activating ERK 1&2 increases sleep in a dose dependent manner, and blocking ERK 1&2 decreases sleep (Foltenyi et al. 2007).
• Figure 7 of the paper describes an entire model of ERK 1&2's involvement in sleep.
• In wakefulness 
• glutamate activity is high enough to activate NMDA receptors (not just kainate receptors)
• Ca2+ rushes in and activates STEP, a phosphatase
• STEP dephosphorylates ERK 1&2
• Ca2+ also activates CaMK2
• In SWS
• GABA activates GABA-b receptors, which are linked to G proteins
• the G proteins inhibit adenylyl cyclase, and CaMK2
• This allows ERK 1&2 and PKA to increase
• In REM sleep
• Glutamate activates kainate receptors
• These let in just a little Ca2+ increasing ERK 1&2
• The Ca2+ activates AC and increases PKA 

Remaining questions:

• Why did they only study the first two hours of sleep? Did it have to do with initial ERK levels being different from later ERK levels? How long does it take ERK to clear?
• This study splits rats into low sleepers and high sleepers. What might cause a rat to sleep less in the first place and could this be correlated to the findings that we see?
• Why do they use phosphorylated myelin basic protein to measure ERK activity levels?