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| Our brain, a pretentious organ For the nourishment of our most precious organ, our brain, only the best is good enough: a minute-to-minute supply with pure glucose, delivered via the blood stream to all parts of the brain. However, our brain contains essentially no fuel reserves of either glycogen or fat (Lehninger 1975). If blood glucose falls to less than 50% of its normal level, symptoms of brain dysfunction appear, and with still lower levels coma ensues. Apparently, each cubic centimeter in our skull is needed for acutely functioning cells (neurons and glia), with no room to waste for energy deposits. |
| Nevertheless,
a small amount of glycogen has been found even in the brain, and it has
been shown (Benington & Heller 1995) to increase during sleep and
to decrease during waking (curiously, for C57BL/6J mice, the contrary
was demonstrated recently by Franken et al 2006). In rats artificially
kept awake for 5 h, brain glycogen turnover time decreases from 5.3 to
2.9 h (Morgen thaler et al 2009), with no change in steady state level.
Is this small amount of glycogen necessary for the proper functioning
of the brain, and is the main mission of sleep to restore the brain
glycogen stores? |
| It
has been visualized with an elegant autoradiographic tech nique, that
in rats short term sensory stimulation results in depletion of newly
synthesized glycogen from discrete brain regions (Swanson et al 1992).
Apparently, this mechanism guarantees the immediate adaptation of
glucose supply to abrupt increases in demand, faster than can be
accomplished via the blood. There is, however, no need to assume that
it should represent a major problem to maintain these - moderate -
glycogen reserves for 24 hours a day. So, why is it that we are
sleeping, if not for replenishing energy stores in the brain? |
| Dreams - a reflection of genetic reprogramming? More than 20 years ago, it has been proposed by Michel Jouvet, that a major function of sleep is the genetic reprogramming of the brain (see Jouvet 1999). According to his proposal, we (and with us probably all mammals) are genetically predisposed to individual patterns of dream activity, with characteristic traits of emotions and events repeated during paradoxical sleep for our whole lifetime. This hypothesis is difficult to prove and largely based on intuition and on anecdotal evidence for dream simila rities in monozygotic twins. |
| The
hypothesis of Jouvet predominately relies on paradoxical sleep (the
term he prefers to the term REM sleep), whereas slow wave sleep (SWS)
according to his proposition rather sets the stage by providing the
necessary energy resources. However, since the energy stores in the
brain are only marginal, it appears disproportionate to evoke several
hours of SWS, just to replenish a few nanomoles of glycogen per mg
protein. In fact, there are indications that, in rats, a few minutes of
SWS should be suffi cient to do the job (Karnovsky et al 1983). |
| Brain glycogen stores: the signature of our ‘self’? Alternatively, paradoxical sleep and SWS may work together to reprogram our ‘selves’: Individuality may be created by the characteristic pattern of glycogen storage capacity in the brain. During SWS, these stores are replenished. They are, however, not really necessary for normal brain activity; they only come into play under special circumstances: (1) In the awake state to enable immediate reaction to fast sensory stimulation; and (2) during reprogramming associated with paradoxical sleep. |
| During
fast sensory stimulation, the organism falls back on its glycogen
stores, since glucose has been used up faster than new glucose could be
provided by the blood (Shulman et al 2001). During paradoxical sleep,
there is no sensory stimulation, but the brain might be forced to use
its glycogen by a still unknown mechanism. One candidate could be a
transient arrest of glucose transport from the blood to the brain,
biasing the activity of the brain towards its own energy resources. In
such a situation, those brain regions with the highest glycogen stores
will have the best chances to participate in free running neuronal
activity. Indivi duals may differ from each other in the detailed
neuroanatomical pattern of glycogen stores. A transient block of
glucose availa bility from the blood might thus function as a trigger
of endoge nous neuronal activity, relying exclusively on biologically
deter mined conditions. |
| Neurotransmitters
that increase the transport of glucose into the brain (histamine, ATP)
have been described (Breat & Leybaert 2001). It might be worthwhile
to search for endogenous com pounds blocking this transport. In a
recent study on rats, Silvani et al (2005) measured glucose transport
into the brain of rats during REM sleep. Although the authors detected
a 24–34% increase in glucose consumption in the brain, the transport of
glucose across the blood brain barrier remained unchanged. Thus, it may
not be necessary to interfere with glucose transport during REM sleep.
Since many brain regions are activated during REM sleep and therefore
increase their glucose consumption, it may be sufficient to increase
glucose demand without a change in glucose transport to render these
brain regions dependent on their glycogen stores. |
| A new diagnostic tool for psychiatry? As a logical consequence of this hypothesis, personality should be correlated to the neuroanatomical pattern of glycogen stores replenished in SWS. Visualizing this pattern in vivo by any means (PET with 11C[3,4]glucose?) might be more promising than visua lizing the firing of neuronal circuits during paradoxical sleep. Such a glycogen imaging procedure might turn out as a valuable dia gnostic tool in psychiatry. To increase the selectivity of the signals, difference scans could be taken, in absence and pre sence, respectively, of a selective blocker of glucose integration into glycogen (i.e. an inhibitor of glycogen synthase). At least in isolated perfused mouse livers, glycogen metabolism was followed by an indirect MRI technique at high magnetic field strength (van Zijl et al 2007). |
| J.H. Benington
& H.C. Heller (1995) Restoration of brain energy metabolism as the
function of sleep. Progr. Neurobiol. 45, 347-360. Breat & Leybaert (2000) Eur. J. Neurosci. 12, S.11, 163.09. P. Franken, P. Gip, G. Hagiwara, N.F. Ruby, H.C. Heller (2006) Glycogen content in the cerebral cortex increases with sleep loss in C57BL/6J mice. Neurosci. Lett. 402, 176-179. M. Jouvet, The paradox of sleep: the story of dreaming. MIT Press, 1999. M.L. Karnovsky, P. Reich, J.M. Anchors, B.L. Burrows (1983) Changes in brain glycogen during slow-wave sleep in the rat. J. Neurochem. 41, 1498-1501. A.L. Lehniger, Biochemistry, 2nd ed., Worth Publishers, New York 1975, p. 838. Morgenthaler FD, Lanz BR, Petit J-M, Frenkel H, Magistretti PJ, Gruetter R (2009). Alteration of brain glycogen turnover in the conscious rat after 5 h of prolonged wakefulness. Neurochem Internat 55: 45-51 Shulman et al (2001) Cerebral energetics and the glycogen shunt: Neurochemical basis of functional imaging. Proc. Natl. Acad. Sci. (USA) 98/11, 6417-6422 Silvani A. et al (2005) Sleep-related brain activation does not increase the permeability of the blood-brain barrier to glucose. J Cerebr Blood Flow & Metabol 25: 990-997. R.A. Swanson et al (1992) Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography. Neurosci. 51, 451-461. P.C.M. van Zijl, C.K. Jones, J. Ren, C.R. Malloy, A.D. Sherry (2007) MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc. Natl. Acad. Sci. USA 104: 4359-64 |
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