448 Neuroanatomy: Draw It to Know It
Flip-Flop Switch ( Advanced )
Here, we will draw the fl ip-fl op switch, which is the cir-
cuit for the transition between sleep and wakefulness.
A fl ip-fl op circuit is an electrical engineering term for a
switch that avoids transitional states; the circuit is in
either one of two states but not a blend of both. If you
are tired when you lie down, you quickly fall asleep,
and when you’re ready to rise, you suddenly wake up.
To begin, indicate the sleep and wake states and then
draw the fl ip-fl op switch, which transitions between
them. In our fi rst diagram, we will show the circuit in a
state of wakefulness. Indicate the following important
hypothalamic areas: the ventrolateral preoptic area and
the median preoptic nucleus, which constitute the sleep
center; the wake-promoting cells; and the perifornical-
lateral hypothalamic orexigenic cells, which form the wake-
fulness stabilizer — discussed in detail at the end. Show that
during wakefulness, the wake-promoting cells inhibit the
sleep center and that the perifornical-lateral hypothalamic
orexigenic cells excite the wake-promoting cells.
Next, let’s show the fl ip-fl op circuitry in the sleep
state. Re-draw the sleep and wake states and the fl ip-fl op
switch, and then again include the previously listed
structures. Now, show that in the sleep state, the sleep
center inhibits the wake-promoting cells and also inhib-
its their stabilizer: the perifornical-lateral hypothalamic
orexigenic cells.
In short, when we consider the sleep and wake states
as a whole, the arousal center inhibits the sleep center;
the orexigenic cells stabilize the arousal center; and the
sleep center inhibits the arousal center and also the orex-
igenic cells.^14
Th e story of the discovery of orexin is both interest-
ing and illuminating. In 1998, two diff erent research
groups concurrently but independently identifi ed a pair
of hypothalamic neuropeptides, named orexins by
Sakurai et al. and hypocretins by de Lecea et al. (we refer
to them here as orexins). Orexins are produced by a dis-
crete neuronal population within the lateral hypothala-
mus, and their functional role in the nervous system
came as a surprise. A decade and a half prior to the iden-
tifi cation of the orexins, in 1982, Baker et al. identifi ed a
candidate gene, designated canarc-1, for the clinical dis-
order of narcolepsy in a colony of Doberman Pinschers
with canine narcolepsy. Despite extensive study of this
gene, however, the protein responsible for narcolepsy
was unable to be identifi ed. In 1999, when researchers
began studying the fi rst orexin knockout mouse, they
were not expecting to fi nd any manifestations of narco-
lepsy; instead, they hypothesized that orexin would be
shown to aff ect energ y metabolism, given the already
proven role of the lateral hypothalamus in energ y homeo-
stasis. However, study of homozygote orexin knockout
mice, instead, demonstrated that the mice expressed a
phenotype consistent with narcolepsy with cataplexy:
they displayed cataplexy and abnormal wake-REM sleep
transitions. Th us, orexin was discovered to play an unan-
ticipated yet highly important role in the stabilization of
wakefulness.^15