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elucidated the amino acid sequences of such peptides. Further data accumu-
lated over a number of years established that these and other peptides are
produced by virtually all neurons and resulted in the expansion of the cur-
rent views of synaptic transmission from an emphasis on small-molecule
neurotransmitters to include peptides and, hence, to extend what was
nal branches of a neuron, there was liberation of the same transmitter sub-
produced and released by hypothalamic neurons in the 1960s was the crucial
validation of Harris' hypotheses on control of the anterior pituitary (cf. Refs.
new peptides and, with rapid developments in immunohistochemistry,
led to new insights into the nature of chemical neurotransmission.
Colocalization of neuroactive substances in neurons was recognized as the
rule, rather than the exception, and then included findings that a single neu-
ron can produce and release as many as two small-molecule transmitters and
understanding the function of the SCN. Peptides also brought forth a new
problem. Peptides are released from axon terminals but not necessarily into
synaptic clefts so that their effects depend upon the localization of appropri-
ate receptors. These data have stimulated development of the concept of
“volume transmission” (cf. Refs.
30-32
, for reviews). The importance of
peptides as complex and important signaling molecules in the CTS will
be discussed below.
2. THE EMERGENCE OF A CIRCADIAN NEUROBIOLOGY
Over the first half of the twentieth century, the field of circadian biol-
ogy was established by a small group of pioneering scientists working on a
diverse set of organisms from prokaryotes to humans. Daily rhythms in
behavioral state in humans and other animals have been recorded since
antiquity, but the critical contribution of these scientists was recognition that
circadian rhythms are a fundamental property of living systems playing a
critical role in adaptation (cf. Refs.
1,33-37,144
for reviews). The term
circadian was first applied by Franz Halberg in 1959 (from
circa
and
diem
;
rized by Colin Pittendrigh as “Biological activities that characteristically
occur once per day in nature continue in laboratory conditions of constant
darkness and temperature as a persistent rhythmwith a period (
t
) that is close
to but not exactly 24 h: the period is said to be circadian (L. circa, dies). Such
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