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.
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