Neuro-circuitry and transmitters Underlying Wakefulness, NREM and REM Sleep

ARAS: ascending reticular activating system

LDT: lateral dorsal tegmental

PPT: pedunculopontine tegmental

DR : dorsal raphe

LC: locus coeruleus

DA: dopaminergic

VTA: ventral tegmental area

1 Wakefulness

        As mention earlier, wakefulness is associated with a low-voltage/fast-frequency EEG (also known as “activated” or “desynchronized”).  The ARAS maintains an activated EEG/cortex.  Ascending projections from the medulla, pons, and midbrain travel in the ARAS.  These pathways arise from cholinergic cell groups in the pons called LDT, PPT and nucleus reticularis pontis.

      Other ascending axons arise from serotonergic cell groups at the midbrain pons junction, the DR, and medulla. Another contribution to the ascending system arises from cells containing norepinephrine; the cells are in the LC and medulla.  A final “member” of the ascending activating system is comprised of axons of DA cells in the substantia nigra pars compacta and VTA.

Cholinergic LDT, PPT and nucleus reticularis pontis
Serotonergic Midbrain pons junction, the DR, and medulla


Norepinephrine LC and medulla

 DRUG acting on SLEEP

       Drugs such as amphetamine and cocaine, which enhance the release or synaptic concentrations of DA and NE, dramatically enhance and prolong wakefulness.  Acetylcholine is released from nerve terminals in the thalamus and cortex in highest concentrations in association with cortical activation that occurs naturally during wakefulness. Drugs with anticholinergic activity, including tricyclic antidepressants and atropine, can cause sedation and increase slow wave activity.

   Histamine in the tubero mammillary nucleus (TM) also appears important for wakefulness. Drugs containing antihistamine produce drowsiness and a decrease in cortical activation.  The posterior hypothalamus has significance in wakefulness.

      Serotonergic neurons, like LC neurons, fire at higher levels in waking, lower levels in NREM sleep, and fall silent during REM sleep.

      A number of other neurotransmitters and neuromodulators appear to have wakefulness-promoting effects. These include

  • Substance P,
  • Neurotensin,
  • Epinephrine,
  • Hypothalamic peptides such as corticotropin releasing factor,
  • Vasoactive intestinal peptide
  • Thyrotropin releasing factor,

all of which can increase arousal levels.

      Cortisol also promotes wakefulness.  It is thus possible that sleep disturbance in depression including early morning awakening could be related in part to the associated hyperactivity of the HPA axis.


Fig1: HPA axis


VLPO: the ventro lateral preoptic area

      The initiation of non-REM sleep probably begins with the emergence of inhibitory signals from the VLPO.  The preoptic area lies just rostral to the optic chiasm.  VLPO neurons are sleep-active in that they increase their discharge selectively at sleep onset.  The VLPO cells contain GABA and project to serotonergic, noradrenergic and cholinergic cell groups in the brain stem reticular formation and histaminergic populations in the TM, i.e., posterior/caudal hypothalamus.  These wake-promoting neurons in the brain stem show progressive reductions in activity across sleep stages as VLPO neurons show progressive activation.

      Adenosine has long be known to be sleep promoting and its effects are blocked by caffeine.  It is reasonable to expect that adenosine is a “sleep factor” that may directly or indirectly regulate the activity of VLPO neurons. Peptide hypocretin (orexin) role in the maintenance of wakefulness was recently identified by experiments on narcoplepsy.

      In addition to inhibition of the ARAS by the VLPO, other regions of the hypothalamus and forebrain participate in NREM sleep.  In particular the anterior hypothalamus, pre-optic area, and nucleus basalis all contain GABA-ergic neurons that project to cortex and participate in the control of non-REM sleep.


        The EEG of REM sleep closely resembles the EEG of active wakefulness. Areas involved in REM is primarily in pons.  Cholinergic neurons in nucleus reticular pontis participates in REM via projections to cortex and thalamus. Cells in LC and DR inhibit cholinergic cells during wakening and NREM. GABA-ergic inhibition of LC and DR brings transition from NREM to REM. The cholinergic neurons have descending projections to brain stem and spinal cord that inhibit muscle movements during tonic phase.

                    There are evidences that motor paralysis of tonic REM might be protective against acting out of one’s dream. REM behavior disorder is one such disorder causing by defective paralysis system.



Mtech in Clinical Eng Jointly offered by Indian institute of technology Madras& Christian medical college Vellore& Sree chitra tirunal institute for medical sciences and technology Trivandrum.
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