Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 85

nevertheless, feeding has been shown to be one of the most important stim-
uli 4,5 to induce a rhythm. Therefore, it is logical to assume that clock genes
in the periphery somehow are associated with energy metabolism in the cells
of the different tissues. In vitro studies have mainly evidenced that reciprocal
interaction loops between clock genes and metabolic genes could underlie
this food-clock connection. 6
Thus, a system has been suggested with highly intertwined relationships
whereby rhythmic behavioral (neuro)endocrine and autonomic functions
support each other and, in turn, are supported by rhythmic cellular and
molecular processes. All these processes are coordinated and driven by the
SCN, resulting not only in tightly associated sleep-wake and fasting-feeding
cycles but also in rhythmic patterns of core temperature, heart rate, and hor-
monal cycles, resulting in a myriad of functions that are influenced by the
SCN. Thus, we propose that circadian disruption may be an important cause
of severe health impairment, as consequence of a faulty relationship between
the oscillatory processes in the cells of the body and with the rhythm of
the SCN.
2. THE SCN AS MASTER CLOCK
The SCN has the capacity to maintain a 24-h rhythm in electrical
activity, which results in a rhythmic release of its neurotransmitters from
the nerve terminals. 7 The rhythm in neuronal activity is maintained
in vitro and is proposed to be dependent on a molecular machinery of clock
genes that, by mean of positive and negative feedback loops, give a possibil-
ity for the SCN to have this 24-h rhythm in electrical activity. Although it is
assumed that individual neurons may have the capacity to generate an
endogenous rhythm, 8 it has become likely that only when SCN neurons
form a network, these neurons have the possibility to be rhythmic for
long-time periods. 9 Consequently, it is not only the molecular machinery
that gives the SCN neurons their capacity to have an endogenous rhythm
of 24 h, but in addition, these neurons need to function within a network.
That a neuronal network is essential for the SCN rhythmic properties can
also be concluded from studies in which knocking out a vasoactive intestinal
polypeptide (VIP) receptor, which is one of the most abundant neuropep-
tides within the SCN, results in the incapacity to maintain rhythmic behav-
ioral patterns. 10 As these VIP receptors are highly expressed in the SCN and
the electrical activity in the SCN of the knockout animals is strongly
disturbed, 11 it can be concluded that intra-SCN neuronal communication