Medical neuroscience

1. Sleep and wakefulness
Domina Petric, MD

2. Average healthy sleep time is
7,5 hours a day

3. Sleep across the lifespan
Decreases with age.

4. Circadian cycles
sleep
body temperature
growth hormone
cortisol

5. Circadian cycles
Body temperature decreases in the bedtime and rises
in the time when we awake.
Nocturnal body temperature is lower than daytime
body temperature.
Growth hormone levels rise in the bedtime, whilst
cortisol hormone levels rise in the time of awakening.

6. Retino-hypothalamic projection
Suprachiasmatic hypothalamic nucleus
contains a molecular clock responsible for
generating circadian rhythm.
Retino-hypothalamic projection connects the
molecular clock with signals from environment.

7. Retino-hypothalamic projection
• Photosensitive retinal ganglion cells contain the
pigment MELANOPSIN.
• Photosensitive RGC are important for sensing
the overall level of illumination in the
environment.
• Projections from photosensitive RGC go into the
suprachiasmatic hypothalamic nucleus.

8. Molecular mechanisms
• When light strikes photosensitive RGC and they
send signals into the cells of suprachiasmatic
hypothalamic nucleus, certain genes are activated.
• Those genes produce proteins CLOCK and BMAL1.
• CLOCK and BMAL1 associate as dimers and enter
the nucleus of the hypothalamic cell.
• Dimers bind to regulatory elements called E-boxes.

9. Molecular mechanisms
• Another set of genes is then activated with production
of protein CCG and proteins from the PER family (PER 2
and PER3).
• These proteins form their own dimers that enter the
nucleus of the cell.
• CCG, PER2 and PER3 proteins dimers prevent BMAL1
and CLOCK dimers to bind to the E-boxes.
• This is form of negative feedback.

10. Molecular mechanisms
This cycle with a negative
feedback endures a little bit more
than 24 hours (24 and a half
hours) and represents our
circadian rhythm.

11. Melatonin
• It is produced by PINEAL GLAND (EPYPHISIS).
• Melatonin begins to promote a transition from
wakefulness towards drowsiness and sleep.
• Levels of melatonin start to rise in the later
afternoon and are high during the night sleep
and then begin to fall before awakening.
• During the day melatonin levels are low.

12. EEG
Normal activity: high frequency,
low amplitude, irregular.
Seizure: highly synchronous, high
amplitude, low frequency.

13. http://www.med.nyu.edu

14. Normal brain waves
• Delta waves are characterised with very large amplitude, very
slow waves, frequency 1-4 Hz: deepest stage of sleep.
• Theta waves are characterised with frequency of 4-7 Hz:
drowsiness.
• Alpha waves are characterised with frequency of 8-13 Hz:
deactivation of sensory cortical areas (state of quiet rest).
• Beta waves are characterised with frequency above 12 Hz.
• Gamma waves are characterised with frequency of 40-60 Hz.
• Both beta and gamma waves are high frequency and low
amplitude waves: high degree of irregular activity and
desynchronization, information processing.

15. Medicalook.com

16. Sleep stages
There are four stages
of non-REM sleep and
there is the REM sleep.

17. Non-REM stages of sleep
• Stage I: drowsiness, modest increase in amplitude of brain
waves and increase in synchronicity.
• Stage II: sleep spindles (very brief high frequency high
amplitude activity in clusters), lasts 15-20 minutes.
• Stage III: larger incrase in amplitude of brain waves and
slower frequencies (moderate levels of sleep).
• Stage IV: large amplitudes, slow delta waves (cerebral
cortex is dissociated from its environment).
• Stage IV is hypersynchronous slow rhythm of
thalamocortical oscillation.

18. REM sleep
• Rapid eye movement or paradoxical sleep.
• Low amplitude, high frequency pattern.
• Cerebral cortex is in the desynchronised state.
• Medial parts of the forebrain are activated in REM sleep:
anterior cingulate cortex, parahippocampal gyrus and
amygdala.
• Dorsolateral prefrontal cortex and posterior cingulate
cortex are inactivated during the REM sleep.
• Most of the dreams occure in REM sleep fase.

19. Body states
• As night progresses we spend more time in REM sleep than
in stage IV of non-REM sleep.
• There is active supression of sceletal muscle activity during
REM sleep.
• In deep fases of non-REM sleep there is decrease in heart
frequency and respiration frequency.
• During REM sleep there is increase in heart and respiration
frequency.
• Men can experience penile erection during REM sleep.

20. Functions of dreams in REM fase
Maintenance: going through intense emotional
states, aggression.
Unlearning: erasing non-adaptive memories.
Learning: consolidation of learning and memory
(synaptic plasticity).

21. Wakefulness cellular mechanisms
Brainstem nuclei Neurotransmitter Activity state of brainstem
neurons
Cholinergic nuclei of
pons-midbrain junction
Acetylcholine Active
Locus coeruleus Norepinephrine Active
Raphe nuclei Serotonin Active
Tuberomammillary nuclei Histamine Active
Lateral hypothalamus Orexin Active

22. Non-REM sleep cellular mechanisms
Brainstem nuclei Neurotransmitter Activity state of
brainstem neurons
Cholinergic
nuclei of pons-
midbrain
junction
Acetylcholine Decreased
Locus coeruleus Norepinephrine Decreased
Raphe nuclei Serotonin Decreased

23. REM sleep cellular mechanisms
Brainstem nuclei Neurotransmitter Activity state of
brainstem
neurons
Cholinergic nuclei
of pons-midbrain
junction
Acetylcholine Active (PGO
waves)
Raphe nuclei Serotonin Inactive
Locus coeruleus Norepinephrine Inactive

24. PGO waves
Ponto-geniculo-occipital waves propagate from
the pons into the lateral geniculate nucleus of
the thalamus, and then into the occipital cortex.
PGO waves are present in REM sleep.

25. Hypothalamic nuclei
Ventrolateral preoptic nucleus (VLPN) has antagonising effect on the
orexin neurons from the lateral hypothalamic area.
Orexin neurons promote wakefulness.
Ventrolateral preoptic neurons promote drowsiness.
Tuberomammillary nucleus promotes wakefulness.

26. Locus
coeruleus
(brainstem)
VLPN
Tuberomammillary
nucleus
Orexin
neurons
To cerebral cortex,
basal forebrain

27. Adenosine
• ADENOSINE activates VLPN (ventrolateral preoptic
nucleus) to promote sleep.
• Adenosine is energy thermostat in the basal forebrain
region that is indicating the energy levels.
• Adenosine accumulates when it is time to go to sleep,
when the energy level is low.
• Caffeine and theophylline block adenosine receptors
promoting wakefulness.

28. Thalamocortical neurons
Oscillatory state in sleep:
hyperpolarisation.
Active, tonic state in
wakefulness: depolarisation.

29. Literature
https://www.coursera.org/learn/medical-
neuroscience: Leonard E. White, PhD, Duke University
http://www.med.nyu.edu
Medicalook.com