Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 15

Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms 239

melatonin-binding sites have been characterized: a high-affin-
ity ML1 site and a low affinity ML2 site. Two subtypes of the
ML1 receptor have been cloned: Mel 1a and Mel 1b. All the
receptors are coupled to G proteins, with ML1 receptors inhib-
iting adenylyl cyclase and ML2 receptors stimulating phospho-
inositide hydrolysis.
The diurnal change in melatonin secretion may function as
a timing signal to coordinate events with the light–dark cycle
in the environment. Melatonin synthesis and secretion are
increased during the dark period of the day and maintained at
a low level during daylight hours (Figure 15–13). This diurnal
variation in secretion is brought about by norepinephrine
secreted by the postganglionic sympathetic nerves that inner-
vate the pineal gland (Figure 15–11). Norepinephrine acts via
β
-adrenergic receptors to increase intracellular cAMP, and the
cAMP in turn produces a marked increase in
N
-acetyltrans-
ferase activity. This results in increased melatonin synthesis
and secretion. Circulating melatonin is rapidly metabolized in
the liver by 6-hydroxylation followed by conjugation, and
over 90% of the melatonin that appears in the urine is in the

form of 6-hydroxy conjugates and 6-sulfatoxymelatonin. The

pathway by which the brain metabolizes melatonin is unset-

tled but may involve cleavage of the indole nucleus.

The discharge of the sympathetic nerves to the pineal is

entrained to the light–dark cycle in the environment via the

retinohypothalamic nerve fibers to the SCN. From the hypo-

thalamus, descending pathways converge onto preganglionic

sympathetic neurons that in turn innervate the superior cer-

vical ganglion, the site of origin of the postganglionic neurons

to the pineal gland.

CHAPTER SUMMARY

■

The major rhythms in the EEG are alpha (8–13 Hz), beta (13–30

Hz), theta (4–7 Hz), delta (0.5–4 Hz), and gamma (30–80 Hz)

oscillations.

■

The EEG is of some value in localizing pathologic processes, and

it is useful in characterizing different types of epilepsy.

■

Throughout NREM sleep, there is some activity of skeletal mus-

cle. A theta rhythm can be seen during stage 1 of sleep. Stage 2

is marked by the appearance of sleep spindles

and occasional K

complexes. In stage 3, a delta rhythm is dominant. Maximum

slowing with slow waves is seen in stage 4.

■

REM sleep is characterized by low-voltage, high-frequency EEG

activity and rapid, roving movements of the eyes.

■

A young adult typically passes through stages 1 and 2, and

spends 70–100 min in stages 3 and 4. Sleep then lightens, and a

REM period follows. This cycle repeats at 90-min intervals

throughout the night. REM sleep occupies 50% of total sleep

time in full-term neonates; this proportion declines rapidly and

plateaus at about 25% until it falls further in old age.

■

Transitions from sleep to wakefulness may involve alternating

reciprocal activity of different groups of RAS neurons. When

the activity of norepinephrine- and serotonin-containing

FIGURE 15–12
A model of how alternating activity of brain
stem and hypothalamic neurons may influence the different
states of consciousness.
(From Widmaier EP, Raff H, Strang KT:
Vander’s
Human Physiology,
11th ed. McGraw-Hill, 2008.)

Hypothalamus with

circadian and

homeostatic centers

Waking NREM sleep REM sleep

Activation

of the thalamus

and cortex

Histamine

GABA

Histamine

GABA

Activation

of the thalamus

and cortex

Acetylcholine

Brainstem nuclei that

are part of the reticular

activating system

Norepinephrine

and

serotonin

Norepinephrine

and

serotonin

Acetylcholine

FIGURE 15–13

Diurnal rhythms of compounds involved in

melatonin synthesis in the pineal.

Melatonin and the enzymes re-

sponsible for its synthesis from serotonin are found in pineal pinealo-

cytes; melatonin is secreted into the bloodstream. Melatonin synthesis

and secretion are increased during the dark period (shaded area) and

maintained at a low level during the light period.

Pineal

paren-

chymal

cells

Blood

Melatonin

N-Acetylserotonin

Serotonin

N-Acetyl-

transferase

Hydroxyindole-

O-methyltransferase

Melatonin

01224

Time (hrs)