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?
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